NCT01390818已完成1 期
An Open-Label, Phase Ib Dose Escalation Trial of Oral Combination Therapy With MSC1936369B and SAR245409 in Subjects With Locally Advanced or Metastatic Solid Tumors
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- EMD Serono
- 入组人数
- 146
- 试验地点
- 7
- 主要终点
- Number of Subjects With Dose Limiting Toxicities (DLT)
研究概览
简要总结
This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 82 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject with advanced solid tumors for which there is no approved therapy:
- •Advanced solid tumor with diagnosed alteration in one or more of the following genes (PTEN, BRAF, KRAS, NRAS, PI3KCA, ErbB1, ErbB2, MET, RET, c-KIT, GNAQ, GNA11 and/or
- •A histologically or cytologically confirmed diagnosis of one of the following solid tumors: pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian carcinoma and melanoma
- •Subject with archived tumor tissue available for transfer to the Sponsor
- •Subject enrolled at lower dose level cohorts and MTD expansion cohorts must have tumor available for biopsy and agree to pre-treatment and on-treatment tumor biopsies
- •Subject has measurable or evaluable disease by response evaluation criteria in solid tumors (RECIST) v1.1
- •Subject is aged greater than or equal to (>=) 18 years
- •Subjects enrolled in disease specific expansion cohorts must fulfill all the inclusion/exclusion criteria listed above with the following restriction to the Inclusion Criterion number 1:
- •Relapsed or refractory Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral oncogene homolog (NRAS) mutated metastatic non-small cell lung cancer (NSCLC) with no approved therapies, or
- •Relapsed or refractory metastatic triple negative breast cancer defined as estrogen, progesterone and HER2 negative carcinoma of the breast with no approved therapies, or
- •Relapsed or refractory metastatic colorectal cancer (CRC) with dual KRAS and PIK3CA mutation with no approved therapies, or
- •BRAF V600E/K mutated unresectable or metastatic melanoma after progression on B-Raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors
- •Other protocol-defined inclusion criteria could apply
排除标准
- •Subject has been previously treated with a PI3K inhibitor or a MEK inhibitor and taken off treatment due to treatment related adverse events
- •Subject has received:
- •Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anti-cancer therapy within 28 days of trial drug treatment
- •Any investigational agent within 28 days of trial drug treatment
- •Extensive prior radiotherapy on more than 30% bone marrow reserves, or prior bone marrow/stem cell transplantation
- •Subject has not recovered from toxicity due to prior therapy
- •Subject has poor organ and marrow function as defined in the protocol
- •Subject has a history of central nervous system metastases, unless subject has been previously treated for CNS metastases
- •Subject has a history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease
- •Subject has a history of recent major surgery or trauma within the last 28 days.
- •Subject has participated in another clinical trial within the past 30 days
- •Other protocol-defined exclusion criteria could apply
研究组 & 干预措施
MSC1936369B and SAR245409 once daily
Experimental
干预措施: MSC1936369B (pimasertib) (Drug)
MSC1936369B and SAR245409 once daily
Experimental
干预措施: SAR245409 (PI3K and mTOR inhibitor) (Drug)
MSC1936369B and SAR245409 twice daily
Experimental
干预措施: MSC1936369B (pimasertib) (Drug)
MSC1936369B and SAR245409 twice daily
Experimental
干预措施: SAR245409 (PI3K and mTOR inhibitor) (Drug)
结局指标
主要结局
Number of Subjects With Dose Limiting Toxicities (DLT)
时间窗: Day 1 up to Day 16 in cycle 1
DLT was defined as any of the following toxicities experienced during the first cycle of treatment at any dose level (DL) and judged not to be related to the underlying disease or any concomitant medication by the Investigator and/or the Sponsor: A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation (DE) would have exposed subjects to unacceptable risk. Any Grade greater than or equal to (\>=) 3 non-hematological toxicity, except for: Grade 3 diarrhea, nausea and vomiting with a duration less than or equal to (\<=) 48 hours despite adequate supportive care and Alopecia. Grade 4 neutropenia of \> 5 days duration or febrile neutropenia. Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia. Any treatment interruption \> 2 weeks due to AEs not related to the underlying disease or concomitant medication at any dose level and any severe, life-threatening impairing daily functions complication or abnormality.
次要结局
- Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)(Baseline up to 30 Days after last dose; assessed up to 4 years)
- Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts)
- Half-Life (t1/2) of MSC1936369B (Pimasertib)(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts)
- Apparent Terminal Half-Life (t1/2) of SAR245409(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Total Body Clearance (CL/f) of SAR245409(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- pERK Concentrations in PBMCs(DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); C1D1 and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose))
- Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Maximum Observed Plasma Concentration (Cmax) for SAR245409(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)(From the date of randomisation every 6 weeks up to assessed up to 4 years)
- Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15(Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts)
- pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)(DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); Cycle 1 Day 1 (C1D1) and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose))
研究者
研究点 (7)
Loading locations...
相似试验
已完成
1 期
Safety and Pilot Efficacy of AKB-9778 in Subjects With Diabetic Macular EdemaDiabetic Macular Edema (DME)NCT01702441Aerpio Therapeutics24
已完成
1 期
A Study to Evaluate RAF265, an Oral Drug Administered to Subjects With Locally Advanced or Metastatic MelanomaMetastatic MelanomaNCT00304525Novartis Pharmaceuticals104
招募中
2 期
Phase 2 Pharmacokinetics Study of TLC590 for Postsurgical Pain Management in Multiple Surgical ModelsPostsurgical Pain ManagementNCT06574269TLC Biopharmaceuticals, Inc.120
终止
1 期
Study to Evaluate Combination Treatment of MGCD0103 and Docetaxel (Taxotere®) for Subjects With Advanced Cancer TumorsBreast CancerPulmonary CancerNon-Small-Cell Lung CarcinomaProstatic CancerProstate CancerLung CancerGastric CancerStomach CancerNCT00511576Mirati Therapeutics Inc.54
终止
1 期
RRx-001 in Combination With Irinotecan in Metastatic or Advanced Cancer (PAYLOAD)Malignant Solid TumorMetastatic CancerAdvanced CancerNCT02801097EpicentRx, Inc.28