<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/NCT03792256</url>
  </required_header>
  <id_info>
    <org_study_id>AINV18P1</org_study_id>
    <secondary_id>NCI-2019-02774</secondary_id>
    <nct_id>NCT03792256</nct_id>
  </id_info>
  <brief_title>Palbociclib in Combination With Chemotherapy in Treating Children With Relapsed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL)</brief_title>
  <official_title>A Phase 1 Study Of Palbociclib (IND#141416), A CDK 4/6 Inhibitor, In Combination With Chemotherapy In Children With Relapsed Acute Lymphoblastic Leukemia (ALL) Or Lymphoblastic Lymphoma (LL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Oncology Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's Oncology Group</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      AINV18P1 is a Phase 1 study where palbociclib will be administrated in combination with a&#xD;
      standard re-induction platform in pediatric relapsed Acute Lymphoblastic Leukemia (ALL) and&#xD;
      lymphoblastic lymphoma (LL). LL patients are included because the patient population is rare&#xD;
      and these patients are most commonly treated with ALL regimens. The proposed palbociclib&#xD;
      starting dose for this study will be 50 mg/m^2/day for 21 days.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of&#xD;
      palbociclib administered in combination with re-induction chemotherapy in pediatric patients&#xD;
      with relapsed B- or T-lineage ALL/LL.&#xD;
&#xD;
      II. To define and describe the toxicities of palbociclib administered on this schedule.&#xD;
&#xD;
      III. To characterize the pharmacokinetics of palbociclib in pediatric patients with relapsed&#xD;
      B- or T-lineage ALL/LL.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To preliminarily define the antitumor activity of palbociclib in combination with&#xD;
      chemotherapy for children with relapsed ALL/LL within the confines of a Phase 1 study.&#xD;
&#xD;
      II. To assess the biologic activity of palbociclib in this patient population.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive Palbociclib PO (or via NG-tube) once daily on Days 1-21; Intrathecal&#xD;
      cytarabine (IT ARAC) on Day 1, Doxorubicin IV push or infusion over 1-15 min on Day 4;&#xD;
      Prednisone or prednisolone PO on days 4-31; Vincristine IV push or mini-bag per institutional&#xD;
      policy on Days 4, 11, 18, and 25; and Pegaspargase IV over 1-2 hours on Days 5, and 18. If&#xD;
      CNS3 leukemia is present, patients receive Intrathecal Triple Therapy (ITT) on days 4, 11,18,&#xD;
      and 25. If CNS1 or 2 disease status, patients receive Methotrexate (IT MTX) on Days 18 and&#xD;
      32. Patients known to be CNS3 at study entry may receive ITT on Day 1 rather than IT ARAC.&#xD;
      Treatment will be given for one cycle, 32 days, in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 11, 2019</start_date>
  <completion_date type="Anticipated">June 30, 2025</completion_date>
  <primary_completion_date type="Actual">June 30, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <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>Frequency of dose limiting toxicities of Palbociclib</measure>
    <time_frame>Up to 32 days</time_frame>
    <description>The frequency (%) of patients experiencing a dose limiting toxicity at least possibly attributable to Palbociclib by study part and dose level.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Frequency of adverse events of Palbociclib</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>The frequency (%) of patients experiencing adverse events at least possibly attributable to Palbociclib by study part and dose level.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the drug concentration curve of Palbociclib</measure>
    <time_frame>Up to 11 days</time_frame>
    <description>The median (min,max) of the area under the drug concentration curve for Palbociclib by study part and dose level.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Half-life of Palbociclib</measure>
    <time_frame>Up to 11 days</time_frame>
    <description>The median (min,max) of the half-life of Palbociclib by study part and dose level</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum serum concentration of Palbociclib</measure>
    <time_frame>Up to 11 days</time_frame>
    <description>Median (min,max) of the maximum serum concentration of Palbociclib by study part and dose level</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Minimum serum concentration of Palbociclib</measure>
    <time_frame>Up to 11 days</time_frame>
