A Phase Ib/II, Open Label, Multicenter Study of MCS110 in Combination With PDR001 in Patients With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 141
- 试验地点
- 5
- 主要终点
- Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per RECIST v1.1 - Mean
研究概览
简要总结
The purpose of this study of MCS110 with PDR001 was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of the combination of MCS110 with PDR001 in adult patients with solid tumors.
详细描述
Combined treatment with MCS110 and PDR001 was expected to result in Tumor-associated macrophages (TAM) depletion, enhanced T-cell activation and synergistic antitumor activity in the clinical setting.
This study was a Phase Ib/II, multi-center, open label study starting with a Phase Ib dose escalation part followed by a Phase II part. MCS110 and PDR001 were administered i.v. Q3W until the patient experienced unacceptable toxicity, progressive disease as per irRC and/or treatment was discontinued at the discretion of the investigator or the patient. Patients were not to discontinue treatment based on progressive disease per Response evaluation criteria in solid tumors (RECIST) v1.1. During the Phase Ib part of the study, cohorts of patients were treated with increasing doses of MCS110 and PDR001 every 3 weeks until a Recommended Phase 2 Dose (RP2D) was determined for this treatment combination.
To assure that the combination RP2D did not exceed the Maximum tolerated dose (MTD), the combination MCS110 and PDR001 dose escalation was guided by a Bayesian logistic regression model (BLRM) with overdose control (EWOC) principle based on dose limiting toxicity data in the context of available safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) information. Once the MTD and/or RP2D was declared, additional patients were enrolled in the Phase II part in order to assess the preliminary anti-tumor activity of MCS110 in combination with PDR001 in anti-PD1/PD-L1-naive triple negative breast cancer (TNBC), pancreatic (PC), endometrial carcinoma (EC) and anti PD1/PD-L1-resistance melanoma (ME).
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
- •Signed informed consent prior to any procedures
- •Phase Ib part: Adult patients with advanced melanoma, endometrial carcinoma, pancreatic or TNBC, with measurable or non-measurable disease who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists.
- •Phase II part: Adult patients with advanced solid tumors who have received standard therapy (no more than 3 prior lines of treatment) or are intolerant of standard therapy, have progressed following their last prior therapy, and fit into one of the following groups:
- •Group 1: TNBC who did not receive prior anti-PD-1/PD-L1 treatment
- •Group 2: Pancreatic adenocarcinoma who did not receive prior anti-PD-1/PD-L1 treatment
- •Group 3: Endometrial carcinoma who did not receive prior anti-PD-1/PD-L1 treatment
- •Group 4: Melanoma who progressed on prior anti-PD-1/PD-L1 treatment.
排除标准
- •Patients with the following:
- •Symptomatic central nervous system (CNS) metastases or those requiring local CNS-directed therapy.
- •Abnormal liver, renal, or blood lab values.
- •Impaired cardiac function or clinically significant cardiac disease.
- •Active autoimmune disease or documented autoimmune disease within 3 years of screening.
- •Active infection requiring antibiotic therapy.
- •Known HIV, active hepatitis B or C virus.
- •Concurrent malignant disease.
- •Patients who received systemic anticancer therapy, major surgery, or radiotherapy within 2 weeks of study treatment, or live vaccines within 4 weeks of study treatment.
- •Patients requiring chronic treatment with systemic steroid therapy or any immunosuppressive therapy.
- •Patients who used hematopoietic colony-stimulating growth factors within 2 weeks of study treatment.
研究组 & 干预措施
Ph Ib: MCS110 1 mg/kg Q3W + PDR001 100 mg Q3W
Phase Ib: MCS110 1 mg/kg every 3 weeks (Q3W) + PDR001 100 mg Q3W
干预措施: PDR001 (Drug)
Ph Ib: MCS110 1 mg/kg Q3W + PDR001 100 mg Q3W
Phase Ib: MCS110 1 mg/kg every 3 weeks (Q3W) + PDR001 100 mg Q3W
干预措施: MCS110 (Drug)
Ph Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W
Phase Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W
干预措施: MCS110 (Drug)
Ph Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W
Phase Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W
干预措施: PDR001 (Drug)
Ph Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W
Phase Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W
干预措施: MCS110 (Drug)
Ph Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W
Phase Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W
干预措施: PDR001 (Drug)
Ph Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W
Phase Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W
干预措施: MCS110 (Drug)
Ph Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W
Phase Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W
干预措施: PDR001 (Drug)
Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - PC
Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Pancreatic cancer (PC)
干预措施: PDR001 (Drug)
Ph Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W
Phase Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W
干预措施: MCS110 (Drug)
Ph Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W
Phase Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W
干预措施: PDR001 (Drug)
Ph Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W
Phase Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W
干预措施: MCS110 (Drug)
Ph Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W
Phase Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W
干预措施: PDR001 (Drug)
Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - TNBC
Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Triple negative breast cancer (TNBC)
干预措施: MCS110 (Drug)
Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - TNBC
Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Triple negative breast cancer (TNBC)
干预措施: PDR001 (Drug)
Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - PC
Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Pancreatic cancer (PC)
干预措施: MCS110 (Drug)
Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - EC
Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Endometrial cancer (EC)
干预措施: MCS110 (Drug)
Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - EC
Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Endometrial cancer (EC)
干预措施: PDR001 (Drug)
Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - ME
Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Melanoma (ME)
干预措施: MCS110 (Drug)
Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - ME
Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Melanoma (ME)
干预措施: PDR001 (Drug)
结局指标
主要结局
Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per RECIST v1.1 - Mean
时间窗: 4 years
Overall Response Rate (ORR) is defined as the proportion of patients with a best overall response assessed by CT scan or MRI of complete response (CR), disappearance of all measurable and non-measurable lesions or partial response (PR), at least a 30% decrease in the sum of diameter of all measurable lesions, taking as reference the baseline sum of diameters,. based on local Investigator assessment, as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) - mean (FAS)
Phase Ib: Planned Dose Intensity - PDR001
时间窗: Measured up to a max of 112.4 weeks
To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II. Planned dose intensity for PDR001 (mg/3wks) is planned cumulative dose (mg)/ number of doses scheduled per protocol during treatment period (i.e., this is equivalent to planned dose level).
