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.
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).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
141
Dana Farber Cancer Center
Boston, Massachusetts, United States
Washington University School of Medicine
St Louis, Missouri, United States
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.
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 4 years
Phase II: Bayesian Inference of Clinical Benefit Rate - Per RECIST v1.1- Mean
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The West Clinic
Germantown, Tennessee, United States
MD Anderson Cancer Center
Houston, Texas, United States
Novartis Investigative Site
Wilrijk, Belgium
Novartis Investigative Site
HUS, Finland
Novartis Investigative Site
Saint-Herblain, France
Novartis Investigative Site
Frankfurt, Germany
Novartis Investigative Site
Ulm, Germany
Novartis Investigative Site
Hong Kong, Hong Kong
...and 10 more locations
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
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: the first 2 cycles of study treatment; cycle = 21 days (i.e., at day 42)
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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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.
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 4 years
Phase Ib and Phase II: Immunogenicity PDR001
Phase Ib and Phase II: Presence of anti-PDR001 antibodies
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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).
Time frame: 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