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
试验速览
- 阶段
- 1 期
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Occurrence within the first 2 cycles of treatment of a DLT
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
PD-0332991
干预措施: PD- 0332991 (Drug)
结局指标
主要结局
Occurrence within the first 2 cycles of treatment of a DLT
时间窗: 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.
次要结局
- Tolerance(6 months)
- Efficacy(42 Days)
- 1 year survival rate(1 year)