<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/NCT03238196</url>
  </required_header>
  <id_info>
    <org_study_id>VICC BRE 16126</org_study_id>
    <nct_id>NCT03238196</nct_id>
  </id_info>
  <brief_title>Fulvestrant, Palbociclib and Erdafitinib in ER+/HER2-/FGFR-amplified Metastatic Breast Cancer</brief_title>
  <official_title>A Phase Ib Trial of Fulvestrant, Palbociclib (CDK4/6 Inhibitor) and Erdafitinib (JNJ- 42756493,Pan-FGFR Tyrosine Kinase Inhibitor) in ER+/HER2-/FGFR-Amplified Metastatic Breast Cancer (MBC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt-Ingram Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt-Ingram Cancer Center</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>
      This is an open-label, multi-institution, phase Ib trial that evaluates the safety and&#xD;
      tolerability and preliminary anti-tumor activity of fulvestrant, palbociclib and erdafitinib&#xD;
      in patients with ER+/HER2-/FGFR-amplified metastatic breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objectives&#xD;
&#xD;
      To determine the safety and tolerability of fulvestrant, palbociclib and erdafitinib in&#xD;
      patients with ER+/HER2-/FGFR-amplified MBC.&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        -  To determine the anti-tumor effect of fulvestrant, palbociclib and erdafitinib in&#xD;
           patients with ER+/HER2-/FGFR-amplified MBC.&#xD;
&#xD;
        -  Pharmacokinetic assessments of erdafitinib&#xD;
&#xD;
      Correlative Objectives&#xD;
&#xD;
        -  To determine the therapeutic predictive role of FGFR1-4, CCND1-2, CDK4 and CDK6&#xD;
           amplifications, and RB1 and ESR1 mutations on clinical outcome&#xD;
&#xD;
        -  To determine if the FGFR1 amplification levels is an early surrogate of response&#xD;
&#xD;
        -  To determine if the cfDNA results at disease progression show new genomic alterations&#xD;
           potentially associated with resistance to CDK4/6 and FGFR inhibition&#xD;
&#xD;
        -  To determine pharmacodynamic biomarkers of FGFR inhibition&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 18, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Actual">April 30, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)</measure>
    <time_frame>From the time of randomization up to 4 weeks of treatment (cycle 1), for each patient</time_frame>
    <description>Number of participants with DLT in the first cycle for the determination of the MTD.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>Imaging studies will be performed every 8 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months</time_frame>
    <description>Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer will be assessed by measuring the interval (in months) between treatment initiation and disease progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>Imaging studies will be performed every 8 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months</time_frame>
    <description>Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer by measure the rate (%) of complete and partial responses seen in patients with measurable disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (CBR; Complete Response + Partial Response + Stable Disease Without Disease Progression at 6 Months)</measure>
    <time_frame>From the time of randomization up to 6 months for each patient</time_frame>
    <description>Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer by measure the rate (%) of complete and partial responses + stability of disease at 6 months seen in patients with measurable disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC)</measure>
    <time_frame>From the time of randomization up to 4 weeks of treatment for each patient</time_frame>
    <description>The area under the plasma concentration-time curve from time zero to the last measurable concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration)</measure>
    <time_frame>From the time of randomization up to 4 weeks of treatment for each patient</time_frame>
    <description>The maximum (peak) observed plasma drug concentration after oral dose administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Assessment of Erdafitinib - Tmax</measure>
    <time_frame>From the time of randomization up to 4 weeks of treatment for each patient</time_frame>
    <description>Time to reach maximum (Cmax) plasma drug concentration after oral dose administration (time)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Assessment of Erdafitinib - CL/F</measure>
    <time_frame>From the time of randomization up to 4 weeks of treatment for each patient</time_frame>
    <description>Apparent total body clearance of drug from the plasma after oral administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events [Tolerability]</measure>
    <time_frame>From date of randomization until 28 days post treatment discontinuation from any cause, assessed up to 48 months</time_frame>
    <description>Assessment of adverse events throughout the study</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Serial Measurements of Serum Phosphate, Calcium, Vitamin D, Parathyroid Hormone (PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4</measure>
    <time_frame>During the first 8 weeks of treatment (days 1, 8, 15, 22 of cycle 1 and days 1 and 15 of cycle 2)</time_frame>
    <description>Serial measurements of serum phosphate, calcium, vitamin D, PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4 will be assessed to detect on target effects of FGFR inhibition (pharmacodynamic assessments).</description>
  </other_outcome>
  <other_outcome>
    <measure>FGFR1 Amplification Levels by FISH and cfDNA</measure>
    <time_frame>At study entry (baseline)</time_frame>
    <description>The level of FGFR1 amplification assessed in tumors by fluorescence in situ hybridization (FISH) will be correlated with clinical outcome.</description>
  </other_outcome>
  <other_outcome>
    <measure>Next Generation Sequencing</measure>
    <time_frame>At study entry (baseline)</time_frame>
