<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/NCT02202200</url>
  </required_header>
  <id_info>
    <org_study_id>D20121106</org_study_id>
    <nct_id>NCT02202200</nct_id>
  </id_info>
  <brief_title>Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma</brief_title>
  <acronym>OPTIMUM</acronym>
  <official_title>An Open Label Multicenter, Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma With BRAFv600 Mutated and CDKN2A Loss and Expression of Rb and Treated by Vemurafenib</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <brief_summary>
    <textblock>
      An open label multicentre, phase I-II study with tumour molecular pharmacodynamics (MPD)&#xD;
      evaluation and pharmacokinetics of PD-0332991 added to vemurafenib in patients suffering&#xD;
      metastatic melanoma with BR.&#xD;
&#xD;
      The main objective is to establish the Maximum Tolerated Dose (MTD) of PD-0332991 when added&#xD;
      to standard vemurafenib therapy (960 mg BID). The estimated MTD is defined as the dose of&#xD;
      PD-0332991 combined with vemurafenib that will be associated with a prespecified proportion&#xD;
      of patients experiencing a Dose-Limiting Toxicity (DLT), ie, 1/3.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>May 2014</start_date>
  <completion_date type="Anticipated">August 2018</completion_date>
  <primary_completion_date type="Anticipated">November 2016</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence within the first 2 cycles of treatment of a DLT</measure>
    <time_frame>42 Days</time_frame>
    <description>DLTs, serious adverse events and adverse events leading to treatment discontinuations will be determined as follows:&#xD;
Any grade 3 or more non-haematological toxicity excluding:&#xD;
Grade 3 asymptomatic increase in liver function tests (AST, ALT, ALP) reversible within 7 days for subjects without liver involvement, or grade 4 for subjects with liver involvement.&#xD;
Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. 5HT3 antagonists and corticosteroids).&#xD;
Grade 3 diarrhoeas if encountered despite adequate and optimal anti diarrhoea therapy.&#xD;
Confirmed grade 3 QTc prolongation (QTc &gt;500 msec) that persists after correction of other possible causes such as electrolyte imbalance&#xD;
Grade 4 hyperlipidemia if it is encountered despite adequate and optimal therapy.&#xD;
Any grade 4 neutropenia of &gt; 5 days duration, or febrile neutropenia lasting for more than 1 day.&#xD;
Grade 4 thrombocytopenia &gt; 1 day, or grade 3 with bleeding.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>42 Days</time_frame>
    <description>Occurrence of clinical benefit (defined as Complete Response (CR), Partial Response (PR) or stable disease (SD)) and progressive disease based on the best overall response which depends on the tumour evaluations assessed using RECIST at the end of each 2 cycles.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>1 year survival rate</measure>
    <time_frame>1 year</time_frame>
    <description>survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tolerance</measure>
    <time_frame>6 months</time_frame>
    <description>Occurrence of clinically significant changes in a laboratory parameter and/or vital signs judged to be related to the trial medication within the first 6 months.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Pharmacodynamic</measure>
    <time_frame>42 days</time_frame>
    <description>Changes from baseline of ANC and platelet levels&#xD;
Efficiency on the cell-cycle machinery and proliferation (tumor sample)&#xD;
Induction of senescence: will be evaluated using the senescence β-Galactosidase assay (Cell Signaling Technology)&#xD;
Induction of apoptosis: will be performed using TUNEL staining with the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Millipore).</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Melanoma BRAF V600E/K Mutated</condition>
  <condition>CDNKN2A Loss Defined</condition>
  <arm_group>
    <arm_group_label>PD-0332991</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PD- 0332991</intervention_name>
    <description>PD-0332991 Inhibitor of cyclin-dependant kinase (CDK) 8 schedules will be evaluated PD-0332991 PO QD either at 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg and 200 mg&#xD;
All patients will receive vemurafenib as background therapy ,bid at 720mg bid for the first group (during the first 2 cycle then 960 mg bid if good tolerance) and 960mg bid for all other patients</description>
    <arm_group_label>PD-0332991</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  Stage IV or un-resectable stage III melanoma&#xD;
&#xD;
          -  Presence of BRAF V600E/K mutation and CDNKN2A loss and expression of Rb using&#xD;
             immunohistochemistry in a recent metastatic sample (&lt; 6 months)&#xD;
&#xD;
          -  A previous exposure to BRAF inhibitor or combination of BRAF and MEK inhibitors&#xD;
             therapy is allowed unless it has been stopped more than 3 months before study&#xD;
             enrolment(This will defined the two strata of the trial)&#xD;
&#xD;
          -  No previous therapy by MEK inhibitor unless associated with BRAF inhibitors&#xD;
&#xD;
          -  No previous therapy with the AKT/PI3K pathway inhibitor&#xD;
&#xD;
          -  Patients should have a tumour available for repeated biopsies for pharmacodynamics&#xD;
             evaluation&#xD;
&#xD;
          -  Life expectancy of &gt; 3 months&#xD;
&#xD;
          -  ECOG performance status &lt;2&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  Patient with health insurance coverage&#xD;
&#xD;
          -  No patient under guardianship or curators&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inadequate hepatic function defined as serum bilirubin&gt;25 μmol/l, transaminases &gt; 3.0&#xD;
