<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02255461</url>
  </required_header>
  <id_info>
    <org_study_id>PBTC-042</org_study_id>
    <secondary_id>U01CA081457</secondary_id>
    <nct_id>NCT02255461</nct_id>
  </id_info>
  <brief_title>Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors</brief_title>
  <official_title>Phase I Study of CDK 4-6 Inhibitor PD-0332991 (Palbociclib; IBRANCE) in Children With Recurrent, Progressive or Refractory Central Nervous System Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pediatric Brain Tumor Consortium</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Pediatric Brain Tumor Consortium</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of palbociclib isethionate in&#xD;
      treating younger patients with central nervous system tumors that have grown, come back, or&#xD;
      not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by&#xD;
      blocking some of the enzymes needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the maximum tolerated dose (MTD)/phase II recommended dose and describe&#xD;
      toxicities related to PD-0332991 (palbociclib isethionate) in children with retinoblastoma&#xD;
      protein 1 (Rb1) positive recurrent, progressive or refractory primary central nervous system&#xD;
      (CNS) tumors.&#xD;
&#xD;
      II. To determine plasma pharmacokinetics of PD-0332991 in children with Rb1positive&#xD;
      recurrent, progressive or refractory primary CNS tumors.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To record preliminary evidence of efficacy of PD-0332991 in children with recurrent CNS&#xD;
      tumors.&#xD;
&#xD;
      II. To evaluate cyclin-dependent kinase (CDK)4/6, cyclin D1-3, Ink4a-ARF copy-number&#xD;
      variations in available tumor tissue by array comparative, genomic hybridization (aCGH).&#xD;
&#xD;
      III. To explore the potential relationships between the pharmacokinetics of PD-0332991 and&#xD;
      pharmacodynamic response (e.g. percentage change in absolute neutrophil count [ANC], platelet&#xD;
      counts).&#xD;
&#xD;
      IV. To explore the pharmacogenetic polymorphisms in PD-0332991 metabolizing enzymes and&#xD;
      transporters and relate these polymorphisms to PD-0332991 pharmacokinetics.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study.&#xD;
&#xD;
      Patients receive palbociclib isethionate orally (PO) once daily (QD) on days 1-21. Treatment&#xD;
      repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable&#xD;
      toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 30 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Data for the primary objectives is complete and the MTD identified in Stratum II.&#xD;
  </why_stopped>
  <start_date type="Actual">December 8, 2014</start_date>
  <completion_date type="Actual">February 25, 2019</completion_date>
  <primary_completion_date type="Actual">February 25, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I</measure>
    <time_frame>4 weeks</time_frame>
    <description>Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level had been determined to be too toxic. Stratum I consisted of less-heavily pre-treated patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II</measure>
    <time_frame>4 weeks</time_frame>
    <description>Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT and the next higher dose level had been determined to be too toxic. Stratum II consisted of heavily pre-treated patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)</measure>
    <time_frame>4 weeks</time_frame>
    <description>DLTs were defined as any of the following adverse events that were at least possibly related to palbociclib that occurred during the first 4 weeks of therapy regardless of expectedness. Hematologic DLTs included grade 3 neutropenia with fever and sepsis, grade 3 thrombocytopenia and/or requiring a platelet transfusion on 2 separate days within a 7-day period, or any grade 4 hematologic toxicity except lymphopenia. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of &lt; 5 days; diarrhea and/or electrolyte disturbances which have not been maximally treated; AST/ALT elevation that returns to levels meeting eligibility criteria within 7 days of study drug interruption and does not recur upon restarting drug), or any grade 2 non-hematologic toxicity that persists for &gt; 7 days and is considered medically significant or sufficiently intolerable by patients requires treatment interruption.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Single Dose Apparent Volume of Central Compartment (Vc/F)</measure>
    <time_frame>Up to day 3</time_frame>
    <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Single Dose Elimination Rate Constant (Ke)</measure>
    <time_frame>Up to day 3</time_frame>
    <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Elimination rate constant (Ke) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Single Dose Half-life (t1/2)</measure>
    <time_frame>Up to day 3</time_frame>
    <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Half-life (t1/2) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Single Dose Apparent Oral Clearance (CL/F)</measure>
    <time_frame>Up to day 3</time_frame>
    <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Single Dose Area Under the Plasma Concentration Time Curve (AUC)</measure>
    <time_frame>Up to day 3</time_frame>
    <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Steady State Apparent Volume of Central Compartment (Vc/F)</measure>
    <time_frame>Up to day 22</time_frame>
    <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Steady State Elimination Rate Constant (Ke)</measure>
    <time_frame>Up to day 22</time_frame>
    <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Elimination rate constant (Ke) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Steady State Half-life (t1/2)</measure>
    <time_frame>Up to day 22</time_frame>
    <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Half-life (t1/2) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Steady State Apparent Oral Clearance (CL/F)</measure>
    <time_frame>Up to day 22</time_frame>
    <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Steady State Area Under the Plasma Concentration Time Curve (AUC)</measure>
    <time_frame>Up to day 22</time_frame>
    <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects With Objective Responses</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Objective responses included complete response (CR) and partial response (PR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association Between Neutropenia and Single Dose Palbociclib AUC</measure>
    <time_frame>Up to approximately 4 weeks</time_frame>
    <description>Neutrophil count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between neutrophil count decreased and single dose palbociclib AUC for all participants was examined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association Between Lymphopenia and Single Dose Palbociclib AUC</measure>
    <time_frame>Up to approximately 4 weeks</time_frame>
    <description>Lymphocyte count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between Lymphocyte count decreased and single dose palbociclib AUC for all participants was examined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association Between Leukopenia and Single Dose Palbociclib AUC</measure>
    <time_frame>Up to approximately 4 weeks</time_frame>
    <description>White blood cell count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between white blood cell count decreased and single dose palbociclib AUC for all participants was examined.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations</measure>