    <description>Will determine if other genomic alterations other than FGFR amplifications correlate with clinical outcome.</description>
  </other_outcome>
  <other_outcome>
    <measure>Plasma Cell-free Deoxyribonucleic Acid (cfDNA)</measure>
    <time_frame>At study entry (baseline), at 4 weeks, and at study discontinuation from disease progression (for each patient), assessed up to 48 months.</time_frame>
    <description>Will determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to CDK4/6 and FGFR inhibition.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Metastatic Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fulvestrant - injection into muscle 1 time per month&#xD;
Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)&#xD;
Erdafitinib tablet taken by mouth 1 time per day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fulvestrant - injection into muscle 1 time per month&#xD;
Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)&#xD;
Erdafitinib tablet taken by mouth 1 time per day</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Erdafitinib</intervention_name>
    <description>4mg - 8mg</description>
    <arm_group_label>Escalation</arm_group_label>
    <arm_group_label>Expansion</arm_group_label>
    <other_name>JNJ-42756493</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Palbociclib</intervention_name>
    <description>125 mg</description>
    <arm_group_label>Escalation</arm_group_label>
    <arm_group_label>Expansion</arm_group_label>
    <other_name>Ibrance</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <description>500 mg</description>
    <arm_group_label>Escalation</arm_group_label>
    <arm_group_label>Expansion</arm_group_label>
    <other_name>Faslodex</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must be able to swallow and retain oral medication&#xD;
&#xD;
          -  Patients must be ≥ 18 years of age&#xD;
&#xD;
          -  Female patients of no childbearing potential must be post-menopausal. Postmenopausal&#xD;
             female subjects should be defined prior to protocol enrollment by any of the&#xD;
             following:&#xD;
&#xD;
          -  Participants at least 60 years of age; OR&#xD;
&#xD;
          -  Participants under 60 years of age and naturally (spontaneous, no alternative&#xD;
             pathologic or physiological cause) amenorrhea for at least 12 months; OR&#xD;
&#xD;
          -  Medical ovarian failure confirmed by follicle-stimulating hormone (FSH) and estradiol&#xD;
             levels in the post menopausal range per local institutional normal range; OR&#xD;
&#xD;
          -  Prior bilateral oophorectomy; OR&#xD;
&#xD;
          -  Prior radiation castration with amenorrhea for at least 6 months; OR&#xD;
&#xD;
          -  Treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (such as&#xD;
             goserelin acetate or leuprolide acetate) is permitted for induction of ovarian&#xD;
             suppression as long as it has been initiated at least 28 days prior to study&#xD;
             enrollment&#xD;
&#xD;
          -  Patients must have ECOG performance status 0 - 1&#xD;
&#xD;
          -  Patients must have clinical stage IV or inoperable locoregional recurrent invasive&#xD;
             mammary carcinoma that is:&#xD;
&#xD;
          -  ER+ and/or PgR+ (≥ 1% positive stained cells) by immunohistochemistry (IHC)&#xD;
&#xD;
          -  HER2-negative (by IHC or FISH, per ASCO guidelines)&#xD;
&#xD;
          -  FGFR1 - 4 amplified&#xD;
&#xD;
          -  Patients must have evaluable (may have either measurable or non-measurable) disease&#xD;
&#xD;
          -  Patients must have available tissue for FGFR determination&#xD;
&#xD;
          -  Patients must have had at least one line of therapy in the metastatic setting&#xD;
&#xD;
          -  Current use of any of the drugs listed on the Cautionary Concomitant Med list has to&#xD;
             be approved by the Study Chair&#xD;
&#xD;
          -  Patients must have adequate hematologic, hepatic and renal function. All laboratory&#xD;
             tests must be obtained within 2 weeks from study drug initiation. These include:&#xD;
&#xD;
          -  ANC ≥ 1,500/mm3&#xD;
&#xD;
          -  Platelet count ≥ 100,000/mm3&#xD;
&#xD;
          -  HgB ≥ 9.0 g/dL&#xD;
&#xD;
          -  Creatinine clearance ≥ 40 mL/min/1.73 m2&#xD;
&#xD;
          -  SGOT, SGPT ≤ 2.5 x ULN if no liver metastasis present; SGOT, SGPT ≤ 4 x ULN if liver&#xD;
             metastasis present&#xD;
&#xD;
          -  Albumin ≥ 2.0 g/dL&#xD;
&#xD;
          -  Total serum bilirubin ≤ 1.5 x ULN (≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN if known&#xD;
             Gilbert's syndrome)&#xD;
&#xD;
          -  Potassium within institutional normal limits&#xD;
&#xD;
          -  Phosphorus ≤ institutional upper limit of normal&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior use of an FGFR inhibitor&#xD;
&#xD;
          -  More than 2 lines of chemotherapy in the metastatic setting. No limit on endocrine&#xD;
             therapy lines. Prior exposure to CDK4/6 inhibitor acceptable.&#xD;
&#xD;
          -  Radiation therapy ≤ 2 weeks prior to study entry. Patients who have received prior&#xD;
             radiotherapy must have recovered from toxicity (≤ grade 1) induced by this treatment&#xD;
             (except for alopecia)&#xD;
&#xD;
          -  Prior cancer therapy (except for endocrine therapy) must have been discontinued for 1&#xD;
             week prior to initiation of study drugs&#xD;
&#xD;
          -  Concurrent anti-cancer therapy other than the ones specified in the protocol is not&#xD;
             permitted during study participation. Bisphosphonates or denosumab are allowed&#xD;
&#xD;
          -  Major surgery within 4 weeks of enrollment&#xD;
&#xD;
          -  Herbal preparations are not allowed throughout the study, and should be discontinued&#xD;
             14 days prior to initiation of study treatment&#xD;
&#xD;
          -  Any corneal or retinal abnormality likely to increase the risk of eye toxicity, such&#xD;
             as:&#xD;
&#xD;
          -  Current corneal pathology such as keratitis, keratoconjunctivitis, keratopathy,&#xD;
