A Study of Nivolumab Combined With Ipilimumab and Nivolumab Alone in Patients With Advanced or Metastatic Solid Tumors of High Tumor Mutational Burden (TMB-H)
- Conditions
- Pan Tumor
- Interventions
- Biological: NivolumabBiological: Ipilimumab
- Registration Number
- NCT03668119
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
The purpose of this study is to demonstrate the clinical activity of nivolumab in combination with ipilimumab in multiple types of tumors based on their Tumor Mutational Burden status.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 212
- Participants with a refractory, metastatic, or unresectable histologically or cytologically confirmed solid malignant tumor with high tumor mutational burden (TMB-H) who are refractory to standard local therapies, or for which no standard treatment is available.
- Must be able to provide tissue and blood TMB-H testing results
- Must have measurable disease for response assessment
- Participants with melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) or hematological malignancy as primary site of disease
- Participants who received prior treatment with an anti-programmed death-1 (anti-PD-1), anti-programmed death ligand 1 (anti-PD-L1), anti-programmed death ligand 2 (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
- Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational therapy within 28 days of first administration of study treatment
Other protocol defined inclusion/exclusion criteria apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Nivolumab Monotherapy Nivolumab - Nivolumab + Ipilimumab Combination Nivolumab - Nivolumab + Ipilimumab Combination Ipilimumab -
- Primary Outcome Measures
Name Time Method Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) - Arm A From date of randomization up to 42 months ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on Blinded Independent Central Review (BICR) assessment.
RECIST Criteria:
CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm.
PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
RANO Criteria:
CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.
- Secondary Outcome Measures
Name Time Method Time to Objective Response (TTR) Per Blinded Independent Central Review (BICR) From date of randomization to date of first confirmed response (CR or PR) (Up to 57 months) TTR is defined as the time from randomization date to the date of the first confirmed response (complete response (CR) or partial response (PR)), based on Blinded Independent Central Review (BICR) assessment.
RECIST Criteria:
CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm.
PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
RANO Criteria:
CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.Clinical Benefit Rate (CBR) Per Blinded Independent Central Review (BICR) From date of randomization up to 57 months CBR is defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) or stable disease (SD) per Blinded Independent Central Review (BICR) assessment.
RECIST Criteria:
CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm PR= ≥ 30% decrease in the sum of diameters of target lesions SD= does not qualify for PR or progressive disease
RANO Criteria:
CR= Disappearance of all enhancing disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; stable or improved clinically SD= does not qualify for CR, PR, or progression; stable nonenhancing T2/FLAIR lesionsObjective Response Rate (ORR) Per Blinded Independent Central Review (BICR) - Arm B From date of randomization up to 57 months ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on Blinded Independent Central Review (BICR) assessment.
RECIST Criteria:
CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm.
PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
RANO Criteria:
CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.Objective Response Rate (ORR) Per Investigator From date of randomization up to 57 months ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on investigator assessment. Calculated using Clopper-Pearson method.
RECIST Criteria:
CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm.
PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
RANO Criteria:
CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.Duration of Response (DoR) Per Investigator From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months) DoR was defined as the time from first confirmed complete or partial response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Calculated using KM method.
RECIST Criteria:
CR= Disappearance of all target lesions. PR= ≥ 30% decrease in the sum of diameters of target lesions. PD= ≥ 20% increase in the sum of diameters of target lesions.
RANO Criteria:
CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable/improved T2/FLAIR; off corticosteroids; stable/improved clinically PR= ≥ 50% decrease in the sum of diameters of all measurable enhancing lesions; no progression of nonmeasurable disease; no new lesions; stable/improved T2/FLAIR; stable/improved clinically.
PD= ≥ 25% increase in sum of diameters of enhancing lesions, on stable/increasing doses of corticosteroids; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.Duration of Response (DoR) Per Blinded Independent Central Review (BICR) From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months) DoR was defined as the time from first confirmed complete or partial response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Calculated using KM method.
RECIST Criteria:
CR= Disappearance of all target lesions. PR= ≥ 30% decrease in the sum of diameters of target lesions. PD= ≥ 20% increase in the sum of diameters of target lesions.
RANO Criteria:
CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable/improved T2/FLAIR; off corticosteroids; stable/improved clinically PR= ≥ 50% decrease in the sum of diameters of all measurable enhancing lesions; no progression of nonmeasurable disease; no new lesions; stable/improved T2/FLAIR; stable/improved clinically.
PD= ≥ 25% increase in sum of diameters of enhancing lesions, on stable/increasing doses of corticosteroids; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.Time to Objective Response (TTR) Per Investigator From date of randomization to date of first confirmed response (CR or PR) (Up to 57 months) TTR is defined as the time from randomization date to the date of the first confirmed response (complete response (CR) or partial response (PR)), based on investigator assessment.
RECIST Criteria:
CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm.
PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
RANO Criteria:
CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.Clinical Benefit Rate (CBR) Per Investigator From date of randomization up to 57 months CBR is defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) or stable disease (SD) based on investigator assessment.
RECIST Criteria:
CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm PR= ≥ 30% decrease in the sum of diameters of target lesions SD= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
RANO Criteria:
CR= Disappearance of all enhancing disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; stable or improved clinically SD= does not qualify for CR, PR, or progression; stable nonenhancing T2/FLAIR lesionsProgression Free Survival (PFS) Per Blinded Independent Central Review (BICR) From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months) PFS is defined as the time from randomization date to the date of the first documented tumor progression, determined by Blinded Independent Central Review (BICR) assessment, or death due to any cause, whichever occurs first. Calculated using KM method.
RECIST Criteria:
Progressive Disease (PD)= ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of ≥ 5 mm.
