Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma (OPTIMUM)
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|ClinicalTrials.gov Identifier: NCT02202200|
Recruitment Status : Unknown
Verified April 2016 by Assistance Publique - Hôpitaux de Paris.
Recruitment status was: Recruiting
First Posted : July 28, 2014
Last Update Posted : April 18, 2016
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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.
|Condition or disease||Intervention/treatment||Phase|
|Melanoma BRAF V600E/K Mutated CDNKN2A Loss Defined||Drug: PD- 0332991||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Study Start Date :||May 2014|
|Estimated Primary Completion Date :||November 2016|
|Estimated Study Completion Date :||August 2018|
Drug: PD- 0332991
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
- Occurrence within the first 2 cycles of treatment of a DLT [ Time Frame: 42 Days ]
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.
- Efficacy [ Time Frame: 42 Days ]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.
- 1 year survival rate [ Time Frame: 1 year ]survival
- Tolerance [ Time Frame: 6 months ]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.
- Pharmacodynamic [ Time Frame: 42 days ]
- Changes from baseline of ANC and platelet levels
- Efficiency on the cell-cycle machinery and proliferation (tumor sample)
- Induction of senescence: will be evaluated using the senescence β-Galactosidase assay (Cell Signaling Technology)
- Induction of apoptosis: will be performed using TUNEL staining with the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Millipore).
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02202200
|Paris, France, 75010|
|Contact: Celeste Lebbe, MDPHD +33 1 42 49 49 49 firstname.lastname@example.org|
|Principal Investigator: celeste lebbe, MD-PHD|
|Responsible Party:||Assistance Publique - Hôpitaux de Paris|
|Other Study ID Numbers:||
|First Posted:||July 28, 2014 Key Record Dates|
|Last Update Posted:||April 18, 2016|
|Last Verified:||April 2016|
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Protein Kinase Inhibitors
Molecular Mechanisms of Pharmacological Action