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Phase Ib: MCS110 1 mg/kg every 3 weeks (Q3W) + PDR001 100 mg Q3W

Phase Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W

Phase Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W

Phase Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W

Phase Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W

Phase Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W

Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Triple negative breast cancer (TNBC)

Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Pancreatic cancer (PC)

Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Endometrial cancer (EC)

Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Melanoma (ME)

MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.

MCS110

PDR001

Novartis Pharmaceuticals

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).

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

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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

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.

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)

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 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

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).

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).

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).

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).

To characterize the tolerability of MCS110 given in combination with PDR001 and to identify a recommended dose combination for Phase II.

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.

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)

Phase Ib: Overall Response Rate (Complete response (CR) or Partial response (PR)), per RECIST v1.1 and per immune related Response criteria (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)- mean (FAS)

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)

Phase II: Clinical Benefit Rate (Complete response (CR) or Partial response (PR) or Stable disease (SD) \> 4 month)) per immune related Response criteria (irRC)

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)

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.

Phase 1b and Phase II: Overall Survival - using Kaplan-Meier method - Median

Phase 1b and Phase II: Duration of Response (DOR) per RECIST v1.1 and per immune related Response criteria (irRC)

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)

Phase II: To further characterize the safety and tolerability of MCS110 given in combination with PDR001

Phase Ib and Phase II: Presence of anti-MCS110 antibodies

Phase Ib and Phase II: Presence of anti-PDR001 antibodies

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

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

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

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

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

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

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

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

Phase Ib and Phase II: PK Parameters - CL, which is the total body clearance of drug from the plasma (volume × time-1) - MCS110

Phase Ib and Phase II: PK Parameters - CL, which is the total body clearance of drug from the plasma (volume × time-1) - PDR001

Phase Ib and Phase II: PK Parameters - Vz, which is the apparent volume of distribution during terminal phase (volume) - MCS110

Phase Ib and Phase II: PK Parameters - Vz, which is the apparent volume of distribution during terminal phase (volume) - PDR001

Phase Ib and Phase II: PK Parameters - Accumulation ratio (AR), which is the AUClast (multiple Dose)/AUClast (single dose) (for cycle 4 only) - MCS110

Phase Ib and Phase II: PK Parameters - Accumulation ratio (AR), which is the AUClast (multiple Dose)/AUClast (single dose) (for cycle 4 only) - PDR001

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).

Ph Ib: MCS110@1 mg/kg Q3W@+ PDR001 100@mg Q3W

Ph Ib: MCS110@3 mg/kg Q3W@+ PDR001 100@mg Q3W

Ph Ib: MCS110@3 mg/kg Q3W@+ PDR001 300@mg Q3W

Ph Ib: MCS110@5 mg/kg Q3W@+ PDR001 300@mg Q3W

Ph Ib: MCS110@7.5 mg/kg Q3W@+ PDR001 300@mg Q3W

Ph Ib: MCS110@10 mg/kg Q3W@+ PDR001 300@mg Q3W

Ph II: MCS110@7.5 mg/kg Q3W@+ PDR001 300@mg Q3W - TNBC

Ph II: MCS110@7.5 mg/kg Q3W@+ PDR001 300@mg Q3W - PC

Ph II: MCS110@7.5 mg/kg Q3W@+ PDR001 300@mg Q3W - EC

Ph II: MCS110@7.5 mg/kg Q3W@+ PDR001 300@mg Q3W - ME

Ph Ib: MCS110 1 mg/kg Q3W + PDR001 100 mg Q3W

Ph Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W

Ph Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W

Ph Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W

Ph Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W

Ph Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W

Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - TNBC

Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - PC

Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - EC

Ph II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - ME

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Study Director

Adverse events (AEs) - all grades

Adverse events - Treatment-related - all grades

Serious Adverse Events (SAEs) - all grades

SAEs - Treatment-related - all grades

Fatal SAEs - all grades

Fatal SAEs - Treatment-related - all grades

AEs leading to discontinuation - all grades

AEs leading to discontinuation - Treatment-related - all grades

AEs leading to dose adjustment / interruption - all grades

AEs requiring additional therapy - all grades

Safety Analysis Set. A statistical analysis for this endpoint was not performed since it is not clinically relevant.

