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Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma

NCT02202200

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Unknown status

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: D20121106
  • NCT ID: NCT02202200

Conditions

  • Melanoma BRAF V600E/K Mutated
  • CDNKN2A Loss Defined

Interventions

DrugSynonymsArms
PD- 0332991PD-0332991

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
PD-0332991Experimental
  • PD- 0332991

Eligibility Criteria

        Inclusion Criteria:

          -  Age > 18 years

          -  Stage IV or un-resectable stage III melanoma

          -  Presence of BRAF V600E/K mutation and CDNKN2A loss and expression of Rb using
             immunohistochemistry in a recent metastatic sample (< 6 months)

          -  A previous exposure to BRAF inhibitor or combination of BRAF and MEK inhibitors
             therapy is allowed unless it has been stopped more than 3 months before study
             enrolment(This will defined the two strata of the trial)

          -  No previous therapy by MEK inhibitor unless associated with BRAF inhibitors

          -  No previous therapy with the AKT/PI3K pathway inhibitor

          -  Patients should have a tumour available for repeated biopsies for pharmacodynamics
             evaluation

          -  Life expectancy of > 3 months

          -  ECOG performance status <2

          -  Signed informed consent

          -  Patient with health insurance coverage

          -  No patient under guardianship or curators

        Exclusion Criteria:

          -  Inadequate hepatic function defined as serum bilirubin>25 μmol/l, transaminases > 3.0
             times the upper limit of normal (ULN) or 5ULN in cases of liver metastases;

          -  Inadequate bone marrow function defined as absolute neutrophil count<1500/mcl,
             platelets<150000/mcl and haemoglobin<8g/dL

          -  Inadequate renal function with serum creatinine>2.0mg/dl) and /or creatinine
             clearance< 60 ml/min

          -  Untreated brain metastases : Patients with brain metastases will be eligible if they
             have completed treatment 1 months prior to the start of study medication, have
             discontinued corticosteroid treatment for these metastases for at least 5 days, and
             are neurologically asymptomatic

          -  Myocardial infarct or unstable angina within the past 6 months

          -  Concomitant take of drugs known to be strong inhibitor or inducers of CYP314

          -  HIV positive.

          -  Chemotherapy, immunotherapy within 4 weeks

          -  Drugs interfering with PD-0332991 and vemurafenib metabolism

          -  Malabsorption syndrome or other condition that would interfere with enteral absorption

          -  Congenital long QT syndrome or screening QTc > 470 msec

          -  Need for chronic corticosteroid therapy of ≥10 mg of prednisone per day
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Occurrence within the first 2 cycles of treatment of a DLT
Time Frame:42 Days
Safety Issue:
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.

Secondary Outcome Measures

Measure:Efficacy
Time Frame:42 Days
Safety Issue:
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
Safety Issue:
Description:survival
Measure:Tolerance
Time Frame:6 months
Safety Issue:
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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Assistance Publique - Hôpitaux de Paris

Trial Keywords

  • Melanoma
  • BRAF mutated

Last Updated

April 15, 2016