    <time_frame>At enrollment</time_frame>
    <description>CDK4 is a key component in signaling pathways inside normal cells and cancer cells. CDK4 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations</measure>
    <time_frame>At enrollment</time_frame>
    <description>CDK6 is a key component in signaling pathways inside normal cells and cancer cells. CDK6 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects With Cyclin D1 Copy Number Variations</measure>
    <time_frame>At enrollment</time_frame>
    <description>Cyclin D1 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D1 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects With Cyclin D2 Copy Number Variations</measure>
    <time_frame>At enrollment</time_frame>
    <description>Cyclin D2 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D2 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects With Cyclin D3 Copy Number Variations</measure>
    <time_frame>At enrollment</time_frame>
    <description>Cyclin D3 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D3 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects With Ink4a-ARF Loss Copy Number Variations</measure>
    <time_frame>At enrollment</time_frame>
    <description>Ink4a-ARF is a key component in signaling pathways inside normal cells and cancer cells. Ink4a-ARF loss copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Polymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1)</measure>
    <time_frame>At enrollment</time_frame>
    <description>Polymorphisms in ABCB1 encode for efflux-transporter proteins P-glycoprotein (P-gp), for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCB1 polymorphisms.</description>
  </other_outcome>
  <other_outcome>
    <measure>Polymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2)</measure>
    <time_frame>At enrollment</time_frame>
    <description>Polymorphisms in ABCG2 encode for BCRP, for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCG2 polymorphisms.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Childhood Choroid Plexus Tumor</condition>
  <condition>Childhood Ependymoblastoma</condition>
  <condition>Childhood Grade III Meningioma</condition>
  <condition>Childhood High-grade Cerebellar Astrocytoma</condition>
  <condition>Childhood High-grade Cerebral Astrocytoma</condition>
  <condition>Childhood Medulloepithelioma</condition>
  <condition>Recurrent Childhood Anaplastic Astrocytoma</condition>
  <condition>Recurrent Childhood Anaplastic Oligoastrocytoma</condition>
  <condition>Recurrent Childhood Anaplastic Oligodendroglioma</condition>
  <condition>Recurrent Childhood Brain Stem Glioma</condition>
  <condition>Recurrent Childhood Cerebellar Astrocytoma</condition>
  <condition>Recurrent Childhood Cerebral Astrocytoma</condition>
  <condition>Recurrent Childhood Giant Cell Glioblastoma</condition>
  <condition>Recurrent Childhood Glioblastoma</condition>
  <condition>Recurrent Childhood Gliomatosis Cerebri</condition>
  <condition>Recurrent Childhood Gliosarcoma</condition>
  <condition>Recurrent Childhood Medulloblastoma</condition>
  <condition>Recurrent Childhood Pineoblastoma</condition>
  <condition>Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor</condition>
  <arm_group>
    <arm_group_label>Treatment (palbociclib isethionate)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive palbociclib isethionate PO QD on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>palbociclib isethionate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (palbociclib isethionate)</arm_group_label>
    <other_name>6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, 827022-33-3, palbociclib, PD 0332991-0054, PD-0332991, PD-332991, PF-00080665-73</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>pharmacological study</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (palbociclib isethionate)</arm_group_label>
    <other_name>pharmacological studies</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (palbociclib isethionate)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with retinoblastoma protein (Rb1) positive recurrent, progressive or&#xD;
             refractory central nervous system (CNS) tumors&#xD;
&#xD;
          -  Histologically confirmed Rb1 positive primary recurrent, progressive, or refractory&#xD;
             central nervous system tumors; patients with low grade gliomas are excluded&#xD;
&#xD;
          -  Formalin fixed paraffin embedded tumor tissue (preferably from current recurrence)&#xD;
             must be available to assess Rb1 protein status prior to enrollment; only patients with&#xD;
             recurrent diffuse intrinsic brain stem glioma (DIPG) can be enrolled without the need&#xD;
             for available tumor tissue for Rb1 protein status confirmation&#xD;
&#xD;
          -  Patients must have measurable disease (in 2-dimensions) on magnetic resonance imaging&#xD;
             (MRI) scan of brain and/or spine to assess preliminary evidence of response&#xD;
&#xD;
          -  Body surface area (BSA):&#xD;
&#xD;
               -  Patients enrolled on dose level 1 (50 mg/m^2) must have BSA &gt;= 1.20 m^2&#xD;
&#xD;
               -  Patients enrolled on dose level 2 (75 mg/m^2) must have BSA &gt;= 0.93 m^2&#xD;
&#xD;
               -  Patients enrolled on dose level 3 (95 mg/m^2) must have BSA &gt;= 0.70 m^2&#xD;
&#xD;
          -  Patients must have received no more than 2 prior chemotherapy regimens and/or focal&#xD;
             radiotherapy for their brain tumor and fully recovered from the acute treatment&#xD;
             related toxicities of all prior therapies prior to entering this study; for those&#xD;
             acute baseline adverse events attributable to prior therapy, patients must meet organ&#xD;
             function criteria&#xD;
&#xD;
          -  Chemotherapy: patients must have received their last dose of known myelosuppressive&#xD;
             anticancer chemotherapy at least three (3) weeks prior to study enrollment in the&#xD;
             study or at least six (6) weeks for those receiving nitrosourea&#xD;
&#xD;
          -  Biologic therapy: patients should have received their last dose of biologic agent &gt;= 7&#xD;
             days prior to enrollment; in the event the patient has received another biologic agent&#xD;
             and has experienced &gt;= grade 2 myelosuppression, then at least three (3) weeks must&#xD;
             have elapsed prior to enrollment; if the investigational or biologic agent has a&#xD;
             prolonged half-life then at least three (3) weeks interval is required&#xD;
&#xD;
          -  Radiotherapy: patients must have had their last fraction of:&#xD;
&#xD;
             * Focal irradiation &gt; 2 weeks prior to enrollment&#xD;
&#xD;
          -  Corticosteroids: patients who are receiving dexamethasone or other corticosteroids&#xD;
             must be on a stable or decreasing dose for at least 1 week prior to enrollment; it is&#xD;
             recommended that patients be off all steroid therapy or receive the least dose that&#xD;
             will control their neurologic symptoms&#xD;
&#xD;
          -  Growth factors: all colony forming growth factor(s) have been discontinued for at&#xD;
             least one week prior to enrollment (filgrastim, sargramostim, and erythropoietin); for&#xD;
             patients on long acting growth factors, the interval should be two weeks&#xD;
&#xD;
          -  Patients with neurological deficits that are stable for a minimum of one week prior to&#xD;
             registration&#xD;
&#xD;
          -  Patients must be able to swallow capsules&#xD;
&#xD;
          -  Karnofsky performance scale (KPS for &gt; 16 years of age) or Lansky performance score&#xD;
