A Double-blind, Randomized, Comparative, Multicenter, Exploratory, and Placebo-controlled Phase II Trial of FOLFIRI Plus MSC1936369B or Placebo With a Safety run-in Part as Second-line Treatment of Metastatic K Ras Mutated Colorectal Cancer Subjects
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- EMD Serono
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Part 2 or Phase 2 Randomised Part: Progression Free Survival (PFS)
研究概览
简要总结
The research trial is testing the experimental treatment pimasertib (MSC1936369B) in combination with FOLFIRI, as second-line treatment in metastatic K Ras mutated colorectal cancer subjects. The study will be run in two parts:
Part 1, or Safety Run-in Part: Will determine the maximum tolerated dose and the recommended Phase 2 dose (RP2D) of pimasertib combined with FOLFIRI as second-line treatment in subjects with metastatic K Ras mutated colorectal cancer.
Part 2 or Phase 2 Randomised Part: Will assess the anti-tumor activity of pimasertib combined with FOLFIRI compared to FOLFIRI with placebo as second-line treatment in metastatic K Ras mutated colorectal cancer subjects.
Phase I which Is an open label dose escalation "3+3" cohort, non-randomized, safety Phase II which is a double blind randomized safety/efficacy
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
- Double (Participant, Investigator)
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
- •For Safety Run-in and Part 2 or Phase 2 Randomised Part
- •Histologically confirmed K-Ras mutated colon/rectum cancer
- •Subject's disease must have progressed during or after a first-line treatment for metastatic disease with oxaliplatin and fluoropyrimidines based chemotherapy with or without bevacizumab
- •Evidence of metastatic measurable disease at trial entry as per Response Evaluation Criteria in Solid Tumors. Complete tumor assessment performed within 14 days prior to first trial drug administration
- •Male/female subjects aged greater than or equal to (>=) 18 years
- •Subject has read and understood the informed consent form
- •Women of childbearing potential must have a negative blood pregnancy test at the screening visit. Subjects and their partners must be willing to avoid pregnancy during the trial
排除标准
- •For Safety Run-in and Part 2 or Phase 2 Randomised Part
- •Bone marrow impairment
- •Renal impairment
- •Liver function and liver cell integrity abnormality
- •History of central nervous system (CNS) metastases
- •History of difficulty of swallowing, malabsorption or other chronic gastrointestinal disease
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than (>)1
- •Known human immunodeficiency virus (HIV) positivity, active hepatitis C, or active hepatitis B
- •Has received extensive prior radiotherapy on more than 30 percent (%) of bone marrow reserves, or prior bone marrow/stem cell transplantation
- •Has received chemotherapy, any investigational drug, or having participated in another clinical trial within the past 4 weeks prior to trial first drug administration
- •Has a history of any other significant medical disease
- •Past or current history (within the last 2 years prior to inclusion) of malignancies except for the indication under this study
- •Has significant cardiac conduction abnormalities and/or pacemaker
- •Is a pregnant or nursing female
- •Has retinal degenerative disease, history of uveitis, or history of retinal vein occlusion
- •Other significant disease that in the Investigator's opinion would exclude the subject from the trial
- •Known hypersensitivity to the trial treatment(s) or diluents (when applicable), including placebo or other comparator drug(s)
- •Legal incapacity or limited legal capacity
研究组 & 干预措施
Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI
干预措施: Pimasertib (Drug)
Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI
干预措施: FOLFIRI (Drug)
Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI
Planned, not performed
干预措施: Pimasertib (Drug)
Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI
Planned, not performed
干预措施: FOLFIRI (Drug)
Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI
Planned, not performed
干预措施: Placebo (Drug)
Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI
Planned, not performed
干预措施: FOLFIRI (Drug)
结局指标
主要结局
Part 2 or Phase 2 Randomised Part: Progression Free Survival (PFS)
时间窗: From randomization up to first documented disease progression maximum up to 2 years
PFS was defined as time (in months) from the date of randomization to the first documentation of disease progression as reported and documented by the Investigator (i.e. radiological progression per RECIST v1.0) or death for any cause.
Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD)
时间窗: Baseline up to Day 28 (Part 1)
MTD was defined as the dose level, at which the treatment-related dose limiting toxicity (DLT) occurred in \>1 of 3 subjects or in \>1 of 6 subjects. DLT was defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Any Grade \>=3 non-hematological toxicity except for Grade 4 asymptomatic increases in liver function tests (LFTs) reversible within 7 days in subjects with liver involvement, Grade 3 asymptomatic increases in LFTs reversible within 7 days in subjects without liver involvement, Grade 3 vomiting controlled with adequate and optimal therapy and prophylaxis, and Grade 3 diarrhea controlled with adequate and optimal anti-diarrhea therapy; any Grade 4 neutropenia lasing \>5 days/ febrile neutropenia lasting \>1 day; any Grade 4 thrombocytopenia/Grade 3 with bleeding; any treatment delay \>2 weeks due to trial treatment-related adverse effects at any dose level and judged to be possibly or probably related to the trial treatment.
次要结局
- Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38)
- Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38)
- Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38)
- Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15)(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38)
- Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38)
- Part 1 or Safety Run-in Part: Circulating Biomarkers in Serum(Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years)
- Part 2 or Phase 2 Randomized Part: Circulating Biomarkers(Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years)
- Part 2 or Phase 2 Randomized Part: Best Overall Response(Up to 2 years)
- Part 2 or Phase 2 Randomized Part: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death(From the first dose of study drug administration up to 28 days after the last dose of study drug administration)
- Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38)
- Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death(From the first dose of study drug administration up to 28 days after the last dose of study drug administration)
- Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38)
- Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15)(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan)
- Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38(Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38)
- Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR)(Up to 2 years)