Clinical trial NCT02807844: Phase Ib/II Study of MCS110 in Combination With PDR001 in Patients With Advanced Malignancies
Official title: A Phase Ib/II, Open Label, Multicenter Study of MCS110 in Combination With PDR001 in Patients With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Triple Negative Breast Cancer
Pancreatic Carcinoma
Melanoma
Endometrial Carcinoma
Keywords: Triple negative breast cancer
Pancreatic carcinoma
Melanoma
Endometrial Carcinoma
Immuno oncology
Monoclonal antibody
PDR001
MCS110
Advanced malignancies
metasteses
advanced cancer
malignant
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-06-21
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Phase Ib: Percentage of Participants With Adverse Events, as a Measure of Safety
timeFrame: From start of treatment to a maximum timeframe of 116.4 weeks for phase Ib
measure: Phase II : Overall Response Rate (ORR) - Per RECIST v1.1
timeFrame: 4 years
measure: Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per RECIST v1.1 - Mean
timeFrame: 4 years
measure: Phase II: Clinical Benefit Rate (Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) > 4 Month)) - Per RECIST v1.1
timeFrame: 4 years
measure: Phase II: Bayesian Inference of Clinical Benefit Rate - Per RECIST v1.1- Mean
timeFrame: 4 years
measure: Phase Ib: Planned Dose Intensity - MCS110
timeFrame: Measured up to a max of 112.4 weeks
measure: Phase Ib: Relative Dose Intensity - MCS110
timeFrame: Measured up to a max of 112.4 weeks
measure: Phase Ib: Planned Dose Intensity - PDR001
timeFrame: Measured up to a max of 112.4 weeks
measure: Phase Ib: Relative Dose Intensity - PDR001
timeFrame: Measured up to a max of 112.4 weeks
measure: Phase Ib: Number of Participants With Dose Reductions
timeFrame: Measured up to a max of 112.4 weeks
measure: Phase Ib: Number of Dose Interruptions Per Participant
timeFrame: Measured up to a max of 112.4 weeks
measure: Phase Ib: Number of Subjects With at Least One Dose Interruption
timeFrame: Measured up to a max of 112.4 weeks
measure: Phase Ib: Number of Participants With Dose Limiting Toxicities (DLTs) During the First 2 Cycles of Study Treatment
timeFrame: the first 2 cycles of study treatment; cycle = 21 days (i.e., at day 42)
Secondary outcomes:
measure: Phase II : Overall Response Rate (ORR) - Per irRC
timeFrame: 4 years
measure: Phase Ib: Overall Response Rate (ORR)
timeFrame: 4 years
measure: Phase II : Bayesian Inference of Overall Response Rate (ORR) - Per irRC - Mean
timeFrame: 4 years
measure: Phase 1b: Clinical Benefit Rate (CBR)
timeFrame: 4 years
measure: Phase II: Clinical Benefit Rate (Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) > 4 Month)) - Per irRC
timeFrame: 4 years
measure: Phase II: Bayesian Inference of Clinical Benefit Rate - Per irRC - Mean
timeFrame: 4 years
measure: 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
timeFrame: Up to year 4
measure: Phase 1b and Phase II: Overall Survival - Using Kaplan-Meier Method - Median
timeFrame: Up to year 4
measure: Phase 1b and Phase II: Duration of Response (DOR)
timeFrame: 4 years
measure: Phase 1b and Phase II: Disease Control Rate (DCR)
timeFrame: 4 years
measure: Phase II: Percentage of Participants With Adverse Events, as a Measure of Safety
timeFrame: From start of treatment to a maximum timeframe of 92.4 weeks for phase II.
measure: Phase Ib and Phase II: Immunogenicity MCS110
timeFrame: 4 years
measure: Phase Ib and Phase II: Immunogenicity PDR001
timeFrame: 4 years
measure: Phase Ib and Phase II: Pharmacokinetics of MCS110 - AUClast and AUCinf
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of PDR001 - AUClast and AUCinf
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of MCS110 - Cmax and Clast
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of PDR001 - Cmax and Clast
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of MCS110 - Tmax
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of PDR001 - Tmax
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of MCS110 - T1/2
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of PDR001 - T1/2
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of MCS110 - CL
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of PDR001 - CL
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of MCS110 - Vz
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of PDR001 - Vz
timeFrame: cycle 1 (day 21) and cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of MCS110 - Accumulation Ratio (AR)
timeFrame: cycle 4 (day 84)
measure: Phase Ib and Phase II: Pharmacokinetics of PDR001 - Accumulation Ratio (AR)
timeFrame: cycle 4 (day 84)
measure: Phase Ib and Phase II: All Collected Deaths
timeFrame: 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
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Germantown
country: United States
facility: The West Clinic
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Wilrijk
country: Belgium
facility: Novartis Investigative Site
city: HUS
country: Finland
facility: Novartis Investigative Site
city: Saint Herblain cedex
country: France
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Koto ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Chur
country: Switzerland
facility: Novartis Investigative Site
city: Geneve 14
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: