First-In-Human Study of Monoclonal Antibody BMS-986218 by Itself and in Combination With Nivolumab in Participants With Advanced Solid Tumors
- Conditions
- Advanced Cancer
- Interventions
- Registration Number
- NCT03110107
- Lead Sponsor
- Bristol-Myers Squibb
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 376
- 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 2C: Expansion Combination Therapy (BMS-986218 + Nivolumab) Nivolumab - Part 1B: Combination Therapy (BMS-986218 + Nivolumab) Nivolumab - Part 2C: Expansion Combination Therapy (BMS-986218 + Nivolumab) BMS-986218 - Part 2D: Expansion Combination Therapy (BMS-986218 + Nivolumab) Nivolumab - Part 1A: Monotherapy (BMS-986218) BMS-986218 - Part 2A: Monotherapy (BMS-986218 OR Ipilimumab) BMS-986218 - Part 1B: Combination Therapy (BMS-986218 + Nivolumab) BMS-986218 - Part 2A: Monotherapy (BMS-986218 OR Ipilimumab) Ipilimumab - Part 2D: Expansion Combination Therapy (BMS-986218 + Nivolumab) BMS-986218 - Part 2B: Monotherapy (BMS-986218) BMS-986218 -
- Primary Outcome Measures
Name Time Method Number of Participants With Adverse Events (AEs) 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) 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 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 toxicityNumber of Participants With Adverse Events (AEs) Leading to Discontinuation 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 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 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 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 responseProgression-free Survival Rate (PFSR) at 24, 36, and 48 Weeks for Part 2 Only 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 Outcome Measures
Name Time Method 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) 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 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) 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 responseProgression-free Survival Rate (PFSR) at 24, 36, and 48 Weeks for Part1A and Part1B Only 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.
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 progression-free survival rateMaximum 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) Cmax is the maximum observed serum concentration for BMS-986218.
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) Tmax is the time taken to reach the maximum observed serum concentration (Cmax) for BMS-986218.
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) AUC (TAU) is the area measured under the concentration-time curve taken over the dosing interval for BMS-986218.
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) Ctau is the observed serum concentration at the end of the dosing interval for BMS-986218.
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) Tmax is the time taken to reach the maximum observed serum concentration (Cmax) for BMS-986218.
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) Ctrough is the lowest observed serum concentration for BMS-986218.
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) Baseline ADA Positive: Participant with baseline ADA-positive sample
ADA Positive: Participant with at least one ADA-positive sample relative to baseline (ADA negative at baseline or ADA titer to be at least 4-fold or greater (\>=) than baseline positive titer) at any time after initiation of treatment
Persistent Positive (PP): ADA-positive sample at 2 or more consecutive timepoints, where the first and last ADA-positive samples are at least 16weeks apart
Not PP-Last Sample Positive: Not persistent but with ADA-positive sample at the last sampling timepoint
Other Positive: Not persistent but some ADA-positive samples with the last sample being negative
ADA Negative: Participant with no ADA-positive sample after initiation of treatment
Trial Locations
- Locations (52)
Local Institution - 0028
🇺🇸New Brunswick, New Jersey, United States
Local Institution - 0010
🇮🇹Siena, Italy
Local Institution - 0004
🇺🇸Philadelphia, Pennsylvania, United States
Local Institution - 0026
🇦🇺Northmead, New South Wales, Australia
Local Institution - 0022
🇨🇦Toronto, Ontario, Canada
Local Institution - 0056
🇪🇸Madrid, Spain
Local Institution - 0062
🇦🇷Córdoba, Cordoba, Argentina
Local Institution - 0034
🇷🇴Cluj Napoca, Romania
Local Institution - 0058
🇺🇸Atlanta, Georgia, United States
Local Institution - 0025
🇺🇸Boston, Massachusetts, United States
Local Institution - 0002
🇺🇸Hackensack, New Jersey, United States
Local Institution - 0001
🇺🇸New York, New York, United States
Local Institution - 0007
🇺🇸New York, New York, United States
Local Institution - 0015
🇺🇸Monroeville, Pennsylvania, United States
Local Institution - 0033
🇺🇸Sioux Falls, South Dakota, United States
Local Institution - 0042
🇦🇷Ciudad Autónoma De Buenos Aires, Buenos Aires, Argentina
Local Institution - 0053
🇦🇷ABB, Ciudad Autónoma De Buenos Aires, Argentina
Local Institution - 0057
🇦🇷Caba, Ciudad Autónoma De Buenos Aires, Argentina
Local Institution - 0060
🇦🇷Rio Cuarto, Cordoba, Argentina
Local Institution - 0059
🇦🇷Buenos Aires, Distrito Federal, Argentina
Local Institution - 0047
🇦🇷Villa Siburu, Cordoba, Argentina
Local Institution - 0037
🇨🇦Edmonton, Alberta, Canada
Local Institution - 0006
🇦🇺Wollstonecraft, New South Wales, Australia
Local Institution - 0049
🇦🇺Murdoch, Western Australia, Australia
Local Institution - 0039
🇧🇪Gent, Belgium
Local Institution - 0023
🇨🇦Vancouver, British Columbia, Canada
Local Institution - 0027
🇨🇦Ottawa, Ontario, Canada
Local Institution - 0048
🇨🇱Santiago, Metropolitana, Chile
Local Institution - 0041
🇨🇱Santiago, Metropolitana, Chile
Local Institution - 0052
🇨🇱Vina del Mar, Valparaiso, Chile
Local Institution - 0045
🇫🇮Helsinki, Finland
Local Institution - 0020
🇫🇷Toulouse Cedex 9, France
Local Institution - 0019
🇫🇷Lyon Cedex 08, France
Local Institution - 0009
🇩🇪Dresden, Germany
Local Institution - 0018
🇫🇷Villejuif, France
Local Institution - 0030
🇩🇪Essen, Germany
Local Institution - 0029
🇮🇱Haifa, Israel
Local Institution - 0011
🇮🇹Napoli, Italy
Local Institution - 0008
🇮🇱Ramat Gan, Israel
Local Institution - 0061
🇮🇹Rozzano, Italy
Local Institution - 0038
🇳🇱Amsterdam, Netherlands
Local Institution - 0043
🇳🇱Nijmegen, Netherlands
Local Institution - 0040
🇳🇴Oslo, Norway
Local Institution - 0035
🇷🇴Craiova, Romania
Local Institution - 0036
🇵🇱Warszawa, Poland
Local Institution - 0014
🇪🇸Barcelona, Spain
Local Institution - 0055
🇪🇸Madrid, Spain
Local Institution - 0013
🇪🇸Madrid, Spain
Local Institution - 0012
🇪🇸Pamplona, Spain
Local Institution - 0054
🇪🇸Malaga, Spain
Local Institution - 0017
🇨🇭Lausanne, Switzerland
Local Institution - 0031
🇨🇭Zuerich, Switzerland