    <description>Median (min,max) of the minimum serum concentration of Palbociclib by study part and dose level</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clearance of Palbociclib</measure>
    <time_frame>Up to 11 days</time_frame>
    <description>Median (min,max) of the clearance of Palbociclib by study part and dose level</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Antitumor effect of Palbociclib</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Frequency (%) of patients with at least partial response to Palbociclib by study part and dose level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute peripheral blast count of palbociclib</measure>
    <time_frame>Up to 3 days</time_frame>
    <description>Median (min, max) of absolute peripheral blast count of palbociclib by study part and dose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiographic response of palbociclib in patients with LL patients</measure>
    <time_frame>Day 32</time_frame>
    <description>Frequency (%) of LL patients with radiographic response by study part and dose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>RB1 expression of palbociclib</measure>
    <time_frame>Up to 4 days</time_frame>
    <description>Median (min,max) of RB1 expression of palbociclib by study part and dose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phospho-RB1 expression of palbociclib</measure>
    <time_frame>Up to 4 days</time_frame>
    <description>Median (min,max) of Phospho-RB1 expression of palbociclib by study part and dose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cyclin D3 expression of palbociclib</measure>
    <time_frame>Up to 4 days</time_frame>
    <description>Median (min,max) of Cyclin D3 expression of palbociclib by study part and dose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CDK4 expression of palbociclib</measure>
    <time_frame>Up to 4 days</time_frame>
    <description>Median (min,max) of CDK4 expression of palbociclib by study part and dose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CDK6 expression of palbociclib</measure>
    <time_frame>Up to 4 days</time_frame>
    <description>Median (min,max) of CDK6 expression of palbociclib by study part and dose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>p27Kip1 expression of palbociclib</measure>
    <time_frame>Up to 4 days</time_frame>
    <description>Median (min,max) of p27Kip1 expression of palbociclib by study part and dose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CD1a biological activity of palbociclib</measure>
    <time_frame>Up to 32 days</time_frame>
    <description>Median (min,max) of CD1a biological activity of palbociclib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CD3 biological activity of palbociclib</measure>
    <time_frame>Up to 32 days</time_frame>
    <description>Median (min,max) of CD3 biological activity of palbociclib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CD4 biological activity of palbociclib</measure>
    <time_frame>Up to 32 days</time_frame>
    <description>Median (min,max) of CD4 biological activity of palbociclib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CD8 biological activity of palbociclib</measure>
    <time_frame>Up to 32 days</time_frame>
    <description>Median (min,max) of CD8 biological activity of palbociclib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ki67 biological activity of palbociclib</measure>
    <time_frame>Up to 32 days</time_frame>
    <description>Median (min,max) of Ki67 biological activity of palbociclib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DAPI biological activity of palbociclib</measure>
    <time_frame>Up to 32 days</time_frame>
    <description>Median (min,max) of DAPI biological activity of palbociclib</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>Leukemia, Lymphocytic</condition>
  <condition>Lymphoblastic Lymphoma</condition>
  <condition>T-cell Lymphoma</condition>
  <condition>T-cell Leukemia</condition>
  <condition>Recurrent Disease</condition>
  <condition>Acute Leukemia</condition>
  <arm_group>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive Palbociclib 50 mg/m^2 (starting dose with maximum dose of 100 mg) PO (or via NG-tube) once daily on Days 1-21; Intrathecal cytarabine (IT ARAC) age-based dosing on Day 1, Doxorubicin 60 mg/m^2 IV push or infusion over 1-15 min on Day 4; Prednisone or prednisolone 40 mg/m^2 PO divided BID or TID on days 4-31; Vincristine 1.5 mg/m^2 (maximum dose 2 mg) IV push or mini-bag per institutional policy on days 4, 11, 18, and 25; and Pegaspargase 2500 IU/m^2 IV over 1-2 hours on Days 5, and 18. If CNS3 leukemia is present, patients receive Intrathecal Triple Therapy (ITT) age-based dosing on days 4, 11, 18, and 25. Patients known to be CNS3 at study entry may receive ITT on Day 1 rather than IT ARAC. If CNS1 and 2 leukemia present, patient receive Methotrexate (IT MTX) age-based dosing on Days 18 and 32. Treatment will be given for one cycle, 32 days, in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Palbociclib</intervention_name>