Phase Ib: Number of Participants With Dose Reductions
时间窗: Measured up to a max of 112.4 weeks
To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II.
Phase Ib: Number of Dose Interruptions Per Participant
时间窗: Measured up to a max of 112.4 weeks
To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II.
Phase II : Overall Response Rate (ORR) - Per RECIST v1.1
时间窗: 4 years
Overall Response Rate (ORR) is defined as the proportion of patients with a best overall response assessed by CT scan or MRI of complete response (CR), disappearance of all measurable and non-measurable lesions or partial response (PR), at least a 30% decrease in the sum of diameter of all measurable lesions, taking as reference the baseline sum of diameters,. based on local Investigator assessment, as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)
Phase II: Clinical Benefit Rate (Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) > 4 Month)) - Per RECIST v1.1
时间窗: 4 years
Phase II: Clinical Benefit Rate (Complete response (CR) or Partial response (PR) or Stable disease (SD) \> 4 month)) per investigator based on Response evaluation criteria in solid tumors (RECIST) v1.1
Phase II: Bayesian Inference of Clinical Benefit Rate - Per RECIST v1.1- Mean
时间窗: 4 years
Phase II: Clinical Benefit Rate (Complete response (CR) or Partial response (PR) or Stable disease (SD) \> 4 month)) per investigator based on Response evaluation criteria in solid tumors (RECIST) v1.1
Phase Ib: Relative Dose Intensity - MCS110
时间窗: Measured up to a max of 112.4 weeks
To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II. Relative dose intensity (%) is 100 × dose intensity (mg/kg/3wks)/planned dose intensity (mg/kg/3wks).
Phase Ib: Number of Subjects With at Least One Dose Interruption
时间窗: Measured up to a max of 112.4 weeks
To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II.
Phase Ib: Percentage of Participants With Adverse Events, as a Measure of Safety
时间窗: From start of treatment to a maximum timeframe of 116.4 weeks for phase Ib
Phase Ib: To characterize the safety and tolerability of MCS110 in combination with PDR001 in patients with advanced solid malignancies and to identify a recommended dose combination for Phase II.
Phase Ib: Planned Dose Intensity - MCS110
时间窗: Measured up to a max of 112.4 weeks
To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II. Planned dose intensity for MCS110 is cumulative planned dose (mg/kg)/ number of doses scheduled per protocol during treatment period (i.e., this is equivalent to planned dose level).
Phase Ib: Relative Dose Intensity - PDR001
时间窗: Measured up to a max of 112.4 weeks
To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II. Relative dose intensity (%) is 100 × dose intensity (mg/3wks)/planned dose intensity (mg/3wks).
Phase Ib: Number of Participants With Dose Limiting Toxicities (DLTs) During the First 2 Cycles of Study Treatment
时间窗: the first 2 cycles of study treatment; cycle = 21 days (i.e., at day 42)
Phase Ib: Dose limiting toxicities occurring during the first 2 cycles by system organ class, preferred term and maximum grade for Phase Ib. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 was used for all grading.
次要结局
- Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per irRC - Mean(4 years)
- Phase II: Clinical Benefit Rate (Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) > 4 Month)) - Per irRC(4 years)
- Phase II : Overall Response Rate (ORR) - Per irRC(4 years)
- Phase Ib: Overall Response Rate (ORR)(4 years)
- Phase 1b: Clinical Benefit Rate (CBR)(4 years)
- Phase 1b and Phase II: Progression Free Survival Based on Investigator Assessment as Per RECIST v1.1 and Per Immune Related Response Criteria (irRC) - Using Kaplan-Meier Method - Median(Up to year 4)
- Phase II: Bayesian Inference of Clinical Benefit Rate - Per irRC - Mean(4 years)
- Phase 1b and Phase II: Overall Survival - Using Kaplan-Meier Method - Median(Up to year 4)
- Phase 1b and Phase II: Duration of Response (DOR)(4 years)
- Phase 1b and Phase II: Disease Control Rate (DCR)(4 years)
- Phase II: Percentage of Participants With Adverse Events, as a Measure of Safety(From start of treatment to a maximum timeframe of 92.4 weeks for phase II.)
- Phase Ib and Phase II: Immunogenicity MCS110(4 years)
- Phase Ib and Phase II: Immunogenicity PDR001(4 years)
- Phase Ib and Phase II: Pharmacokinetics of MCS110 - AUClast and AUCinf(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of PDR001 - AUClast and AUCinf(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of MCS110 - Tmax(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of PDR001 - Tmax(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of MCS110 - Cmax and Clast(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of PDR001 - Cmax and Clast(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of PDR001 - CL(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of MCS110 - Vz(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of PDR001 - Vz(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of MCS110 - T1/2(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of PDR001 - T1/2(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of MCS110 - CL(cycle 1 (day 21) and cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of MCS110 - Accumulation Ratio (AR)(cycle 4 (day 84))
- Phase Ib and Phase II: Pharmacokinetics of PDR001 - Accumulation Ratio (AR)(cycle 4 (day 84))
- Phase Ib and Phase II: All Collected Deaths(For ontreatment deaths: up to maximum timeframe of 116.4 weeks for phase Ib and 92.4 weeks for phase II. For total deaths: up to 3.8 years)