Phase Ib/II Study of MCS110 in Combination With PDR001 in Patients With Advanced Malignancies

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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A Phase Ib/II, Open Label, Multicenter Study of MCS110 in Combination With PDR001 in Patients With Advanced Malignancies

Conditions
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Triple Negative Breast Cancer, Pancreatic Carcinoma, Melanoma, Endometrial Carcinoma

Intervention / Treatment
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* Drug: MCS110
* Drug: PDR001


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: 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. Main Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ph Ib: MCS110 1 mg/kg Q3W + PDR001 100 mg Q3W<br>Phase Ib: MCS110 1 mg/kg every 3 weeks (Q3W) + PDR001 100 mg Q3W | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W<br>Phase Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W<br>Phase Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W<br>Phase Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W<br>Phase Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W<br>Phase Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - TNBC<br>Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Triple negative breast cancer (TNBC) | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - PC<br>Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Pancreatic cancer (PC) | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - EC<br>Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Endometrial cancer (EC) | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|
| Experimental: Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - ME<br>Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Melanoma (ME) | Drug: MCS110<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>* Other names: colony-stimulating factor-1 [CSF-1]);Drug: PDR001<br>* MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Percentage of Participants With Adverse Events, as a Measure of Safety | 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. | From start of treatment to a maximum timeframe of 116.4 weeks for phase Ib | 
| Phase II : Overall Response Rate (ORR) - Per RECIST v1.1 | 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) | 4 years | 
| Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per RECIST v1.1 - Mean | 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) | 4 years | 
| Phase II: Clinical Benefit Rate (Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) > 4 Month)) - Per RECIST v1.1 | 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 | 4 years | 
| Phase II: Bayesian Inference of Clinical Benefit Rate - Per RECIST v1.1- Mean | 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 | 4 years | 
| Phase Ib: Planned Dose Intensity - MCS110 | 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). | Measured up to a max of 112.4 weeks | 
| Phase Ib: Relative Dose Intensity - MCS110 | 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). | Measured up to a max of 112.4 weeks | 
| Phase Ib: Planned Dose Intensity - PDR001 | 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). | Measured up to a max of 112.4 weeks | 
| Phase Ib: Relative Dose Intensity - PDR001 | 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). | Measured up to a max of 112.4 weeks | 
| Phase Ib: Number of Participants With Dose Reductions | To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II. | Measured up to a max of 112.4 weeks | 
| Phase Ib: Number of Dose Interruptions Per Participant | To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II. | Measured up to a max of 112.4 weeks | 
| Phase Ib: Number of Subjects With at Least One Dose Interruption | To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II. | Measured up to a max of 112.4 weeks | 
| Phase Ib: Number of Participants With Dose Limiting Toxicities (DLTs) During the First 2 Cycles of Study Treatment | 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. | the first 2 cycles of study treatment; cycle = 21 days (i.e., at day 42) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II : Overall Response Rate (ORR) - Per irRC | Phase II: Overall Response Rate (Complete response (CR) or Partial response (PR)) (with confirmation) as per investigator based on immune related Response criteria (irRC) (FAS) | 4 years | 
| Phase Ib: Overall Response Rate (ORR) | Phase Ib: Overall Response Rate (Complete response (CR) or Partial response (PR)), per RECIST v1.1 and per immune related Response criteria (irRC) | 4 years | 
| Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per irRC - Mean | Phase II: Overall Response Rate (Complete response (CR) or Partial response (PR)) (with confirmation) as per investigator based on immune related Response criteria (irRC)- mean (FAS) | 4 years | 
| Phase 1b: Clinical Benefit Rate (CBR) | Phase 1b: Clinical Benefit Rate (Complete response (CR) or Partial response (PR) or Stable disease (SD) > 4 month)) per RECIST v1.1 and per immune related Response criteria (irRC) | 4 years | 
| Phase II: Clinical Benefit Rate (Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) > 4 Month)) - Per irRC | Phase II: Clinical Benefit Rate (Complete response (CR) or Partial response (PR) or Stable disease (SD) > 4 month)) per immune related Response criteria (irRC) | 4 years | 