             (LPS for =&lt; 16 years of age) assessed within two weeks of enrollment must be &gt;= 60&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,000/mm^3&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mm^3 transfusion independent (no platelet transfusion one week&#xD;
             prior to enrollment)&#xD;
&#xD;
          -  Hemoglobin &gt;= 8 g/dl&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 times upper limit of institutional normal (ULN) for age&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 3 x institutional upper limit of normal for age&#xD;
&#xD;
          -  Serum albumin &gt;= 3 g/dL&#xD;
&#xD;
          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) &gt;= 70&#xD;
             ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:&#xD;
&#xD;
               -  1 to &lt; 2 years: 0.6 (male), 0.6 (female)&#xD;
&#xD;
               -  2 to &lt; 6 years: 0.8 (male), 0.8 (female)&#xD;
&#xD;
               -  6 to &lt; 10 years: 1 (male), 1 (female)&#xD;
&#xD;
               -  10 to &lt; 13 years: 1.2 (male), 1.2 (female)&#xD;
&#xD;
               -  13 to &lt; 16 years: 1.5 (male), 1.4 (female)&#xD;
&#xD;
               -  &gt;= 16 years: 1.7 (male), 1.4 (female)&#xD;
&#xD;
          -  Female patients of childbearing potential must have a negative serum pregnancy test at&#xD;
             the time of enrollment&#xD;
&#xD;
          -  Patients of childbearing or child fathering potential must be willing to use a&#xD;
             medically acceptable form of birth control while being treated on this study&#xD;
&#xD;
          -  Patient and/or guardian have the ability to understand and the willingness to sign a&#xD;
             written informed consent document according to institutional guidelines&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with any clinical significant unrelated systemic illness (serious infections&#xD;
             or significant cardiac, pulmonary, hepatic or other organ dysfunction) that is likely&#xD;
             to interfere with the study procedures or results&#xD;
&#xD;
          -  Patients with low grade gliomas and Rb1 negative tumors&#xD;
&#xD;
          -  Patients who have received any of the following:&#xD;
&#xD;
               -  &gt; 2 chemotherapy regimens&#xD;
&#xD;
               -  Myeloablative chemotherapy with stem cell rescue&#xD;
&#xD;
               -  Craniospinal irradiation&#xD;
&#xD;
          -  Patients with corrected QT (QTc) interval of &gt; 450 msec or those on medications known&#xD;
             to prolong QTc interval&#xD;
&#xD;
          -  Prior treatment on a CDK inhibitor&#xD;
&#xD;
          -  Patients who are receiving drugs that are strong inducers or inhibitors of cytochrome&#xD;
             P450, family 3, subfamily A, polypeptide 4 (CYP3A4)&#xD;
&#xD;
          -  Patients who are receiving any other investigational therapy&#xD;
&#xD;
          -  Patients who require enzyme inducing anti-convulsants to control seizures&#xD;
&#xD;
          -  Patients with cataracts on ophthalmologic examination&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>4 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Van Mater, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Pediatric Brain Tumor Consortium</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Childrens Hospital Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lucile Packard Children Hospital Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Childrens National Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010-2970</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lurie Childrens Hospital-Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60614</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children Hospital of Pittsburgh of UPMC</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Jude Children Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Childrens Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Children Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>September 30, 2014</study_first_submitted>
  <study_first_submitted_qc>September 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2014</study_first_posted>
  <results_first_submitted>February 20, 2020</results_first_submitted>
  <results_first_submitted_qc>March 26, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">April 8, 2020</results_first_posted>
  <last_update_submitted>February 10, 2021</last_update_submitted>
  <last_update_submitted_qc>February 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
    <mesh_term>Meningioma</mesh_term>
    <mesh_term>Gliosarcoma</mesh_term>
    <mesh_term>Nervous System Neoplasms</mesh_term>
    <mesh_term>Medulloblastoma</mesh_term>
    <mesh_term>Central Nervous System Neoplasms</mesh_term>
    <mesh_term>Oligodendroglioma</mesh_term>
    <mesh_term>Neuroectodermal Tumors</mesh_term>
    <mesh_term>Neuroectodermal Tumors, Primitive</mesh_term>
    <mesh_term>Choroid Plexus Neoplasms</mesh_term>
    <mesh_term>Pinealoma</mesh_term>
    <mesh_term>Neoplasms, Neuroepithelial</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Palbociclib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 28, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/61/NCT02255461/ICF_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 28, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/61/NCT02255461/Prot_SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Patients between 4 and 21 years of age with histologically confirmed retinoblastoma protein (Rb1) positive, primary recurrent, progressive, or refractory central nervous system tumors were enrolled at Pediatric Brain Tumor Consortium member institutions. The first patient was enrolled on 12/8/2014 and the last patient was enrolled on 10/10/2018.</recruitment_details>
      <pre_assignment_details>All 35 eligible patients enrolled were included. The 'Completed' row included patients who completed all protocol therapy or who experienced a protocol endpoint which took them off therapy. These included dose limiting toxicities and progression/relapse events. Adverse events not related to study agent were included in the 'Not Completed' row.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="P2">
          <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="P3">
          <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="P4">
          <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
          <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="P5">
          <title>Stratum II, Dose Level 2 (75mg/m2)</title>
          <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="6"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="5"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Not meet dose reduction BSA requirement</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Summary statistics for baseline characteristics are shown for all enrolled patients (n = 35).</population>
      <group_list>
        <group group_id="B1">
          <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B2">
          <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B3">
          <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B4">
          <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
          <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B5">
          <title>Stratum II, Dose Level 2 (75mg/m2)</title>
          <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B6">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="12"/>
            <count group_id="B3" value="6"/>
            <count group_id="B4" value="4"/>
            <count group_id="B5" value="10"/>
            <count group_id="B6" value="35"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16.6" lower_limit="9.7" upper_limit="16.6"/>
