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

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Melanoma BRAF V600E/K Mutated, CDNKN2A Loss Defined

Intervention / Treatment
-----------------
* Drug: PD- 0332991


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD-0332991<br> | Drug: PD- 0332991<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence within the first 2 cycles of treatment of a DLT | 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. | 42 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy | 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. | 42 Days | 
| 1 year survival rate | survival | 1 year | 
| Tolerance | 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. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Melanoma, BRAF mutated