| Phase II: Bayesian Inference of Clinical Benefit Rate - Per irRC - Mean | Phase II: Clinical Benefit Rate (Complete response (CR) or Partial response (PR) or Stable disease (SD) > 4 month)) per investigator based on immune related Response criteria (irRC)- mean (FAS) | 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 | Phase 1b and Phase II: Progression Free Survival. Progression is defined as a 20% increase in the sum of diameter of measurable lesions taking as reference the smallest sum of diameter recorded at or after baseline, or worsening of non-measurable lesions or the appearance of new lesions, using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or Per Immune Related Response Criteria (irRC). Unlike RECIST 1.1, PD per irRC requires confirmation at a new assessment after at least 4 weeks - using Kaplan-Meier method - Median. | Up to year 4 | 
| Phase 1b and Phase II: Overall Survival - Using Kaplan-Meier Method - Median | 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) | Phase 1b and Phase II: Duration of Response (DOR) per RECIST v1.1 and per immune related Response criteria (irRC) | 4 years | 
| Phase 1b and Phase II: Disease Control Rate (DCR) | Phase 1b and Phase II: Disease Control Rate (Complete response (CR) or Partial response (PR) or Stable disease (SD) > 4 month)) per RECIST v1.1 and per immune related Response criteria (irRC) | 4 years | 
| Phase II: Percentage of Participants With Adverse Events, as a Measure of Safety | Phase II: To further characterize the safety and tolerability of MCS110 given in combination with PDR001 | From start of treatment to a maximum timeframe of 92.4 weeks for phase II. | 
| Phase Ib and Phase II: Immunogenicity MCS110 | Phase Ib and Phase II: Presence of anti-MCS110 antibodies | 4 years | 
| Phase Ib and Phase II: Immunogenicity PDR001 | Phase Ib and Phase II: Presence of anti-PDR001 antibodies | 4 years | 
| Phase Ib and Phase II: Pharmacokinetics of MCS110 - AUClast and AUCinf | Phase Ib and Phase II: PK Parameters - AUClast, which is the AUC from time zero to the last measurable concentration sampling time (tlast) (mass × time × volume-1); and AUCinf, which is the AUC from time zero to infinity (mass × time × volume-1) - MCS110 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of PDR001 - AUClast and AUCinf | Phase Ib and Phase II: Pharmacokinetics (PK) Parameters - AUClast, which is the AUC from time zero to the last measurable concentration sampling time (tlast) (mass × time × volume-1); and AUCinf, which is the AUC from time zero to infinity (mass × time × volume-1) and AUCinf - PDR001 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of MCS110 - Cmax and Clast | Phase Ib and Phase II: PK Parameters - Cmax, which is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass × volume-1); and Clast - MCS110 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of PDR001 - Cmax and Clast | Phase Ib and Phase II: PK Parameters - Cmax, which is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass × volume-1); and Clast - PDR001 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of MCS110 - Tmax | Phase Ib and Phase II: PK Parameters - Tmax, which is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time) - MCS110 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of PDR001 - Tmax | Phase Ib and Phase II: PK Parameters - Tmax, which is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time) - PDR001 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of MCS110 - T1/2 | Phase Ib and Phase II: PK Parameters - T1/2, which is the terminal half-life associated with the terminal slope of a semi logarithmic concentration time curve (time) - MCS110 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of PDR001 - T1/2 | Phase Ib and Phase II: PK Parameters - T1/2, which is the terminal half-life associated with the terminal slope of a semi logarithmic concentration time curve (time) - PDR001 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of MCS110 - CL | Phase Ib and Phase II: PK Parameters - CL, which is the total body clearance of drug from the plasma (volume × time-1) - MCS110 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of PDR001 - CL | Phase Ib and Phase II: PK Parameters - CL, which is the total body clearance of drug from the plasma (volume × time-1) - PDR001 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of MCS110 - Vz | Phase Ib and Phase II: PK Parameters - Vz, which is the apparent volume of distribution during terminal phase (volume) - MCS110 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of PDR001 - Vz | Phase Ib and Phase II: PK Parameters - Vz, which is the apparent volume of distribution during terminal phase (volume) - PDR001 | cycle 1 (day 21) and cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of MCS110 - Accumulation Ratio (AR) | Phase Ib and Phase II: PK Parameters - Accumulation ratio (AR), which is the AUClast (multiple Dose)/AUClast (single dose) (for cycle 4 only) - MCS110 | cycle 4 (day 84) | 
| Phase Ib and Phase II: Pharmacokinetics of PDR001 - Accumulation Ratio (AR) | Phase Ib and Phase II: PK Parameters - Accumulation ratio (AR), which is the AUClast (multiple Dose)/AUClast (single dose) (for cycle 4 only) - PDR001 | cycle 4 (day 84) | 
| Phase Ib and Phase II: All Collected Deaths | On treatment deaths are reported from the start of treatment until end of study treatment plus 30 days, up to maximum duration of 116.4 weeks for phase Ib and 92.4 weeks for phase II. Deaths post treatment survival follow up are reported after the on-treatment period, up to a maximum timeframe of 46 months (3.8 years). | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple negative breast cancer, Pancreatic carcinoma, Melanoma, Endometrial Carcinoma, Immuno oncology, Monoclonal antibody, PDR001, MCS110, Advanced malignancies, metasteses, advanced cancer, malignant