    <description>Given PO (or via NG- tube)</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <description>Given intrathecally (IT)</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>Given intrathecally (IT)</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydrocortisone</intervention_name>
    <description>Given IT</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin</intervention_name>
    <description>Given intravenously (IV)</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisolone</intervention_name>
    <description>Either prednisone or prednisolone is given PO</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vincristine</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pegaspargase</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydrocortisone</intervention_name>
    <description>Given intrathecally (IT)</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Either prednisone or prednisolone is given PO</description>
    <arm_group_label>Treatment (Palbociclib)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with recurrent or refractory B- or T-lineage lymphoblastic leukemia and&#xD;
             lymphoma.&#xD;
&#xD;
          -  Patients with leukemia must have ≥ 5% (M2 or M3) bone marrow blasts with or without an&#xD;
             extramedullary site of relapse. Morphologic relapse for M2 should be confirmed using&#xD;
             flow cytometry, FISH and/or cytogenetics or molecular techniques.&#xD;
&#xD;
          -  Patients with LL must have either measurable or evaluable disease.&#xD;
&#xD;
          -  Patients with first or greater relapsed T-lineage ALL or LL and second or greater&#xD;
             relapsed B-lineage ALL or LL are eligible.&#xD;
&#xD;
          -  Patients with primary refractory disease with at least 2 prior induction attempts or&#xD;
             first relapse refractory to at least one prior re-induction attempt are eligible.&#xD;
&#xD;
          -  Karnofsky &gt;= 50% for patients &gt; 16 years of age and Lansky &gt;= 50 for patients &lt;= 16&#xD;
             years of age.&#xD;
&#xD;
               -  Note: Patients who are unable to walk because of paralysis, but who are up in a&#xD;
                  wheelchair, will be considered ambulatory for the purpose of assessing the&#xD;
                  performance score.&#xD;
&#xD;
          -  Patients must have fully recovered from the acute toxic effects of all prior&#xD;
             anti-cancer therapy and must meet the following minimum duration from prior&#xD;
             anti-cancer directed therapy prior to enrollment. If after the required timeframe, the&#xD;
             numerical eligibility criteria are met, e.g., blood count criteria, the patient is&#xD;
             considered to have recovered adequately.&#xD;
&#xD;
               1. Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.&#xD;
                  See DVL homepage for commercial and Phase 1 investigational agent&#xD;
                  classifications. For agents not listed, the duration of this interval must be&#xD;
                  discussed with the study chair and the study-assigned Research Coordinator prior&#xD;
                  to enrollment.&#xD;
&#xD;
                    -  A waiting period prior to enrollment is not required for patients receiving&#xD;
                       standard cytotoxic maintenance chemotherapy (i.e., corticosteroid,&#xD;
                       vincristine, 6MP, and/or methotrexate).&#xD;
&#xD;
                    -  Intrathecal cytotoxic therapy: No waiting period is required for patients&#xD;
                       having received intrathecal cytarabine, methotrexate, and/or hydrocortisone.&#xD;
                       Intrathecal chemotherapy given at the time of diagnostic LP to evaluate for&#xD;
                       relapse prior to study enrollment is allowed.&#xD;
&#xD;
                         -  14 days must have elapsed after the completion of other cytotoxic&#xD;
                            therapy, with the exception of hydroxyurea, for patients not receiving&#xD;
                            standard maintenance therapy. Additionally, patients must have fully&#xD;
