Phase 1/2a First-In-Human Study of BMS-986218 Monoclonal Antibody Alone and in Combination With Nivolumab in Advanced Solid Tumors
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Enrollment
- 376
- Locations
- 52
- Primary Endpoint
- Number of Participants With Adverse Events (AEs)
Study Overview
Brief Summary
The purpose of this study is to determine whether BMS-986218 both by itself and in combination with Nivolumab is safe and tolerable in the treatment of advanced solid tumors.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologic or cytologic confirmation of a solid tumor that is advanced (metastatic, recurrent and/or unresectable)
- •Eastern Cooperative Oncology Group Performance Status of 0 or 1
- •Participants must have received, and then progressed, relapsed, or been intolerant to at least 2 standard treatment regimens with proven survival benefit in the advanced or metastatic setting according to tumor type, if such a therapy exists
- •Advanced stage cutaneous melanoma who have received standard therapies with proven survival benefit including prior immunotherapy with an anti-programmed cell death 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) (For Part 2A)
- •Non-small cell lung cancer (NSCLC) (adenocarcinoma or squamous cell carcinoma) who have received standard therapies with proven survival benefit including prior immunotherapy with an anti-PD-1 or anti-PD-L1 (For Parts 2B & 2C)
- •Microsatellite Stable Colorectal Cancer (MSS CRC) who have received standard therapies with proven survival benefit (Part 2D)
Exclusion Criteria
- •Participants with primary CNS malignancies, or tumors with CNS metastases as the only site of disease, will be excluded
- •Cytotoxic agents, unless at least 4 weeks have elapsed from last dose of prior anti-cancer therapy and initiation of study therapy
- •Prior anti-cancer treatments such as chemotherapy, radiotherapy, hormonal, or immunotherapy (including anti-PD-1/PD-L1) are permitted
- •Other protocol-defined inclusion/exclusion criteria apply
Arms & Interventions
Part 1A: Monotherapy (BMS-986218)
Intervention: BMS-986218 (Biological)
Part 1B: Combination Therapy (BMS-986218 + Nivolumab)
Intervention: BMS-986218 (Biological)
Part 1B: Combination Therapy (BMS-986218 + Nivolumab)
Intervention: Nivolumab (Biological)
Part 2A: Monotherapy (BMS-986218 OR Ipilimumab)
Intervention: Ipilimumab (Biological)
Part 2A: Monotherapy (BMS-986218 OR Ipilimumab)
Intervention: BMS-986218 (Biological)
Part 2B: Monotherapy (BMS-986218)
Intervention: BMS-986218 (Biological)
Part 2C: Expansion Combination Therapy (BMS-986218 + Nivolumab)
Intervention: BMS-986218 (Biological)
Part 2C: Expansion Combination Therapy (BMS-986218 + Nivolumab)
Intervention: Nivolumab (Biological)
Part 2D: Expansion Combination Therapy (BMS-986218 + Nivolumab)
Intervention: BMS-986218 (Biological)
Part 2D: Expansion Combination Therapy (BMS-986218 + Nivolumab)
Intervention: Nivolumab (Biological)
Outcomes
Primary Outcomes
Number of Participants With Adverse Events (AEs)
Time Frame: From first dose of study medication through 100 days following last dose of study treatment (assessed for an average of 8 months up to a max of approximately 28 months)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Number of Participants With Serious Adverse Events (SAEs)
Time Frame: From first dose of study medication through 100 days following last dose of study treatment (assessed for an average of 8 months up to a max of approximately 28 months)
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, and requires inpatient hospitalization or causes prolongation of existing hospitalization.