                    <measurement group_id="B2" value="12.6" lower_limit="7.0" upper_limit="21.1"/>
                    <measurement group_id="B3" value="9.3" lower_limit="4.9" upper_limit="19.3"/>
                    <measurement group_id="B4" value="16.5" lower_limit="13.3" upper_limit="17.2"/>
                    <measurement group_id="B5" value="10.5" lower_limit="6.3" upper_limit="21.6"/>
                    <measurement group_id="B6" value="12.7" lower_limit="4.9" upper_limit="21.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="3"/>
                    <measurement group_id="B6" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="7"/>
                    <measurement group_id="B6" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="3"/>
                    <measurement group_id="B6" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="5"/>
                    <measurement group_id="B6" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="7"/>
                    <measurement group_id="B6" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="10"/>
                    <measurement group_id="B6" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I</title>
        <description>Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level had been determined to be too toxic. Stratum I consisted of less-heavily pre-treated patients.</description>
        <time_frame>4 weeks</time_frame>
        <population>Patients who were enrolled on stratum I and were evaluable for dose finding assessment were used to determine the MTD for stratum I.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I</title>
            <description>Of 21 patients enrolled on stratum I, 2 patients were not evaluable for dose finding assessment due to receiving less than required dose of study drug. The remaining 19 patients were used to determine the MTD for stratum I.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I</title>
          <description>Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level had been determined to be too toxic. Stratum I consisted of less-heavily pre-treated patients.</description>
          <population>Patients who were enrolled on stratum I and were evaluable for dose finding assessment were used to determine the MTD for stratum I.</population>
          <units>mg/m2/day</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II</title>
        <description>Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT and the next higher dose level had been determined to be too toxic. Stratum II consisted of heavily pre-treated patients.</description>
        <time_frame>4 weeks</time_frame>
        <population>Patients who were enrolled on stratum II and were evaluable for dose finding assessment were used to determine the MTD for stratum II.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum II</title>
            <description>Of 14 patients enrolled on stratum II, 3 patients were not evaluable for dose finding assessment: 2 patients due to receiving less than required dose of study drug and 1 due to withdrawal consent prior to beginning protocol therapy. The remaining 11 patients were used to determine the MTD for stratum II.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II</title>
          <description>Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT and the next higher dose level had been determined to be too toxic. Stratum II consisted of heavily pre-treated patients.</description>
          <population>Patients who were enrolled on stratum II and were evaluable for dose finding assessment were used to determine the MTD for stratum II.</population>
          <units>mg/m2/day</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)</title>
        <description>DLTs were defined as any of the following adverse events that were at least possibly related to palbociclib that occurred during the first 4 weeks of therapy regardless of expectedness. Hematologic DLTs included grade 3 neutropenia with fever and sepsis, grade 3 thrombocytopenia and/or requiring a platelet transfusion on 2 separate days within a 7-day period, or any grade 4 hematologic toxicity except lymphopenia. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of &lt; 5 days; diarrhea and/or electrolyte disturbances which have not been maximally treated; AST/ALT elevation that returns to levels meeting eligibility criteria within 7 days of study drug interruption and does not recur upon restarting drug), or any grade 2 non-hematologic toxicity that persists for &gt; 7 days and is considered medically significant or sufficiently intolerable by patients requires treatment interruption.</description>
        <time_frame>4 weeks</time_frame>
        <population>Patients who received at least one dose of palbociclib were included in the analysis. One patient in stratum II dose level 2 who withdrew prior to beginning protocol therapy was excluded.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)</title>
          <description>DLTs were defined as any of the following adverse events that were at least possibly related to palbociclib that occurred during the first 4 weeks of therapy regardless of expectedness. Hematologic DLTs included grade 3 neutropenia with fever and sepsis, grade 3 thrombocytopenia and/or requiring a platelet transfusion on 2 separate days within a 7-day period, or any grade 4 hematologic toxicity except lymphopenia. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of &lt; 5 days; diarrhea and/or electrolyte disturbances which have not been maximally treated; AST/ALT elevation that returns to levels meeting eligibility criteria within 7 days of study drug interruption and does not recur upon restarting drug), or any grade 2 non-hematologic toxicity that persists for &gt; 7 days and is considered medically significant or sufficiently intolerable by patients requires treatment interruption.</description>
          <population>Patients who received at least one dose of palbociclib were included in the analysis. One patient in stratum II dose level 2 who withdrew prior to beginning protocol therapy was excluded.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Single Dose Apparent Volume of Central Compartment (Vc/F)</title>
        <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 3</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Single Dose Apparent Volume of Central Compartment (Vc/F)</title>
          <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
          <units>L/m^2</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="672" lower_limit="622" upper_limit="1189"/>
                    <measurement group_id="O2" value="741" lower_limit="562" upper_limit="1856"/>
                    <measurement group_id="O3" value="708" lower_limit="601" upper_limit="819"/>
                    <measurement group_id="O4" value="847" lower_limit="373" upper_limit="1153"/>
                    <measurement group_id="O5" value="850" lower_limit="398" upper_limit="3653"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Single Dose Elimination Rate Constant (Ke)</title>
        <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Elimination rate constant (Ke) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 3</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Single Dose Elimination Rate Constant (Ke)</title>
          <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Elimination rate constant (Ke) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
          <units>per hour</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.053" lower_limit="0.045" upper_limit="0.055"/>
                    <measurement group_id="O2" value="0.053" lower_limit="0.030" upper_limit="0.070"/>