             corneal abrasion, inflammation or ulceration&#xD;
&#xD;
          -  Uncontrolled glaucoma despite standard of care therapy&#xD;
&#xD;
          -  Diabetic retinopathy with macular edema&#xD;
&#xD;
          -  Known active wet, age-related macular degeneration (AMD)&#xD;
&#xD;
          -  Known central serous retinopathy (CSR) or retinal vascular occlusion (RVO)&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to:&#xD;
&#xD;
          -  Malabsorption syndrome significantly affecting gastrointestinal function&#xD;
&#xD;
          -  Ongoing or active infection requiring antibiotics/antivirals&#xD;
&#xD;
          -  Impairment of lung function (COPD &gt; grade 2, lung conditions requiring oxygen therapy)&#xD;
&#xD;
          -  Symptomatic congestive heart failure&#xD;
&#xD;
          -  Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6&#xD;
             months&#xD;
&#xD;
          -  Clinically significant cardiac arrhythmia (multifocal premature ventricular&#xD;
             contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or&#xD;
             requires treatment [National Cancer Institute -Common Terminology Criteria for Adverse&#xD;
             Events, Version 4.03, grade 3]&#xD;
&#xD;
          -  QTcF ≥ 480 msec on screening EKG&#xD;
&#xD;
          -  Known history of clinically significant QT/QTc prolongation or Torsades de&#xD;
             Pointes(TdP)&#xD;
&#xD;
          -  ST depression or elevation of ≥ 1.5 mm in 2 or more leads&#xD;
&#xD;
          -  Diarrhea of any cause ≥ CTCAE grade 2 that does not resolve within a few days when&#xD;
             adequately treated with anti-diarrhea medications&#xD;
&#xD;
          -  Psychiatric illness/social situations that would compromise patient safety or limit&#xD;
             compliance with study requirements including maintenance of a compliance/pill diary&#xD;
&#xD;
          -  Symptomatic brain metastases (patients with a history of brain metastases must be&#xD;
             clinically stable for more than 4 weeks from completion of radiation treatment and be&#xD;
             off steroids)&#xD;
&#xD;
          -  Known history of chronic liver or chronic renal failure&#xD;
&#xD;
          -  Poor wound healing capacity&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Brent Rexer, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt-Ingram Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</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>University of Pittsburgh Medical Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baptist Memorial Hospital MEMPHIS</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38120</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt-Ingram Cancer Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Southwestern Simmons Comprehensive Cancer Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75235</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.vicc.org/ct/protocols.php?cancer-type=Breast</url>
    <description>Clinical Trials Webpage - Vanderbilt-Ingram Cancer Center</description>
  </link>
  <link>
    <url>https://www.mycancergenome.org/content/disease/breast-cancer/fgfr1/</url>
    <description>Mycancergenome - FGFR1 Webpage</description>
  </link>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>July 24, 2017</study_first_submitted>
  <study_first_submitted_qc>August 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <results_first_submitted>August 13, 2022</results_first_submitted>
  <results_first_submitted_qc>January 21, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">February 16, 2023</results_first_posted>
  <last_update_submitted>January 21, 2023</last_update_submitted>
  <last_update_submitted_qc>January 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt-Ingram Cancer Center</investigator_affiliation>
    <investigator_full_name>Brent Rexer</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>FGFR inhibitor</keyword>
  <keyword>ER+ metastatic breast cancer</keyword>
  <keyword>CDK4/6 inhibitor</keyword>
  <keyword>Endocrine therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fulvestrant</mesh_term>
    <mesh_term>Palbociclib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <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>November 4, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/96/NCT03238196/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited to this trial from August 2017 to January 2021 at five medical centers.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Expansion</title>
          <description>Fulvestrant - injection into muscle 1 time per month&#xD;
Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)&#xD;
Erdafitinib tablet taken by mouth 1 time per day&#xD;
Erdafitinib: 6 mg&#xD;
Palbociclib: 125 mg&#xD;
Fulvestrant: 500 mg</description>
        </group>
        <group group_id="P2">
          <title>Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation)</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 5mg.</description>
        </group>
        <group group_id="P3">
          <title>Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation)</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 6mg.</description>
        </group>
        <group group_id="P4">
          <title>Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation)</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="6"/>
                <participants group_id="P4" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="6"/>
                <participants group_id="P4" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Disease progression</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Still on treatment</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Expansion</title>
          <description>Fulvestrant - injection into muscle 1 time per month&#xD;
Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)&#xD;
Erdafitinib tablet taken by mouth 1 time per day&#xD;
Erdafitinib: 6mg&#xD;
Palbociclib: 125 mg&#xD;
Fulvestrant: 500 mg</description>
        </group>
