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.
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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