                            recovered from all acute toxic effects of prior therapy.&#xD;
&#xD;
                              -  NOTE: Cytoreduction with hydroxyurea in patients can be initiated&#xD;
                                 and continued for up to 24 hours prior to the start of protocol&#xD;
                                 therapy.&#xD;
&#xD;
                              -  Note: Intrathecal chemotherapy that is given up to 72 hours prior&#xD;
                                 to initiation of systemic chemotherapy per AINV18P1 counts as&#xD;
                                 protocol therapy and not prior anti-cancer therapy. Intrathecal&#xD;
                                 chemotherapy given &gt; 72 hours prior does not count as protocol&#xD;
                                 therapy.&#xD;
&#xD;
               2. Anti-cancer agents not known to be myelosuppressive (e.g. not associated with&#xD;
                  reduced platelet or ANC counts): &gt;= 7 days after the last dose of agent. See DVL&#xD;
                  homepage for commercial and Phase 1 investigational agent classifications. For&#xD;
                  agents not listed, the duration of this interval must be discussed with the study&#xD;
                  chair and the study-assigned Research Coordinator prior to enrollment.&#xD;
&#xD;
                    -  NOTE: Cytoreduction with prednisone or methylprednisolone for &lt;= 120 hours&#xD;
                       (5 days) in patients can be initiated and continued for up to 24 hours prior&#xD;
                       to the start of protocol therapy.&#xD;
&#xD;
               3. Antibodies: &gt;= 21 days must have elapsed from infusion of last dose of antibody&#xD;
                  with the exception of blinatumomab, and toxicity related to prior antibody&#xD;
                  therapy must be recovered to Grade &lt;= 1. Patients must have been off blinatumomab&#xD;
                  infusion for at least 14 days and all drug related toxicity must have resolved to&#xD;
                  Grade &lt;= 1.&#xD;
&#xD;
               4. Corticosteroids: If used to modify immune adverse events related to prior&#xD;
                  therapy, &gt;= 14 days must have elapsed since last dose of corticosteroid and&#xD;
                  toxicity related to prior immune therapy must be recovered to Grade &lt;= 1 off&#xD;
                  corticosteroids.&#xD;
&#xD;
               5. Hematopoietic growth factors: &gt;= 14 days after the last dose of a long-acting&#xD;
                  growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For&#xD;
                  agents that have known adverse events occurring beyond 7 days after&#xD;
                  administration, this period must be extended beyond the time during which adverse&#xD;
                  events are known to occur. The duration of this interval must be discussed with&#xD;
                  the study chair and the study-assigned Research Coordinator.&#xD;
&#xD;
               6. Interleukins, Interferons and Cytokines (other than Hematopoietic Growth&#xD;
                  Factors): &gt;= 21 days after the completion of interleukins, interferon or&#xD;
                  cytokines (other than Hematopoietic Growth Factors)&#xD;
&#xD;
               7. Stem cell Infusions (with or without TBI):&#xD;
&#xD;
                    -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem&#xD;
                       cell infusion including DLI or boost infusion: &gt;= 84 days after infusion and&#xD;
                       no evidence of GVHD.&#xD;
&#xD;
                    -  Autologous stem cell infusion including boost infusion: &gt;= 42 days.&#xD;
&#xD;
               8. Cellular Therapy: &gt;= 30 days after the completion of any type of cellular therapy&#xD;
                  (e.g. modified T cells, NK cells, dendritic cells, etc.)&#xD;
&#xD;
               9. XRT/External Beam Irradiation including Protons: &gt;= 14 days after local XRT; &gt;=&#xD;
                  150 days after TBI, craniospinal XRT or if radiation to &gt;= 50% of the pelvis; &gt;=&#xD;
                  42 days if other substantial BM radiation.&#xD;
&#xD;
              10. Patients must not have received prior exposure to palbociclib or another CDK4/6&#xD;
                  inhibitor.&#xD;
&#xD;
          -  Adequate Renal Function Defined as:&#xD;
&#xD;
               -  Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or&#xD;
&#xD;
               -  A serum creatinine based on age/gender as follows:&#xD;
&#xD;
