Phase II Trial With Safety-Run-In of MEK Inhibitor MSC1936369B in Subjects With Poor Prognosis Acute Myeloid Leukemia and Other Hematological Malignancies
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- EMD Serono
- 入组人数
- 81
- 试验地点
- 9
- 主要终点
- Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This is an open-label, multi-center, dose-escalation trial of pimasertib (MSC1936369B) in blood and bone marrow cancers. The trial will be conducted in two parts:
Part 1 (safety run-in period): Will determine the maximum tolerated dose (MTD) of the study drug in subjects with advanced hematological malignancies.
Part 2: Will assess the anti-leukemic activity of the study drug in older subjects with newly diagnosed poor prognosis acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- 未提供
排除标准
- •Part 1 and Part 2:
- •ECOG performance status 3 or greater
- •Hyperleukocytosis with greater than 30 x 10 to the ninth power per liter leukemia blasts in peripheral blood
- •Acute promyelocytic leukemia [t(15;17)]
- •Administration of any antineoplastic therapy within at least 2 weeks or 5 half lives of that therapy of the first pimasertib dose; except the use of hydroxyurea as permitted in inclusion criteria
- •Participation in other clinical trials within at least 2 weeks of the first pimasertib dose
- •Clinical evidence of active central nervous system leukemia
- •Active and uncontrolled infection including but not limited to known infection with human immunodeficiency virus (HIV), active hepatitis B or hepatitis C. Subjects with an infection receiving treatment with antibiotics may be entered into the trial if they are afebrile and hemodynamically stable for 48 hours prior to trial entry
- •Major surgery within two weeks prior to trial entry
- •Liver function tests above the following limits at screening: total bilirubin >1.5 x upper limit of normal (ULN) unless related to Gilbert's syndrome or hemolysis, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x ULN, or for subjects with liver involvement AST and/or ALT >5 x ULN
- •Serum creatinine >1.5 x ULN and /or creatinine clearance <30 milliliter per minute (mL/min) at screening
- •International normalized ratio (INR) greater than 1.5 x ULN unless on treatment with warfarin
- •For female subjects: pregnant or breast-feeding
- •History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product
- •Has significant cardiac conduction abnormalities and/or pacemaker
- •Has retinal degenerative disease (heredity retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion and/or any medically relevant abnormal findings at the initial ophthalmologic examination
- •Subjects with solid tumors, for whom the Investigator has clinical suspicion of active disease at the time of enrolment. Subjects with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study
- •Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such
- •Other significant disease that in the Investigator's opinion would exclude the subject from the trial
- •Legal incapacity or limited legal capacity
研究组 & 干预措施
Regimen 1 (Part 1)
干预措施: Pimasertib (Drug)
Regimen 2 (Part 1)
干预措施: Pimasertib (Drug)
Regimen 3 (Part 1)
干预措施: Pimasertib (Drug)
Regimen 1 (Part 2)
干预措施: Pimasertib (Drug)
Regimen 2 (Part 2)
干预措施: Pimasertib (Drug)
结局指标
主要结局
Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs)
时间窗: Baseline Up to Day 29 of Cycle 1
The DLT was any toxicity that resulted in treatment delay for more than (\>) 2 weeks due to treatment-related adverse effects, or any Grade greater than or equal to (\>=) 3 non-hematological toxicity excluding Grade 4 asymptomatic increases in liver function tests reversible within 7 days in subjects with liver involvement, and Grade 3 asymptomatic increases in liver function tests reversible within 7 days for subjects without liver involvement, Grade 3 vomiting unless encountered and persistent for more than 3 days despite adequate and optimal therapy, and Grade 3 diarrhea unless encountered and persistent for more than 3 days despite adequate and optimal anti-diarrhea therapy at any DL and judged to be possibly or probably related to the trial treatment by the Investigator and/or the Sponsor.
Part 2: Percentage of Subjects With Best Overall Response
时间窗: Day 29 of every 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012
The best overall response was to be reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) \>1.0x10\^9 per liter (/L), platelets \>100x10\^9 /L, bone marrow aspirate with less than or equal to (\<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC \>1.0x10\^9/L, platelets \>100x10\^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (\<) 5%. (4) Progressive disease (PD) = \>50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = subjects who failed to achieve CR, CRi or PR and without criteria for PD.
次要结局
- Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation(Baseline up to 3 years)
- Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose(Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).)
- Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose(Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3))
- Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose(Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).)
- Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Multiple Dose(Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).)
- Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose(Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3))
- Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose(Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3))
- Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose(Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3)
- Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose(Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3))
- Part 1: Percentage of Subjects With Best Overall Response(Day 29 of every alternate 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012)
- Part 2: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation(Up to 3 years)