             times the upper limit of normal (ULN) or 5ULN in cases of liver metastases;&#xD;
&#xD;
          -  Inadequate bone marrow function defined as absolute neutrophil count&lt;1500/mcl,&#xD;
             platelets&lt;150000/mcl and haemoglobin&lt;8g/dL&#xD;
&#xD;
          -  Inadequate renal function with serum creatinine&gt;2.0mg/dl) and /or creatinine&#xD;
             clearance&lt; 60 ml/min&#xD;
&#xD;
          -  Untreated brain metastases : Patients with brain metastases will be eligible if they&#xD;
             have completed treatment 1 months prior to the start of study medication, have&#xD;
             discontinued corticosteroid treatment for these metastases for at least 5 days, and&#xD;
             are neurologically asymptomatic&#xD;
&#xD;
          -  Myocardial infarct or unstable angina within the past 6 months&#xD;
&#xD;
          -  Concomitant take of drugs known to be strong inhibitor or inducers of CYP314&#xD;
&#xD;
          -  HIV positive.&#xD;
&#xD;
          -  Chemotherapy, immunotherapy within 4 weeks&#xD;
&#xD;
          -  Drugs interfering with PD-0332991 and vemurafenib metabolism&#xD;
&#xD;
          -  Malabsorption syndrome or other condition that would interfere with enteral absorption&#xD;
&#xD;
          -  Congenital long QT syndrome or screening QTc &gt; 470 msec&#xD;
&#xD;
          -  Need for chronic corticosteroid therapy of ≥10 mg of prednisone per day&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Saint-Louis Hospital</name>
      <address>
        <city>Paris</city>
        <zip>75010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Celeste Lebbe, MDPHD</last_name>
      <phone>+33 1 42 49 49 49</phone>
      <email>celeste.lebbe@sls.aphp.fr</email>
    </contact>
    <investigator>
      <last_name>celeste lebbe, MD-PHD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>April 2016</verification_date>
  <study_first_submitted>July 25, 2014</study_first_submitted>
  <study_first_submitted_qc>July 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 28, 2014</study_first_posted>
  <last_update_submitted>April 15, 2016</last_update_submitted>
  <last_update_submitted_qc>April 15, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 18, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Melanoma</keyword>
  <keyword>BRAF mutated</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Palbociclib</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02202200
org study id: D20121106
nct id: NCT02202200
lead sponsor: 
An open label multicentre, phase I-II study with tumour molecular pharmacodynamics (MPD)
      evaluation and pharmacokinetics of PD-0332991 added to vemurafenib in patients suffering
      metastatic melanoma with BR.

      The main objective is to establish the Maximum Tolerated Dose (MTD) of PD-0332991 when added
      to standard vemurafenib therapy (960 mg BID). The estimated MTD is defined as the dose of
      PD-0332991 combined with vemurafenib that will be associated with a prespecified proportion
      of patients experiencing a Dose-Limiting Toxicity (DLT), ie, 1/3.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence within the first 2 cycles of treatment of a DLT
time frame: 42 Days
description: DLTs, serious adverse events and adverse events leading to treatment discontinuations will be determined as follows:
Any grade 3 or more non-haematological toxicity excluding:
Grade 3 asymptomatic increase in liver function tests (AST, ALT, ALP) reversible within 7 days for subjects without liver involvement, or grade 4 for subjects with liver involvement.
Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. 5HT3 antagonists and corticosteroids).
Grade 3 diarrhoeas if encountered despite adequate and optimal anti diarrhoea therapy.
Confirmed grade 3 QTc prolongation (QTc >500 msec) that persists after correction of other possible causes such as electrolyte imbalance
Grade 4 hyperlipidemia if it is encountered despite adequate and optimal therapy.
Any grade 4 neutropenia of > 5 days duration, or febrile neutropenia lasting for more than 1 day.
Grade 4 thrombocytopenia > 1 day, or grade 3 with bleeding.
measure: Efficacy
time frame: 42 Days
description: Occurrence of clinical benefit (defined as Complete Response (CR), Partial Response (PR) or stable disease (SD)) and progressive disease based on the best overall response which depends on the tumour evaluations assessed using RECIST at the end of each 2 cycles.
measure: 1 year survival rate
time frame: 1 year
description: survival
measure: Tolerance
time frame: 6 months
description: Occurrence of clinically significant changes in a laboratory parameter and/or vital signs judged to be related to the trial medication within the first 6 months.
measure: Pharmacodynamic
time frame: 42 days
description: Changes from baseline of ANC and platelet levels
Efficiency on the cell-cycle machinery and proliferation (tumor sample)
Induction of senescence: will be evaluated using the senescence β-Galactosidase assay (Cell Signaling Technology)
Induction of apoptosis: will be performed using TUNEL staining with the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Millipore).
arm group label: PD-0332991
arm group type: Experimental
intervention type: Drug
intervention name: PD- 0332991
description: PD-0332991 Inhibitor of cyclin-dependant kinase (CDK) 8 schedules will be evaluated PD-0332991 PO QD either at 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg and 200 mg
All patients will receive vemurafenib as background therapy ,bid at 720mg bid for the first group (during the first 2 cycle then 960 mg bid if good tolerance) and 960mg bid for all other patients
arm group label: PD-0332991
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
status: Recruiting
contact: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Palbociclib