                    -  Age: 1 to &lt; 2 years; Male: 0.6 mg/dL; Female: 0.6 mg/dL&#xD;
&#xD;
                    -  Age: 2 to &lt; 6 years; Male: 0.8 mg/dL; Female: 0.8 mg/dL&#xD;
&#xD;
                    -  Age: 6 to &lt; 10 years; Male: 1 mg/dL; Female: 1 mg/dL&#xD;
&#xD;
                    -  Age: 10 to &lt; 13 years; Male: 1.2 mg/dL; Female: 1.2 mg/dL&#xD;
&#xD;
                    -  Age: 13 to &lt; 16 years; Male: 1.5 mg/dL; Female: 1.4 mg/dL&#xD;
&#xD;
                    -  Age: &gt;= 16 years; Male: 1.7 mg/dL; Female: 1.4 mg/dL&#xD;
&#xD;
          -  Adequate Liver Function Defined as:&#xD;
&#xD;
               -  bilirubin (sum of conjugated + unconjugated) &lt;= 1.5 x upper limit of normal (ULN)&#xD;
                  for age&#xD;
&#xD;
               -  SGPT (ALT) &lt;= 225 U/L unless disease-related. For the purpose of this study, the&#xD;
                  ULN for SGPT is 45 U/L.&#xD;
&#xD;
               -  Serum albumin &gt;= 2 g/dL.&#xD;
&#xD;
          -  Adequate Cardiac Function Defined As:&#xD;
&#xD;
               -  Shortening fraction of &gt;= 27% by echocardiogram, or&#xD;
&#xD;
               -  Ejection fraction of &gt;= 50% by gated radionuclide study.&#xD;
&#xD;
          -  All patients and/or their parents or legally authorized representatives must sign a&#xD;
             written informed consent. Assent, when appropriate, will be obtained according to&#xD;
             institutional guidelines.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast-feeding women will not be entered on this study due to risks of&#xD;
             fetal and teratogenic adverse events as seen in animal/human studies. Based on the&#xD;
             mechanism of action, palbociclib may be expected to cause fetal harm if used during&#xD;
             pregnancy. Pregnancy tests must be obtained in girls who are post-menarche. Males or&#xD;
             females of reproductive potential may not participate unless they have agreed to use&#xD;
             an effective contraceptive method for the duration of study therapy. Women of&#xD;
             reproductive potential should use effective contraception during treatment and for at&#xD;
             least 3 weeks after the last dose of palbociclib. Males with female partners of&#xD;
             reproductive potential should use effective contraception during treatment and for 3&#xD;
             months after the last dose of palbociclib. Animal data suggests that palbociclib may&#xD;
             affect male fertility.&#xD;
&#xD;
          -  Prednisone or methylprednisolone for ≤ 120 hours (5 days) may be administered for&#xD;
             cytoreduction up to 24 hours prior to the start of protocol therapy and as treatment&#xD;
             for allergic reactions or for physiologic replacement/stress dosing of hydrocortisone&#xD;
             for documented adrenal insufficiency. Corticosteroids are not allowed for other&#xD;
             indications. If used to modify immune adverse events related to prior therapy, ≥ 14&#xD;
             days must have elapsed since last dose of corticosteroid.&#xD;
&#xD;
          -  Patients who are currently receiving another investigational drug.&#xD;
&#xD;
          -  Patients who are currently receiving other anti-cancer agents are not eligible [except&#xD;
             patients receiving hydroxyurea, which may be continued until 24 hours prior to start&#xD;
             of protocol therapy].&#xD;
&#xD;
          -  Patients who are currently receiving drugs that are strong inhibitors and/or inducers&#xD;
             of CYP3A4 or sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow&#xD;
             therapeutic range are not eligible. Strong inducers or inhibitors of CYP3A4 are&#xD;
             prohibited from 14 days prior to enrollment to the end of the study.&#xD;
&#xD;
          -  Patients who are receiving cyclosporine, tacrolimus or other agents to prevent&#xD;
             graft-versus-host disease post bone marrow transplant.&#xD;
&#xD;
          -  Patients must be able to swallow intact capsules or liquid. Patients that are unable&#xD;
             to swallow oral medications may receive palbociclib through an NG tube. G tube&#xD;
             administration is not allowed.&#xD;
&#xD;
          -  Patients who have an uncontrolled infection defined as below:&#xD;
&#xD;
               -  Fever above 38.2°C within 48 hours of study enrollment with clinical signs of&#xD;
                  infection. Fever that is determined to be due to tumor burden is allowed if&#xD;
                  patients have documented negative blood cultures for at least 48 hours prior to&#xD;