        <group group_id="B2">
          <title>Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation)</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 5mg.</description>
        </group>
        <group group_id="B3">
          <title>Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation)</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 6mg.</description>
        </group>
        <group group_id="B4">
          <title>Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation)</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg.</description>
        </group>
        <group group_id="B5">
          <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="22"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="6"/>
            <count group_id="B4" value="4"/>
            <count group_id="B5" value="35"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</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_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="7"/>
                  </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="22"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</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_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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="13"/>
                  </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="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" 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_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="24"/>
                  </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="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="6"/>
                  </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="22"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)</title>
        <description>Number of participants with DLT in the first cycle for the determination of the MTD.</description>
        <time_frame>From the time of randomization up to 4 weeks of treatment (cycle 1), for each patient</time_frame>
        <population>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib in Escalation phase.</population>
        <group_list>
          <group group_id="O1">
            <title>Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation)</title>
            <description>Participants take Erdafitinib 5mg orally once a day in 28-day cycle, with Fulvestrant 500mg IM once every 28 days (for cycle 1 it is administered at day 15) and Palbociclib 125mg daily for 21 days out of a 28-day cycle.</description>
          </group>
          <group group_id="O2">
            <title>Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation)</title>
            <description>Participants take Erdafitinib 6mg orally once a day in 28-day cycle, with Fulvestrant 500mg IM once every 28 days (for cycle 1 it is administered at day 15) and Palbociclib 125mg daily for 21 days out of a 28-day cycle.</description>
          </group>
          <group group_id="O3">
            <title>Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation)</title>
            <description>Participants take Erdafitinib 8mg orally once a day in 28-day cycle, with Fulvestrant 500mg IM once every 28 days (for cycle 1 it is administered at day 15) and Palbociclib 125mg daily for 21 days out of a 28-day cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)</title>
          <description>Number of participants with DLT in the first cycle for the determination of the MTD.</description>
          <population>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib in Escalation phase.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="4"/>
              </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="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival</title>
        <description>Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer will be assessed by measuring the interval (in months) between treatment initiation and disease progression.</description>
        <time_frame>Imaging studies will be performed every 8 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate</title>
        <description>Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer by measure the rate (%) of complete and partial responses seen in patients with measurable disease</description>
        <time_frame>Imaging studies will be performed every 8 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate (CBR; Complete Response + Partial Response + Stable Disease Without Disease Progression at 6 Months)</title>
        <description>Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer by measure the rate (%) of complete and partial responses + stability of disease at 6 months seen in patients with measurable disease</description>
        <time_frame>From the time of randomization up to 6 months for each patient</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC)</title>
        <description>The area under the plasma concentration-time curve from time zero to the last measurable concentration</description>
        <time_frame>From the time of randomization up to 4 weeks of treatment for each patient</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration)</title>
        <description>The maximum (peak) observed plasma drug concentration after oral dose administration</description>
        <time_frame>From the time of randomization up to 4 weeks of treatment for each patient</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Assessment of Erdafitinib - Tmax</title>
        <description>Time to reach maximum (Cmax) plasma drug concentration after oral dose administration (time)</description>
        <time_frame>From the time of randomization up to 4 weeks of treatment for each patient</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Assessment of Erdafitinib - CL/F</title>
        <description>Apparent total body clearance of drug from the plasma after oral administration</description>
        <time_frame>From the time of randomization up to 4 weeks of treatment for each patient</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Treatment-Emergent Adverse Events [Tolerability]</title>