                    <measurement group_id="O3" value="0.048" lower_limit="0.023" upper_limit="0.083"/>
                    <measurement group_id="O4" value="0.051" lower_limit="0.031" upper_limit="0.070"/>
                    <measurement group_id="O5" value="0.051" lower_limit="0.014" upper_limit="0.097"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Single Dose Half-life (t1/2)</title>
        <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Half-life (t1/2) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 3</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Single Dose Half-life (t1/2)</title>
          <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Half-life (t1/2) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
          <units>hour</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.0" lower_limit="12.5" upper_limit="15.5"/>
                    <measurement group_id="O2" value="13.0" lower_limit="9.9" upper_limit="22.8"/>
                    <measurement group_id="O3" value="14.6" lower_limit="8.4" upper_limit="29.8"/>
                    <measurement group_id="O4" value="13.8" lower_limit="10.0" upper_limit="22.0"/>
                    <measurement group_id="O5" value="13.5" lower_limit="7.1" upper_limit="48.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Single Dose Apparent Oral Clearance (CL/F)</title>
        <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 3</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Single Dose Apparent Oral Clearance (CL/F)</title>
          <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
          <units>L/h/m^2</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.8" lower_limit="34.4" upper_limit="53.1"/>
                    <measurement group_id="O2" value="38.4" lower_limit="29.3" upper_limit="72.0"/>
                    <measurement group_id="O3" value="33.7" lower_limit="17.3" upper_limit="63.3"/>
                    <measurement group_id="O4" value="37.2" lower_limit="16.9" upper_limit="64.3"/>
                    <measurement group_id="O5" value="24.4" lower_limit="11.7" upper_limit="355.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Single Dose Area Under the Plasma Concentration Time Curve (AUC)</title>
        <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 3</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Single Dose Area Under the Plasma Concentration Time Curve (AUC)</title>
          <description>On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.</population>
          <units>h*ng/mL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1156" lower_limit="810" upper_limit="1164"/>
                    <measurement group_id="O2" value="1743" lower_limit="892" upper_limit="2537"/>
                    <measurement group_id="O3" value="2407" lower_limit="1485" upper_limit="3252"/>
                    <measurement group_id="O4" value="1289" lower_limit="747" upper_limit="2834"/>
                    <measurement group_id="O5" value="2538" lower_limit="189" upper_limit="2951"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Steady State Apparent Volume of Central Compartment (Vc/F)</title>
        <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 22</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Steady State Apparent Volume of Central Compartment (Vc/F)</title>
          <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
          <units>L/m^2</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="491" lower_limit="465" upper_limit="517"/>
                    <measurement group_id="O2" value="449" lower_limit="282" upper_limit="1560"/>
                    <measurement group_id="O3" value="442" lower_limit="383" upper_limit="501"/>
                    <measurement group_id="O4" value="705" lower_limit="250" upper_limit="1308"/>
                    <measurement group_id="O5" value="458" lower_limit="247" upper_limit="919"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Steady State Elimination Rate Constant (Ke)</title>
        <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Elimination rate constant (Ke) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 22</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Steady State Elimination Rate Constant (Ke)</title>
          <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Elimination rate constant (Ke) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
          <units>per hour</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.052" lower_limit="0.041" upper_limit="0.066"/>
                    <measurement group_id="O2" value="0.050" lower_limit="0.017" upper_limit="0.110"/>
                    <measurement group_id="O3" value="0.062" lower_limit="0.054" upper_limit="0.071"/>
                    <measurement group_id="O4" value="0.032" lower_limit="0.024" upper_limit="0.049"/>
                    <measurement group_id="O5" value="0.039" lower_limit="0.032" upper_limit="0.074"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Steady State Half-life (t1/2)</title>
        <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Half-life (t1/2) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 22</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Steady State Half-life (t1/2)</title>
          <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Half-life (t1/2) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
          <units>hour</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.7" lower_limit="10.5" upper_limit="16.9"/>
                    <measurement group_id="O2" value="13.7" lower_limit="6.5" upper_limit="41.6"/>
                    <measurement group_id="O3" value="11.3" lower_limit="9.8" upper_limit="12.8"/>
                    <measurement group_id="O4" value="23.1" lower_limit="14.2" upper_limit="29.4"/>
                    <measurement group_id="O5" value="17.9" lower_limit="9.4" upper_limit="21.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Steady State Apparent Oral Clearance (CL/F)</title>
        <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 22</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Steady State Apparent Oral Clearance (CL/F)</title>
          <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
          <units>L/h/m^2</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.6" lower_limit="19.0" upper_limit="34.2"/>
                    <measurement group_id="O2" value="25.8" lower_limit="12.3" upper_limit="101.0"/>
                    <measurement group_id="O3" value="28.1" lower_limit="20.8" upper_limit="35.3"/>
                    <measurement group_id="O4" value="17.0" lower_limit="9.7" upper_limit="64.0"/>
                    <measurement group_id="O5" value="16.1" lower_limit="12.1" upper_limit="62.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Steady State Area Under the Plasma Concentration Time Curve (AUC)</title>
        <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.</description>
        <time_frame>Up to day 22</time_frame>
        <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Steady State Area Under the Plasma Concentration Time Curve (AUC)</title>
          <description>On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.</description>
          <population>Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.</population>
          <units>h*ng/mL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1211" lower_limit="972" upper_limit="1450"/>
                    <measurement group_id="O2" value="2143" lower_limit="521" upper_limit="4070"/>
                    <measurement group_id="O3" value="2193" lower_limit="1520" upper_limit="3168"/>
                    <measurement group_id="O4" value="1410" lower_limit="559" upper_limit="3301"/>
