NCT01378377终止1 期
Phase I Dose Escalation Trial of MEK1/2 Inhibitor MSC1936369B Combined With Temsirolimus in Subjects With Advanced Solid Tumors
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- EMD Serono
- 入组人数
- 33
- 试验地点
- 3
- 主要终点
- Number of Subjects With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The research trial is testing the experimental drug pimasertib and the drug Torisel, given together, in the treatment of advanced solid tumors. The primary purpose of the study is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of the drug combination.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Subjects with histologically or cytologically confirmed solid tumors, either refractory to standard therapy or for which no effective standard therapy is available.
- •Measurable or evaluable disease at baseline by RECIST 1.
- •Age >= 18 years.
- •Subject has read and understands the informed consent form and is willing and able to give informed consent.
- •Performance Status score of less than or equal to (<=) 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
- •Women of childbearing potential must have a negative blood pregnancy test at the screening visit.
- •Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during the trial and for 3 months after the last dose of trial medication.
- •Additional inclusion criteria also apply.
排除标准
- •The subject has previously been treated with mammalian target of rapamycin (mTOR) inhibitor or a mitogen-activated protein kinase (MEK) inhibitor and taken off treatment due to drug-related AEs.
- •The subject has received any of the following:
- •Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, any investigational agent or any other anti-cancer therapy within 28 days (6 weeks for nitrosoureas or mitomycin C) of Day 1 of trial treatment; non-cytotoxic chemotherapy or investigational agent with limited potential for delayed toxicity is permitted if terminated at least 5 half-lives prior to Day 1 of trial treatment.
- •Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation.
- •The subject has not recovered from toxicity due to prior therapy to baseline or CTCAE v4.0 of Grade 1 or less (except alopecia).
- •The subject has poor organ or marrow function as defined in protocol.
- •History of central nervous system (CNS) metastases or primary CNS tumor, unless subject has been previously treated for these conditions, is asymptomatic and has had no requirement for anticonvulsants or high dose corticosteroids for a minimum of 2 weeks prior to entry into the trial.
- •History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of Day 1 of trial drug treatment.
- •Recent major surgery or trauma (within the last 28 days), unhealing/open wounds, diabetic ulcers, recent drainage of significant volume of ascites or pleural effusion.
- •History of congestive heart failure, unstable angina, myocardial infarction, symptomatic cardiac conduction abnormality, pacemaker, or other clinically significant cardiac disease or history of a stroke within 3 months prior to entering the trial.
- •Baseline corrected QT interval on screening electrocardiogram (ECG) (QTc) >= 460 ms or left ventricular ejection fraction (LVEF) < 40% on screening echocardiogram.
- •Other uncontrolled intercurrent diseases
- •Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion, or medically relevant abnormal ophthalmology assessments at screening.
- •Known or suspected allergy to pimasertib, temsirolimus, other rapamycins (sirolimus, everolimus, etc.), their excipients, or any agent given in the course of this trial.
- •Immunization with attenuated live vaccines within one week of trial entry (examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, etc.).
- •Concomitant use of any medications or substances that are strong inhibitors or inducers of CYP3A enzyme, including, but not limited to, phenytoin, carbamazepine, barbiturates, azoles, rifampin, phenobarbital, or St. John's Wort.
- •Pregnant or lactating female.
- •Legal incapacity or limited legal capacity.
- •Additional exclusion criteria also apply.
研究组 & 干预措施
Pimasertib 45 mg+Temsirolimus 12.5 mg
Experimental
干预措施: Pimasertib (Drug)
Pimasertib 45 mg+Temsirolimus 12.5 mg
Experimental
干预措施: Temsirolimus (Drug)
Pimasertib 45 mg+Temsirolimus 25 mg
Experimental
干预措施: Pimasertib (Drug)
Pimasertib 45 mg+Temsirolimus 25 mg
Experimental
干预措施: Temsirolimus (Drug)
Pimasertib 75 mg+Temsirolimus 25 mg
Experimental
干预措施: Pimasertib (Drug)
Pimasertib 75 mg+Temsirolimus 25 mg
Experimental
干预措施: Temsirolimus (Drug)
结局指标
主要结局
Number of Subjects With Dose Limiting Toxicities (DLTs)
时间窗: Up to 21 Days (within Cycle 1)
DLT was defined as any of the following toxicities graded as per National Cancer Institute (NCI) common terminology criteria for adverse events (NCI CTCAE v4.0) encountered within cycle 1 of treatment at any dose level and judged not to be related to the underlying disease or concomitant medications. A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation would expose subjects to unacceptable risk; any Grade \>=3 non-hematological toxicity except Grade 3 asymptomatic increases in liver function tests, diarrhea, nausea or vomiting with duration \<= 48 hours and alopecia; Grade 4 neutropenia of \>5 days duration or febrile neutropenia of \>1 day duration; Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia; any treatment interruption \>2 weeks due to adverse events; any severe, impairing daily functions or life-threatening, complication or abnormality not defined in NCI-CTCAE that is attributable to the therapy.
次要结局
- Apparent Volume of Distribution (Vz/F) of Pimasertib(DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus(DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus(DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus(DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Phospho Extracellular Signal Regulated Kinase (pERK ) Levels and Phospho Ribosomal Protein S6 (pS6) Levels in in Peripheral Blood Mononuclear Cells (PBMCs)(DDI cohorts: Days 1, 9 and 10 of Cycle 1; Non-DDI cohorts: Days 1, 8 and 9 of Cycle 1)
- Number of Subjects With Treatment-emergent Adverse Events (TEAEs)(From the start of the trial treatment until data cut-off date (23 February 2012))
- Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib(DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Apparent Terminal Half-life (t1/2) of Pimasertib(DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib(DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Maximum Plasma Concentration (Cmax) of Pimasertib(Drug-drug interaction (DDI) cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Maximum Plasma Concentration (Cmax) of Temsirolimus(DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 8)
- Volume of Distribution (Vz) of Temsirolimus(DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib(DDI cohorts: Days 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 for AUCtau; DDI cohorts: Day 1 of Cycle 1 AUC0-inf)
- Apparent Terminal Half-life (t1/2) of Temsirolimus(DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1)
- Number of Subjects With Disease Control Rate(From the start of the trial treatment until data cut-off date (23 February 2012))
研究者
研究点 (3)
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