        <description>Assessment of adverse events throughout the study</description>
        <time_frame>From date of randomization until 28 days post treatment discontinuation from any cause, assessed up to 48 months</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Serial Measurements of Serum Phosphate, Calcium, Vitamin D, Parathyroid Hormone (PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4</title>
        <description>Serial measurements of serum phosphate, calcium, vitamin D, PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4 will be assessed to detect on target effects of FGFR inhibition (pharmacodynamic assessments).</description>
        <time_frame>During the first 8 weeks of treatment (days 1, 8, 15, 22 of cycle 1 and days 1 and 15 of cycle 2)</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>FGFR1 Amplification Levels by FISH and cfDNA</title>
        <description>The level of FGFR1 amplification assessed in tumors by fluorescence in situ hybridization (FISH) will be correlated with clinical outcome.</description>
        <time_frame>At study entry (baseline)</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Next Generation Sequencing</title>
        <description>Will determine if other genomic alterations other than FGFR amplifications correlate with clinical outcome.</description>
        <time_frame>At study entry (baseline)</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Plasma Cell-free Deoxyribonucleic Acid (cfDNA)</title>
        <description>Will determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to CDK4/6 and FGFR inhibition.</description>
        <time_frame>At study entry (baseline), at 4 weeks, and at study discontinuation from disease progression (for each patient), assessed up to 48 months.</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Time frame for Serious adverse events and Other (Not Including Serious) Adverse Events: From time of informed consent signature to within 30 days of the last documented dose of study medication up to approximately 36 months.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 5mg.</description>
        </group>
        <group group_id="E2">
          <title>Expansion</title>
          <description>Fulvestrant - injection into muscle 1 time per month&#xD;
Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)&#xD;
Erdafitinib tablet taken by mouth 1 time per day&#xD;
Erdafitinib: 6mg&#xD;
Palbociclib: 125 mg&#xD;
Fulvestrant: 500 mg</description>
        </group>
        <group group_id="E3">
          <title>Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 6mg.</description>
        </group>
        <group group_id="E4">
          <title>Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg</title>
          <description>Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE 4.03</default_vocab>
        <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="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Dry eye</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Lung infection</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase 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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase 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="22"/>
                <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"/>
              </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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle weakness</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary embolism</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="22"/>
                <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"/>
              </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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Deep Vein Thrombosis</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE 4.03</default_vocab>
        <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="22" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="4"/>
              </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="11" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="11" subjects_affected="7" subjects_at_risk="22"/>
                <counts group_id="E3" events="6" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Dry eyes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="10" subjects_affected="9" subjects_at_risk="22"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Blurred vision</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oral mucositis</sub_title>
                <counts group_id="E1" events="10" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="22" subjects_affected="13" subjects_at_risk="22"/>
                <counts group_id="E3" events="11" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E4" events="8" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="23" subjects_affected="14" subjects_at_risk="22"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="14" subjects_affected="12" subjects_at_risk="22"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="20" subjects_affected="10" subjects_at_risk="22"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="22"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="4"/>
              </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="3" subjects_affected="3" subjects_at_risk="22"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Dyspesia</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="22"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Dental caries</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Esophagitis</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Cheilitis</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Rectal hemorrhage</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="22"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Toothache</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="19" subjects_affected="11" subjects_at_risk="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="24" subjects_affected="12" subjects_at_risk="22"/>