                    <measurement group_id="O5" value="2359" lower_limit="952" upper_limit="4253"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Subjects With Objective Responses</title>
        <description>Objective responses included complete response (CR) and partial response (PR).</description>
        <time_frame>Up to 2 years</time_frame>
        <population>Patients who received at least one dose of palbociclib were included in the analysis. One patient in stratum II dose level 2 who withdrew prior to beginning protocol therapy was excluded.</population>
        <group_list>
          <group group_id="O1">
            <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
            <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Stratum II, Dose Level 2 (75mg/m2)</title>
            <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With Objective Responses</title>
          <description>Objective responses included complete response (CR) and partial response (PR).</description>
          <population>Patients who received at least one dose of palbociclib were included in the analysis. One patient in stratum II dose level 2 who withdrew prior to beginning protocol therapy was excluded.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Association Between Neutropenia and Single Dose Palbociclib AUC</title>
        <description>Neutrophil count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between neutrophil count decreased and single dose palbociclib AUC for all participants was examined.</description>
        <time_frame>Up to approximately 4 weeks</time_frame>
        <population>It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between neutropenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.</population>
        <group_list>
          <group group_id="O1">
            <title>All Patients</title>
            <description>All 34 patients who had course 1 single dose palbociclib AUC data available were included in analysis. Patients were classified into no neutropenia (n = 9), grade 1 or 2 neutropenia (n = 7), and grade 3 or 4 neutropenia (n = 18).</description>
          </group>
        </group_list>
        <measure>
          <title>Association Between Neutropenia and Single Dose Palbociclib AUC</title>
          <description>Neutrophil count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between neutrophil count decreased and single dose palbociclib AUC for all participants was examined.</description>
          <population>It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between neutropenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.</population>
          <units>h*ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>No neutropenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1424.4" spread="966.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 1 or 2 neutropenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2166.3" spread="797.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 or 4 neutropenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1937.6" spread="621.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Ordinal logistic regression model was built for outcome neutropenia (0/1/2). Explanatory variable AUC was transformed by dividing by 100.</non_inferiority_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.06</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.97</ci_lower_limit>
            <ci_upper_limit>1.15</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Association Between Lymphopenia and Single Dose Palbociclib AUC</title>
        <description>Lymphocyte count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between Lymphocyte count decreased and single dose palbociclib AUC for all participants was examined.</description>
        <time_frame>Up to approximately 4 weeks</time_frame>
        <population>It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between lymphopenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.</population>
        <group_list>
          <group group_id="O1">
            <title>All Patients</title>
            <description>All 34 patients who had course 1 single dose palbociclib AUC data available were included in analysis. Patients were classified into no lymphopenia (n = 17), grade 1 or 2 lymphopenia (n = 10), and grade 3 or 4 lymphopenia (n = 7).</description>
          </group>
        </group_list>
        <measure>
          <title>Association Between Lymphopenia and Single Dose Palbociclib AUC</title>
          <description>Lymphocyte count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between Lymphocyte count decreased and single dose palbociclib AUC for all participants was examined.</description>
          <population>It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between lymphopenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.</population>
          <units>h*ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>No lymphopenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1727.5" spread="882.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 1 or 2 lymphopenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1837.9" spread="592.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 or 4 lymphopenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2159.0" spread="793.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Ordinal logistic regression model was built for outcome lymphopenia (0/1/2). Explanatory variable AUC was transformed by dividing by 100.</non_inferiority_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.05</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.97</ci_lower_limit>
            <ci_upper_limit>1.15</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Association Between Leukopenia and Single Dose Palbociclib AUC</title>
        <description>White blood cell count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between white blood cell count decreased and single dose palbociclib AUC for all participants was examined.</description>
        <time_frame>Up to approximately 4 weeks</time_frame>
        <population>It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between leukopenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.</population>
        <group_list>
          <group group_id="O1">
            <title>All Patients</title>
            <description>All 34 patients who had course 1 single dose palbociclib AUC data available were included in analysis. Patients were classified into no leukopenia (n = 8), grade 1 or 2 leukopenia (n = 17), and grade 3 or 4 leukopenia (n = 9).</description>
          </group>
        </group_list>
        <measure>
          <title>Association Between Leukopenia and Single Dose Palbociclib AUC</title>
          <description>White blood cell count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between white blood cell count decreased and single dose palbociclib AUC for all participants was examined.</description>
          <population>It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between leukopenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.</population>
          <units>h*ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>No leukopenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1420.3" spread="955.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 1 or 2 leukopenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1879.6" spread="682.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 or 4 leukopenia</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2171.6" spread="712.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Ordinal logistic regression model was built for outcome leukopenia (0/1/2). Explanatory variable AUC was transformed by dividing by 100.</non_inferiority_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.10</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.01</ci_lower_limit>
