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

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

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.

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