                <counts group_id="E3" events="8" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Limb edema</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Fever</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest 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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</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="22"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="35" subjects_affected="15" subjects_at_risk="22"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="11" subjects_affected="9" subjects_at_risk="22"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="6" subjects_affected="3" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="3" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglyemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="5" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </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="3" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</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="22"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="4"/>
              </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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</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="22"/>
                <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"/>
              </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="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Back 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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Flank 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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Myalgia</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Pain 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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="13" subjects_affected="12" subjects_at_risk="22"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="4"/>
              </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="7" subjects_affected="4" subjects_at_risk="22"/>
                <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"/>
              </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="3" subjects_affected="3" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Syncope</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E4" events="3" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary tract pain</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Hematuria</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="7" subjects_affected="5" subjects_at_risk="22"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="22"/>
                <counts group_id="E3" events="11" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Cough</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Dyspnea</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="22"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Nasal congestion</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="20" subjects_affected="12" subjects_at_risk="22"/>
                <counts group_id="E3" events="6" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="13" subjects_affected="11" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="22"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Nail loss</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Nail discoloration</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Nail ridging</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Pruritus</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="10" subjects_affected="2" subjects_at_risk="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Bullous dermatitis</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Rash maculo-paular</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="22"/>
                <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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</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="22"/>
                <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"/>
              </event>
              <event>
                <sub_title>Hyperparathyroidism</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="22"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Teresa Melton</name_or_title>
      <organization>Vanderbilt-Ingram Cancer Center</organization>
      <phone>615-936-7423</phone>
      <email>teresa.melton@vumc.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/NCT03238196
org study id: VICC BRE 16126
nct id: NCT03238196
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is an open-label, multi-institution, phase Ib trial that evaluates the safety and
      tolerability and preliminary anti-tumor activity of fulvestrant, palbociclib and erdafitinib
      in patients with ER+/HER2-/FGFR-amplified metastatic breast cancer.
Primary Objectives

      To determine the safety and tolerability of fulvestrant, palbociclib and erdafitinib in
      patients with ER+/HER2-/FGFR-amplified MBC.

      Secondary Objectives

        -  To determine the anti-tumor effect of fulvestrant, palbociclib and erdafitinib in
           patients with ER+/HER2-/FGFR-amplified MBC.

        -  Pharmacokinetic assessments of erdafitinib

      Correlative Objectives

        -  To determine the therapeutic predictive role of FGFR1-4, CCND1-2, CDK4 and CDK6
           amplifications, and RB1 and ESR1 mutations on clinical outcome

        -  To determine if the FGFR1 amplification levels is an early surrogate of response

        -  To determine if the cfDNA results at disease progression show new genomic alterations
           potentially associated with resistance to CDK4/6 and FGFR inhibition

        -  To determine pharmacodynamic biomarkers of FGFR inhibition
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
time frame: From the time of randomization up to 4 weeks of treatment (cycle 1), for each patient
description: Number of participants with DLT in the first cycle for the determination of the MTD.
