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

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