Phase Ib: Percentage of Participants With Adverse Events, as a Measure of Safety

Full Analysis Set. A statistical analysis for this endpoint was not performed since it is not clinically relevant.

Phase II : Overall Response Rate (ORR) - Per RECIST v1.1

Full Analysis Set. Since objective responses are rare in advanced pancreatic cancer and that long lasting stable disease is considered beneficial to patients, clinical benefit rate (confirmed objective response or SD\>4 months) was used as the primary endpoint for antitumor activity in this study changed from objective response to for this patient population.

Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per RECIST v1.1 - Mean

Phase II: Clinical Benefit Rate (Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) > 4 Month)) - Per RECIST v1.1

Phase II: Bayesian Inference of Clinical Benefit Rate - Per RECIST v1.1- Mean

Safety Set. A statistical analysis for this endpoint was not performed since it is not clinically relevant.

Phase Ib: Planned Dose Intensity - MCS110

Phase Ib: Relative Dose Intensity - MCS110

Phase Ib: Planned Dose Intensity - PDR001

Phase Ib: Relative Dose Intensity - PDR001

n (%) of participants with no dose reduction- Study drug: MCS110

n (%) of participants with no dose reduction- Study drug: PDR001

Phase Ib: Number of Participants With Dose Reductions

Number of dose interruptions per subject - Study drug: MCS110

Number of dose interruptions per subject - Study drug: PDR001

Phase Ib: Number of Dose Interruptions Per Participant

Number of subjects with at least one dose interruption - by reason - Adverse Event - MCS110

Number of subjects with at least one dose interruption - by reason - Adverse Event - PDR001

Phase Ib: Number of Subjects With at Least One Dose Interruption

n (%) of subjects with at least one event - all grades

n (%) Investigations - all grades

n (%) Blood creatine phosphokinase increased - all grades

Dose Determination Set (DDS). A statistical analysis for this endpoint was not performed since it is not clinically relevant.

Phase Ib: Number of Participants With Dose Limiting Toxicities (DLTs) During the First 2 Cycles of Study Treatment

Phase II : Overall Response Rate (ORR) - Per irRC

Overall Response Rate as per investigator based on RECIST v1.1

Overall Response Rate - as per investigator based on irRC

Phase Ib: Overall Response Rate (ORR)

Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per irRC - Mean

Clinical Benefit Rate - as per investigator based on RECIST v1.1

Clinical Benefit Rate - as per investigator based on irRC

Phase 1b: Clinical Benefit Rate (CBR)

Phase II: Clinical Benefit Rate (Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) > 4 Month)) - Per irRC

Phase II: Bayesian Inference of Clinical Benefit Rate - Per irRC - Mean

Median PFS - per RECIST v1.1

Median PFS - per iiRC

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase Ib/II Study of MCS110 in Combination With PDR001 in Patients With Advanced Malignancies	NCT02807844	Triple Negative... Pancreatic Carc... Melanoma Endometrial Car...	MCS110 PDR001	18 Years -	Novartis
Phase Ib/II Study of MCS110 in Combination With PDR001 in Patients With Advanced Malignancies	NCT02807844	Triple Negative... Pancreatic Carc... Melanoma Endometrial Car...	MCS110 PDR001	18 Years -	Novartis
A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer	NCT04069026	Advanced Solid ...	BAY2416964 BAY2416964	18 Years -	Bayer
Study of Veliparib in Combination With Nivolumab and Platinum Doublet Chemotherapy in Participants With Metastatic or Advanced Non-Small Cell Lung Cancer (NSCLC)	NCT02944396	Non-Small Cell ...	pemetrexed nivolumab paclitaxel veliparib carboplatin	18 Years -	AbbVie

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