            <ci_upper_limit>1.20</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations</title>
        <description>CDK4 is a key component in signaling pathways inside normal cells and cancer cells. CDK4 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
        <time_frame>At enrollment</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations</title>
        <description>CDK6 is a key component in signaling pathways inside normal cells and cancer cells. CDK6 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
        <time_frame>At enrollment</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Subjects With Cyclin D1 Copy Number Variations</title>
        <description>Cyclin D1 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D1 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
        <time_frame>At enrollment</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Subjects With Cyclin D2 Copy Number Variations</title>
        <description>Cyclin D2 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D2 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
        <time_frame>At enrollment</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Subjects With Cyclin D3 Copy Number Variations</title>
        <description>Cyclin D3 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D3 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
        <time_frame>At enrollment</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Subjects With Ink4a-ARF Loss Copy Number Variations</title>
        <description>Ink4a-ARF is a key component in signaling pathways inside normal cells and cancer cells. Ink4a-ARF loss copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.</description>
        <time_frame>At enrollment</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Polymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1)</title>
        <description>Polymorphisms in ABCB1 encode for efflux-transporter proteins P-glycoprotein (P-gp), for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCB1 polymorphisms.</description>
        <time_frame>At enrollment</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Polymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2)</title>
        <description>Polymorphisms in ABCG2 encode for BCRP, for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCG2 polymorphisms.</description>
        <time_frame>At enrollment</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 2 years after starting treatment</time_frame>
      <desc>Adverse events (AEs) were graded using CTCAE v4.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to palbociclib and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs that were at least possibly attributable to palbociclib were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. One patient in stratum II dose level 2 withdrew prior to protocol therapy and was not at risk.</desc>
      <group_list>
        <group group_id="E1">
          <title>Stratum I, Dose Level 1 (50 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E2">
          <title>Stratum I, Dose Level 2 (75 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E3">
          <title>Stratum I, Dose Level 3 (95 mg/m2)</title>
          <description>Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E4">
          <title>Stratum II, Dose Level 1 (50 mg/m2)</title>
          <description>Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E5">
          <title>Stratum II, Dose Level 2 (75mg/m2)</title>
          <description>Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E5" subjects_affected="9" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="12"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="8" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E5" events="11" subjects_affected="6" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye disorders - other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="6" subjects_affected="4" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="10" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Stomach pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="4" subjects_affected="2" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="3" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Electrocardiogram qt corrected interval prolonged</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Investigations - other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="44" subjects_affected="8" subjects_at_risk="12"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E4" events="10" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E5" events="8" subjects_affected="4" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="54" subjects_affected="10" subjects_at_risk="12"/>
                <counts group_id="E3" events="6" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E4" events="13" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E5" events="25" subjects_affected="7" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="23" subjects_affected="6" subjects_at_risk="12"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E4" events="10" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E5" events="13" subjects_affected="5" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="57" subjects_affected="10" subjects_at_risk="12"/>
                <counts group_id="E3" events="10" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E4" events="15" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E5" events="22" subjects_affected="7" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Ataxia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E5" events="2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Jie Huang</name_or_title>
      <organization>St. Jude Children's Research Hospital</organization>
      <phone>9015955750</phone>
      <email>jie.huang@stjude.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02255461
org study id: PBTC-042
secondary id: U01CA081457
nct id: NCT02255461
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
This phase I trial studies the side effects and best dose of palbociclib isethionate in
      treating younger patients with central nervous system tumors that have grown, come back, or
      not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by
      blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD)/phase II recommended dose and describe
      toxicities related to PD-0332991 (palbociclib isethionate) in children with retinoblastoma
      protein 1 (Rb1) positive recurrent, progressive or refractory primary central nervous system
      (CNS) tumors.

      II. To determine plasma pharmacokinetics of PD-0332991 in children with Rb1positive
      recurrent, progressive or refractory primary CNS tumors.

      SECONDARY OBJECTIVES:

      I. To record preliminary evidence of efficacy of PD-0332991 in children with recurrent CNS
      tumors.

      II. To evaluate cyclin-dependent kinase (CDK)4/6, cyclin D1-3, Ink4a-ARF copy-number
      variations in available tumor tissue by array comparative, genomic hybridization (aCGH).

      III. To explore the potential relationships between the pharmacokinetics of PD-0332991 and
      pharmacodynamic response (e.g. percentage change in absolute neutrophil count [ANC], platelet
      counts).

      IV. To explore the pharmacogenetic polymorphisms in PD-0332991 metabolizing enzymes and
      transporters and relate these polymorphisms to PD-0332991 pharmacokinetics.

      OUTLINE: This is a dose-escalation study.