                  enrollment and no concurrent signs or symptoms of active infection or hemodynamic&#xD;
                  instability.&#xD;
&#xD;
               -  A positive fungal culture within 30 days of study enrollment or active therapy&#xD;
                  for presumed invasive fungal infection.&#xD;
&#xD;
               -  Patients may be receiving IV or oral antibiotics to complete a course of therapy&#xD;
                  for a prior documented infection as long as cultures have been negative for at&#xD;
                  least 48 hours and signs or symptoms of active infection have resolved. For&#xD;
                  patients with c. difficile diarrhea, at least 72 hours of antibacterial therapy&#xD;
                  must have elapsed and stools must have normalized to baseline.&#xD;
&#xD;
               -  Active viral or protozoal infection requiring IV treatment.&#xD;
&#xD;
          -  Patients known to have one of the following concomitant genetic syndromes: Down&#xD;
             syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome,&#xD;
             Shwachmann syndrome or any other known bone marrow failure syndrome.&#xD;
&#xD;
          -  Patients who in the opinion of the investigator may not be able to comply with the&#xD;
             safety monitoring requirements of the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Months</minimum_age>
    <maximum_age>31 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizabeth Raetz, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Children's Oncology Group</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Loma Linda University Medical Center</name>
      <address>
        <city>Loma Linda</city>
        <state>California</state>
        <zip>92354</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Orange County</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lucile Packard Children's 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>Children's Hospital Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's National Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Healthcare of Atlanta - Egleston</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Riley Hospital for Children</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>C S Mott Children's Hospital</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota/Masonic Cancer Center</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Laura and Isaac Perlmutter Cancer Center at NYU Langone</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Oklahoma Health Sciences Center</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's 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>Saint Jude Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Primary Children's Hospital</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84113</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Children's 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>June 2021</verification_date>
  <study_first_submitted>November 29, 2018</study_first_submitted>
  <study_first_submitted_qc>December 31, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">January 3, 2019</study_first_posted>
  <last_update_submitted>February 25, 2022</last_update_submitted>
  <last_update_submitted_qc>February 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 2, 2022</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>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
    <mesh_term>Leukemia, T-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Hydrocortisone</mesh_term>
    <mesh_term>Hydrocortisone 17-butyrate 21-propionate</mesh_term>
    <mesh_term>Hydrocortisone acetate</mesh_term>
    <mesh_term>Hydrocortisone hemisuccinate</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Palbociclib</mesh_term>
    <mesh_term>Pegaspargase</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>June 29, 2022</submitted>
    <returned>May 25, 2023</returned>
    <submitted>June 29, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03792256
org study id: AINV18P1
secondary id: NCI-2019-02774
nct id: NCT03792256
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
AINV18P1 is a Phase 1 study where palbociclib will be administrated in combination with a
      standard re-induction platform in pediatric relapsed Acute Lymphoblastic Leukemia (ALL) and
      lymphoblastic lymphoma (LL). LL patients are included because the patient population is rare
      and these patients are most commonly treated with ALL regimens. The proposed palbociclib
      starting dose for this study will be 50 mg/m^2/day for 21 days.