Number of Participants With Adverse Events (AEs) Meeting Protocol-defined Dose-limiting Toxicity (DLT) Criteria
Time Frame: From first dose of study medication through 60 days following last dose of study treatment (assessed for an average of 7 months up to a max of approximately 27 months)
Dose-Limiting Toxicities (DLTs) are effects of a treatment that are serious enough to prevent an increase in dose of that treatment. Grade 1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening, 5=Death Gastrointestinal DLT: * Grade 2 colitis \>5 days * Grade ≥3 diarrhea/colitis Hepatic DLT: * Grade 4 serum transaminases (AST \& ALT), alkaline phosphatase (ALP), or total bilirubin elevations * Grade 3 serum AST, ALT, or ALP elevations lasting \>5 days or with clinical symptoms or bilirubin \> 2×ULN without cholestasis Hematologic DLT: * Grade 4 neutropenia ≥7 days * Grade 4 thrombocytopenia Dermatologic DLT: * Grade 4 rash * Grade 3 rash if no improvement after 1-2-week infusion delay Other DLTs: * Grade 2 drug-related uveitis, episcleritis, iritis, eye pain, or blurred vision that doesn't respond to treatment, doesn't improve within the re-treatment period OR requires systemic treatment * Grade 3 drug-related uveitis, episcleritis, iritis, pneumonitis, bronchospasm, or neurologic toxicity
Number of Participants With Adverse Events (AEs) Leading to Discontinuation
Time Frame: From first dose of study medication through 100 days following last dose of study treatment (assessed for an average of 8 months up to a max of approximately 28 months)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Number of Participants Who Died
Time Frame: From randomization (Part 2A and 2B) or first dose (Part 1, 2C and 2D) until study closure (Up to approximately 83 months)
Number of participants who died during the study
Objective Response Rate (ORR) for Part 2 Only
Time Frame: From the start of the study treatment until disease progression, or the last response recorded, taking into account any requirement for confirmation and censoring rules regarding subsequent therapy (Up to approximately 83 months)
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Median Duration of Response (mDOR) for Part 2 Only
Time Frame: From the date of first dose to the date of the first objectively documented tumor progression, or death, whichever occurs first (Up to approximately 83 months)
Duration of response (DOR) for a participant with a BOR of CR or PR is defined as the time between the date of first response and the date of the first objectively documented tumor progression per RECIST v1.1 or death, whichever occurs first. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression). Based on Kaplan-Meier estimates of duration of response
Progression-free Survival Rate (PFSR) at 24, 36, and 48 Weeks for Part 2 Only
Time Frame: At 24, 36, and 48 weeks
Progression-free survival (PFS) for a participant is defined as the time from the first dosing date to the date of first objectively documented disease progression or death due to any cause, whichever occurs first. Based on Kaplan-Meier estimates of progression-free survival rate Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Secondary Outcomes
- Total Body Clearance (CLT/F) for BMS-986218(At Cycle 3 Day 1 (Each Cycle is of 28 Days))
- Average Concentration Over a Dosing Interval (AUC[TAU]/Tau) at Steady State (Css-avg) for BMS-986218(At Cycle 3 Day 1 (Each Cycle is of 28 Days))
- Ratio of an Exposure Measure at Steady State to That After the First Dose (Exposure Measure Includes Cmax) (AI_Cmax) for BMS-986218(At Cycle 3 Day 1 (Each Cycle is of 28 Days))
- Accumulation Index Ratio of AUC at Steady State to That After the First Dose (AI_AUC) for BMS-986218(At Cycle 3 Day 1 (Each Cycle is of 28 Days))
- Terminal Serum Half-life (T-HALF) for BMS-986218(At Cycle 3 Day 1 (Each Cycle is of 28 Days))
- Objective Response Rate (ORR) for Part1A and Part1B Only(From the start of the study treatment until disease progression, or the last response recorded, taking into account any requirement for confirmation and censoring rules regarding subsequent therapy (Up to approximately 83 months))
- Median Duration of Response (mDOR) for Part1A and Part1B Only(From the date of first dose to the date of the first objectively documented tumor progression, or death, whichever occurs first (Up to approximately 83 months))
- Progression-free Survival Rate (PFSR) at 24, 36, and 48 Weeks for Part1A and Part1B Only(At 24, 36, and 48 weeks)
- Maximum Observed Serum Concentration (Cmax) for BMS-986218(On Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, Cycle 3 Day 15 (Each Cycle is of 28 Days))
- Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] for BMS-986218(On Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, Cycle 3 Day 15 (Each Cycle is of 28 Days))
- Area Under the Concentration-time Curve in 1 Dosing Interval [AUC(TAU)] for BMS-986218(On Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, Cycle 3 Day 15 (Each Cycle is of 28 Days))
- Observed Concentration at the End of a Dosing Interval (Ctau) for BMS-986218(On Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, Cycle 3 Day 15 (Each Cycle is of 28 Days))
- Time of Maximum Observed Concentration (Tmax) for BMS-986218(On Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, Cycle 3 Day 15 (Each Cycle is of 28 Days))
- Trough Observed Plasma Concentration (Ctrough) for BMS-986218(At Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 3 Day 15, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 17 Day 1, Cycle 21 Day 1 (Each Cycle is of 28 Days))
- Number of Participants With Anti-drug Antibodies (ADA) to BMS-986218(From first dose of study medication through 100 days following last dose of study treatment (assessed for an average of 8 months up to a max of approximately 28 months))