      Patients receive palbociclib isethionate orally (PO) once daily (QD) on days 1-21. Treatment
      repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up for 30 days.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I
time frame: 4 weeks
description: Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level had been determined to be too toxic. Stratum I consisted of less-heavily pre-treated patients.
measure: Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II
time frame: 4 weeks
description: Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT and the next higher dose level had been determined to be too toxic. Stratum II consisted of heavily pre-treated patients.
measure: Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)
time frame: 4 weeks
description: DLTs were defined as any of the following adverse events that were at least possibly related to palbociclib that occurred during the first 4 weeks of therapy regardless of expectedness. Hematologic DLTs included grade 3 neutropenia with fever and sepsis, grade 3 thrombocytopenia and/or requiring a platelet transfusion on 2 separate days within a 7-day period, or any grade 4 hematologic toxicity except lymphopenia. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of < 5 days; diarrhea and/or electrolyte disturbances which have not been maximally treated; AST/ALT elevation that returns to levels meeting eligibility criteria within 7 days of study drug interruption and does not recur upon restarting drug), or any grade 2 non-hematologic toxicity that persists for > 7 days and is considered medically significant or sufficiently intolerable by patients requires treatment interruption.
measure: Single Dose Apparent Volume of Central Compartment (Vc/F)
time frame: Up to day 3
description: On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.
measure: Single Dose Elimination Rate Constant (Ke)
time frame: Up to day 3
description: On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Elimination rate constant (Ke) was estimated using a non-compartmental method.
measure: Single Dose Half-life (t1/2)
time frame: Up to day 3
description: On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Half-life (t1/2) was estimated using a non-compartmental method.
measure: Single Dose Apparent Oral Clearance (CL/F)
time frame: Up to day 3
description: On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.
measure: Single Dose Area Under the Plasma Concentration Time Curve (AUC)
time frame: Up to day 3
description: On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.
measure: Steady State Apparent Volume of Central Compartment (Vc/F)
time frame: Up to day 22
description: On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.
measure: Steady State Elimination Rate Constant (Ke)
time frame: Up to day 22
description: On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Elimination rate constant (Ke) was estimated using a non-compartmental method.
measure: Steady State Half-life (t1/2)
time frame: Up to day 22
description: On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Half-life (t1/2) was estimated using a non-compartmental method.
measure: Steady State Apparent Oral Clearance (CL/F)
time frame: Up to day 22
description: On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.
measure: Steady State Area Under the Plasma Concentration Time Curve (AUC)
time frame: Up to day 22
description: On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.
measure: Number of Subjects With Objective Responses
time frame: Up to 2 years
description: Objective responses included complete response (CR) and partial response (PR).
measure: Association Between Neutropenia and Single Dose Palbociclib AUC
time frame: Up to approximately 4 weeks
description: Neutrophil count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between neutrophil count decreased and single dose palbociclib AUC for all participants was examined.
measure: Association Between Lymphopenia and Single Dose Palbociclib AUC
time frame: Up to approximately 4 weeks
description: Lymphocyte count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between Lymphocyte count decreased and single dose palbociclib AUC for all participants was examined.
measure: Association Between Leukopenia and Single Dose Palbociclib AUC
time frame: Up to approximately 4 weeks
description: White blood cell count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between white blood cell count decreased and single dose palbociclib AUC for all participants was examined.
measure: Number of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations
time frame: At enrollment
description: CDK4 is a key component in signaling pathways inside normal cells and cancer cells. CDK4 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
measure: Number of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations
time frame: At enrollment
description: CDK6 is a key component in signaling pathways inside normal cells and cancer cells. CDK6 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
measure: Number of Subjects With Cyclin D1 Copy Number Variations
time frame: At enrollment
description: Cyclin D1 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D1 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
measure: Number of Subjects With Cyclin D2 Copy Number Variations
time frame: At enrollment
description: Cyclin D2 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D2 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
measure: Number of Subjects With Cyclin D3 Copy Number Variations
time frame: At enrollment
description: Cyclin D3 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D3 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
measure: Number of Subjects With Ink4a-ARF Loss Copy Number Variations
time frame: At enrollment
description: Ink4a-ARF is a key component in signaling pathways inside normal cells and cancer cells. Ink4a-ARF loss copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.
measure: Polymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1)
time frame: At enrollment
description: Polymorphisms in ABCB1 encode for efflux-transporter proteins P-glycoprotein (P-gp), for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCB1 polymorphisms.
measure: Polymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2)
time frame: At enrollment
description: Polymorphisms in ABCG2 encode for BCRP, for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCG2 polymorphisms.
arm group label: Treatment (palbociclib isethionate)
arm group type: Experimental
description: Patients receive palbociclib isethionate PO QD on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: palbociclib isethionate
description: Given PO
arm group label: Treatment (palbociclib isethionate)
other name: 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, 827022-33-3, palbociclib, PD 0332991-0054, PD-0332991, PD-332991, PF-00080665-73
intervention type: Other
intervention name: pharmacological study
description: Correlative studies
arm group label: Treatment (palbociclib isethionate)
other name: pharmacological studies
intervention type: Other
intervention name: laboratory biomarker analysis
description: Correlative studies
arm group label: Treatment (palbociclib isethionate)
criteria: 
gender: All
minimum age: 4 Years
maximum age: 21 Years
healthy volunteers: No
last name: David Van Mater, MD
role: Principal Investigator
affiliation: Pediatric Brain Tumor Consortium
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Glioblastoma
mesh term: Astrocytoma
mesh term: Meningioma
mesh term: Gliosarcoma
mesh term: Nervous System Neoplasms
mesh term: Medulloblastoma
mesh term: Central Nervous System Neoplasms
mesh term: Oligodendroglioma
mesh term: Neuroectodermal Tumors
mesh term: Neuroectodermal Tumors, Primitive
mesh term: Choroid Plexus Neoplasms
mesh term: Pinealoma
mesh term: Neoplasms, Neuroepithelial
mesh term: Recurrence
mesh term: Palbociclib
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 