PRIMARY OBJECTIVES:

      I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of
      palbociclib administered in combination with re-induction chemotherapy in pediatric patients
      with relapsed B- or T-lineage ALL/LL.

      II. To define and describe the toxicities of palbociclib administered on this schedule.

      III. To characterize the pharmacokinetics of palbociclib in pediatric patients with relapsed
      B- or T-lineage ALL/LL.

      SECONDARY OBJECTIVES:

      I. To preliminarily define the antitumor activity of palbociclib in combination with
      chemotherapy for children with relapsed ALL/LL within the confines of a Phase 1 study.

      II. To assess the biologic activity of palbociclib in this patient population.

      OUTLINE:

      Patients receive Palbociclib PO (or via NG-tube) once daily on Days 1-21; Intrathecal
      cytarabine (IT ARAC) on Day 1, Doxorubicin IV push or infusion over 1-15 min on Day 4;
      Prednisone or prednisolone PO on days 4-31; Vincristine IV push or mini-bag per institutional
      policy on Days 4, 11, 18, and 25; and Pegaspargase IV over 1-2 hours on Days 5, and 18. If
      CNS3 leukemia is present, patients receive Intrathecal Triple Therapy (ITT) on days 4, 11,18,
      and 25. If CNS1 or 2 disease status, patients receive Methotrexate (IT MTX) on Days 18 and
      32. Patients known to be CNS3 at study entry may receive ITT on Day 1 rather than IT ARAC.
      Treatment will be given for one cycle, 32 days, in the absence of disease progression or
      unacceptable toxicity.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Frequency of dose limiting toxicities of Palbociclib
time frame: Up to 32 days
description: The frequency (%) of patients experiencing a dose limiting toxicity at least possibly attributable to Palbociclib by study part and dose level.
measure: Frequency of adverse events of Palbociclib
time frame: Up to 4 years
description: The frequency (%) of patients experiencing adverse events at least possibly attributable to Palbociclib by study part and dose level.
measure: Area under the drug concentration curve of Palbociclib
time frame: Up to 11 days
description: The median (min,max) of the area under the drug concentration curve for Palbociclib by study part and dose level.
measure: Half-life of Palbociclib
time frame: Up to 11 days
description: The median (min,max) of the half-life of Palbociclib by study part and dose level
measure: Maximum serum concentration of Palbociclib
time frame: Up to 11 days
description: Median (min,max) of the maximum serum concentration of Palbociclib by study part and dose level
measure: Minimum serum concentration of Palbociclib
time frame: Up to 11 days
description: Median (min,max) of the minimum serum concentration of Palbociclib by study part and dose level
measure: Clearance of Palbociclib
time frame: Up to 11 days
description: Median (min,max) of the clearance of Palbociclib by study part and dose level
measure: Antitumor effect of Palbociclib
time frame: Up to 4 years
description: Frequency (%) of patients with at least partial response to Palbociclib by study part and dose level.