RANO Criteria:
PD= ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.Overall Survival (OS) From date of randomization to date of death (Up to 57 months) OS is defined as the time between the date of randomization and the date of death due to any cause. Participants who did not have a date of death were censored on the last date for which a participant was known to be alive. Calculated using KM method.
Progression Free Survival (PFS) Per Investigator From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months) PFS is defined as the time from randomization date to the date of the first documented tumor progression, determined by investigator assessment, or death due to any cause, whichever occurs first. Calculated using KM method.
RECIST Criteria:
Progressive Disease (PD)= ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of ≥ 5 mm.
RANO Criteria:
PD= ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) From first dose to 30 days post last dose (Up to 25 months) Number of participants with any grade adverse events (AEs), serious adverse events (SAEs), drug-related AEs, and drug-related SAEs by Tumor Mutational Burden- High (TMB-H) status using worst grade per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) v5 criteria. An 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.
TMB-H = ≥ 10 mutations per megabase bTMB-H and tTMB-H are not mutually exclusiveNumber of Participants With On-Treatment Laboratory Parameters From first dose to 30 days post last dose (Up to 25 months) Number of participants with grade 3-4 on-treatment laboratory parameters. Parameters include hematology, chemistry, liver function, and renal function using worst grade per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) v5 criteria.
Grade 3=Severe event Grade 4=Life threatening event TMB-H = ≥ 10 mutations per megabase bTMB-H and tTMB-H are not mutually exclusive
Trial Locations
- Locations (60)
John Wayne Cancer Center
🇺🇸Santa Monica, California, United States
Local Institution - 0078
🇦🇷Caba, Argentina
Broome Oncology
🇺🇸Johnson City, New York, United States
Local Institution - 0094
🇺🇸Dallas, Texas, United States
Local Institution - 0090
🇺🇸Houston, Texas, United States
Texas Oncology - Northeast Texas
🇺🇸Tyler, Texas, United States
Local Institution - 0016
🇦🇷Ciudad Autonoma Beunos Aires, Buenos Aires, Argentina
Local Institution - 0087
🇦🇷Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Local Institution - 0015
🇦🇷Caba, Argentina
Local Institution - 0118
🇦🇺St Leonards, New South Wales, Australia
Local Institution - 0117
🇦🇺Woolloongabba, Queensland, Australia
Local Institution - 0119
🇦🇷Cordoba, Argentina
Local Institution - 0062
🇦🇺Sydney, New South Wales, Australia
Local Institution - 0112
🇧🇪Brussels, Belgium
Local Institution - 0113
🇧🇪Bruxelles, Belgium
Local Institution - 0010
🇨🇦Edmonton, Alberta, Canada
Local Institution - 0036
🇨🇦Montreal, Quebec, Canada
Local Institution - 0114
🇧🇪Leuven, Belgium
Local Institution - 0088
🇨🇦Montreal, Quebec, Canada
Local Institution - 0060
🇨🇦Hamilton, Ontario, Canada
Local Institution - 0018
🇨🇱Santiago, Metropolitana, Chile
Local Institution - 0082
🇨🇱Santiago, Metropolitana, Chile
Local Institution - 0080
🇩🇰Copenhagen, Denmark
Local Institution - 0073
🇫🇷Paris Cedex 5, France
Local Institution - 0072
🇫🇷Lyon Cedex 08, France
Local Institution - 0075
🇫🇷Marseille Cedex 9, France
Local Institution - 0074
🇫🇷Toulouse, France
Local Institution - 0039
🇩🇪Berlin, Germany
Local Institution - 0085
🇫🇷Villejuif, France
Local Institution - 0001
🇩🇪Bonn, Germany
Local Institution - 0002
🇩🇪Dresden, Germany
Local Institution - 0086
🇩🇪Essen, Germany
Local Institution - 0029
🇮🇹Napoli, Italy
Local Institution - 0032
🇮🇹Genova, Italy
Local Institution - 0043
🇩🇪Wuerzburg, Germany
IRCCS Istituto Nazionale Tumori Milano
🇮🇹Milano, Italy
Local Institution - 0116
🇳🇱Rotterdam, Zuid-Holland, Netherlands
Local Institution - 0031
🇮🇹Siena, Italy
Local Institution - 0115
🇳🇱Amsterdam, Netherlands
Local Institution - 0076
🇵🇱Warszawa, Mazowieckie, Poland
Local Institution - 0077
🇵🇱Gdansk, Poland
Fundacion De Investigacion
🇵🇷San Juan, Puerto Rico
Local Institution - 0069
🇷🇴Bucuresti, Romania
Local Institution - 0067
🇷🇴Craiova, Romania
Local Institution - 0070
🇷🇴Floresti, Romania
Local Institution - 0071
🇷🇴Timisoara, Timis, Romania
Local Institution - 0066
🇸🇬Singapore, Singapore
Local Institution - 0084
🇪🇸Barcelona, Spain
Local Institution - 0110
🇪🇸Pamplona, Spain
Local Institution - 0083
🇪🇸Madrid, Spain
Local Institution - 0106
🇬🇧London, Greater London, United Kingdom
Local Institution - 0107
🇬🇧Preston, United Kingdom
Local Institution - 0093
🇺🇸Minneapolis, Minnesota, United States
Duke Cancer Institute
🇺🇸Durham, North Carolina, United States
Local Institution - 0068
🇷🇴Cluj-Napoca, Cluj, Romania
Local Institution - 0065
🇸🇬Singapore, Central Singapore, Singapore
Local Institution - 0081
🇩🇰Herlev, Denmark
Rocky Mountain Cancer Centers
🇺🇸Denver, Colorado, United States
Local Institution - 0079
🇺🇸Portland, Oregon, United States
Local Institution - 0095
🇺🇸Austin, Texas, United States