measure: Progression-free Survival
time frame: Imaging studies will be performed every 8 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
description: Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer will be assessed by measuring the interval (in months) between treatment initiation and disease progression.
measure: Overall Response Rate
time frame: Imaging studies will be performed every 8 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
description: Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer by measure the rate (%) of complete and partial responses seen in patients with measurable disease
measure: Clinical Benefit Rate (CBR; Complete Response + Partial Response + Stable Disease Without Disease Progression at 6 Months)
time frame: From the time of randomization up to 6 months for each patient
description: Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer by measure the rate (%) of complete and partial responses + stability of disease at 6 months seen in patients with measurable disease
measure: Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC)
time frame: From the time of randomization up to 4 weeks of treatment for each patient
description: The area under the plasma concentration-time curve from time zero to the last measurable concentration
measure: Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration)
time frame: From the time of randomization up to 4 weeks of treatment for each patient
description: The maximum (peak) observed plasma drug concentration after oral dose administration
measure: Pharmacokinetic Assessment of Erdafitinib - Tmax
time frame: From the time of randomization up to 4 weeks of treatment for each patient
description: Time to reach maximum (Cmax) plasma drug concentration after oral dose administration (time)
measure: Pharmacokinetic Assessment of Erdafitinib - CL/F
time frame: From the time of randomization up to 4 weeks of treatment for each patient
description: Apparent total body clearance of drug from the plasma after oral administration
measure: Incidence of Treatment-Emergent Adverse Events [Tolerability]
time frame: From date of randomization until 28 days post treatment discontinuation from any cause, assessed up to 48 months
description: Assessment of adverse events throughout the study
measure: Serial Measurements of Serum Phosphate, Calcium, Vitamin D, Parathyroid Hormone (PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4
time frame: During the first 8 weeks of treatment (days 1, 8, 15, 22 of cycle 1 and days 1 and 15 of cycle 2)
description: Serial measurements of serum phosphate, calcium, vitamin D, PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4 will be assessed to detect on target effects of FGFR inhibition (pharmacodynamic assessments).
measure: FGFR1 Amplification Levels by FISH and cfDNA
time frame: At study entry (baseline)
description: The level of FGFR1 amplification assessed in tumors by fluorescence in situ hybridization (FISH) will be correlated with clinical outcome.
measure: Next Generation Sequencing
time frame: At study entry (baseline)
description: Will determine if other genomic alterations other than FGFR amplifications correlate with clinical outcome.
measure: Plasma Cell-free Deoxyribonucleic Acid (cfDNA)
time frame: At study entry (baseline), at 4 weeks, and at study discontinuation from disease progression (for each patient), assessed up to 48 months.
description: Will determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to CDK4/6 and FGFR inhibition.
arm group label: Escalation
arm group type: Experimental
description: Fulvestrant - injection into muscle 1 time per month
Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)
Erdafitinib tablet taken by mouth 1 time per day
arm group label: Expansion
arm group type: Experimental
description: Fulvestrant - injection into muscle 1 time per month
Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)
Erdafitinib tablet taken by mouth 1 time per day
intervention type: Drug
intervention name: Erdafitinib
description: 4mg - 8mg
arm group label: Escalation
arm group label: Expansion
other name: JNJ-42756493
intervention type: Drug
intervention name: Palbociclib
description: 125 mg
arm group label: Escalation
arm group label: Expansion
other name: Ibrance
intervention type: Drug
intervention name: Fulvestrant
description: 500 mg
arm group label: Escalation
arm group label: Expansion
other name: Faslodex
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Brent Rexer, MD, PhD
role: Principal Investigator
affiliation: Vanderbilt-Ingram Cancer Center
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://www.vicc.org/ct/protocols.php?cancer-type=Breast
description: Clinical Trials Webpage - Vanderbilt-Ingram Cancer Center
url: https://www.mycancergenome.org/content/disease/breast-cancer/fgfr1/
description: Mycancergenome - FGFR1 Webpage
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt-Ingram Cancer Center
investigator full name: Brent Rexer
investigator title: Principal Investigator
mesh term: Breast Neoplasms
mesh term: Fulvestrant
mesh term: Palbociclib
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 