measure: Absolute peripheral blast count of palbociclib
time frame: Up to 3 days
description: Median (min, max) of absolute peripheral blast count of palbociclib by study part and dose level
measure: Radiographic response of palbociclib in patients with LL patients
time frame: Day 32
description: Frequency (%) of LL patients with radiographic response by study part and dose level
measure: RB1 expression of palbociclib
time frame: Up to 4 days
description: Median (min,max) of RB1 expression of palbociclib by study part and dose level
measure: Phospho-RB1 expression of palbociclib
time frame: Up to 4 days
description: Median (min,max) of Phospho-RB1 expression of palbociclib by study part and dose level
measure: Cyclin D3 expression of palbociclib
time frame: Up to 4 days
description: Median (min,max) of Cyclin D3 expression of palbociclib by study part and dose level
measure: CDK4 expression of palbociclib
time frame: Up to 4 days
description: Median (min,max) of CDK4 expression of palbociclib by study part and dose level
measure: CDK6 expression of palbociclib
time frame: Up to 4 days
description: Median (min,max) of CDK6 expression of palbociclib by study part and dose level
measure: p27Kip1 expression of palbociclib
time frame: Up to 4 days
description: Median (min,max) of p27Kip1 expression of palbociclib by study part and dose level
measure: CD1a biological activity of palbociclib
time frame: Up to 32 days
description: Median (min,max) of CD1a biological activity of palbociclib
measure: CD3 biological activity of palbociclib
time frame: Up to 32 days
description: Median (min,max) of CD3 biological activity of palbociclib
measure: CD4 biological activity of palbociclib
time frame: Up to 32 days
description: Median (min,max) of CD4 biological activity of palbociclib
measure: CD8 biological activity of palbociclib
time frame: Up to 32 days
description: Median (min,max) of CD8 biological activity of palbociclib
measure: Ki67 biological activity of palbociclib
time frame: Up to 32 days
description: Median (min,max) of Ki67 biological activity of palbociclib
measure: DAPI biological activity of palbociclib
time frame: Up to 32 days
description: Median (min,max) of DAPI biological activity of palbociclib
arm group label: Treatment (Palbociclib)
arm group type: Experimental
description: Patients receive Palbociclib 50 mg/m^2 (starting dose with maximum dose of 100 mg) PO (or via NG-tube) once daily on Days 1-21; Intrathecal cytarabine (IT ARAC) age-based dosing on Day 1, Doxorubicin 60 mg/m^2 IV push or infusion over 1-15 min on Day 4; Prednisone or prednisolone 40 mg/m^2 PO divided BID or TID on days 4-31; Vincristine 1.5 mg/m^2 (maximum dose 2 mg) IV push or mini-bag per institutional policy on days 4, 11, 18, and 25; and Pegaspargase 2500 IU/m^2 IV over 1-2 hours on Days 5, and 18. If CNS3 leukemia is present, patients receive Intrathecal Triple Therapy (ITT) age-based dosing on days 4, 11, 18, and 25. Patients known to be CNS3 at study entry may receive ITT on Day 1 rather than IT ARAC. If CNS1 and 2 leukemia present, patient receive Methotrexate (IT MTX) age-based dosing on Days 18 and 32. Treatment will be given for one cycle, 32 days, in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Palbociclib
description: Given PO (or via NG- tube)
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Cytarabine
description: Given intrathecally (IT)
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Methotrexate
description: Given intrathecally (IT)
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Hydrocortisone
description: Given IT
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Doxorubicin
description: Given intravenously (IV)
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Prednisolone
description: Either prednisone or prednisolone is given PO
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Vincristine
description: Given IV
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Pegaspargase
description: Given IV
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Hydrocortisone
description: Given intrathecally (IT)
arm group label: Treatment (Palbociclib)
intervention type: Drug
intervention name: Prednisone
description: Either prednisone or prednisolone is given PO
arm group label: Treatment (Palbociclib)
criteria: 
gender: All
minimum age: 12 Months
maximum age: 31 Years
healthy volunteers: No
last name: Elizabeth Raetz, MD
role: Study Chair
affiliation: Children's Oncology Group
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Lymphoma, Non-Hodgkin
mesh term: Leukemia, T-Cell
mesh term: Cytarabine
mesh term: Prednisone
mesh term: Prednisolone
mesh term: Hydrocortisone
mesh term: Hydrocortisone 17-butyrate 21-propionate
mesh term: Hydrocortisone acetate
mesh term: Hydrocortisone hemisuccinate
mesh term: Doxorubicin
mesh term: Methotrexate
mesh term: Vincristine
mesh term: Palbociclib
mesh term: Pegaspargase
submitted: June 29, 2022
returned: May 25, 2023
submitted: June 29, 2023