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) (CheckMate 848)

A Randomized, Open-Label, Phase 2 Study of Nivolumab in Combination With Ipilimumab or Nivolumab Monotherapy in Participants With Advanced or Metastatic Solid Tumors of High Tumor Mutational Burden (TMB-H)

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.

Study Overview

• Status: Completed
• Conditions: Pan Tumor
• Intervention / Treatment: Biological: Nivolumab; Biological: Ipilimumab

• Study Type: Interventional
• Enrollment (Actual): 212
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, 1199
    • Local Institution - 0078
  • Caba, Argentina, 1426
    • Local Institution - 0015
  • Cordoba, Argentina, 5000
    • Local Institution - 0119
  • Buenos Aires
    • Ciudad Autonoma Beunos Aires, Buenos Aires, Argentina, 1431
      • Local Institution - 0016
    • Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina, 1280
      • Local Institution - 0087
• Australia
  • New South Wales
    • St Leonards, New South Wales, Australia, 2065
      • Local Institution - 0118
    • Sydney, New South Wales, Australia, 2010
      • Local Institution - 0062
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Local Institution - 0117
• Belgium
  • Brussels, Belgium, 1090
    • Local Institution - 0112
  • Bruxelles, Belgium, 1200
    • Local Institution - 0113
  • Leuven, Belgium, 3000
    • Local Institution - 0114
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Local Institution - 0010
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Local Institution - 0060
  • Quebec
    • Montreal, Quebec, Canada, H2X 3E4
      • Local Institution - 0036
    • Montreal, Quebec, Canada, H3T 1E2
      • Local Institution - 0088
• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile, 8330024
      • Local Institution - 0018
    • Santiago, Metropolitana, Chile, 8420383
      • Local Institution - 0082
• Denmark
  • Copenhagen, Denmark, 2100
    • Local Institution - 0080
  • Herlev, Denmark, 2730
    • Local Institution - 0081
• France
  • Lyon Cedex 08, France, 69373
    • Local Institution - 0072
  • Marseille Cedex 9, France, 13273
    • Local Institution - 0075
  • Paris Cedex 5, France, 75248
    • Local Institution - 0073
  • Toulouse, France, 31100
    • Local Institution - 0074
  • Villejuif, France, 94805
    • Local Institution - 0085
• Germany
  • Berlin, Germany, 12200
    • Local Institution - 0039
  • Bonn, Germany, 53127
    • Local Institution - 0001
  • Dresden, Germany, 01307
    • Local Institution - 0002
  • Essen, Germany, 45147
    • Local Institution - 0086
  • Wuerzburg, Germany, 97080
    • Local Institution - 0043
• Italy
  • Genova, Italy, 16132
    • Local Institution - 0032
  • Milano, Italy, 20133
    • IRCCS Istituto Nazionale Tumori Milano
  • Napoli, Italy, 80131
    • Local Institution - 0029
  • Siena, Italy, 53100
    • Local Institution - 0031
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Local Institution - 0115
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
      • Local Institution - 0116
• Poland
  • Gdansk, Poland, 80-214
    • Local Institution - 0077
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-781
      • Local Institution - 0076
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Fundacion de Investigacion
• Romania
  • Bucuresti, Romania, 022328
    • Local Institution - 0069
  • Craiova, Romania, 200542
    • Local Institution - 0067
  • Floresti, Romania, 407280
    • Local Institution - 0070
  • Timisoara, Timis, Romania, 300239
    • Local Institution - 0071
  • Cluj
    • Cluj-Napoca, Cluj, Romania, 400015
      • Local Institution - 0068
• Singapore
  • Singapore, Singapore, 117599
    • Local Institution - 0066
  • Central Singapore
    • Singapore, Central Singapore, Singapore, 168583
      • Local Institution - 0065
• Spain
  • Barcelona, Spain, 08035
    • Local Institution - 0084
  • Madrid, Spain, 28041
    • Local Institution - 0083
  • Pamplona, Spain, 31008
    • Local Institution - 0110
• United Kingdom
  • Preston, United Kingdom, PR2 9HT
    • Local Institution - 0107
  • Greater London
    • London, Greater London, United Kingdom, W12 OHS
      • Local Institution - 0106
• United States
  • California
    • Santa Monica, California, United States, 90404
      • John Wayne Cancer Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Centers
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Local Institution - 0093
  • New York
    • Johnson City, New York, United States, 13790
      • Broome Oncology
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Local Institution - 0079
  • Texas
    • Austin, Texas, United States, 78731
      • Local Institution - 0095
    • Dallas, Texas, United States, 75231
      • Local Institution - 0094
    • Houston, Texas, United States, 77030
      • Local Institution - 0090
    • Tyler, Texas, United States, 75702
      • Texas Oncology - Northeast Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab + Ipilimumab Combination	Biological: Nivolumab; Specified dose on specified days; Other Names: BMS-936558; Opdivo; Biological: Ipilimumab; Specified dose on specified days; Other Names: BMS-734016; Yervoy
Experimental: Nivolumab Monotherapy	Biological: Nivolumab; Specified dose on specified days; Other Names: BMS-936558; Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) - Arm A	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.	From date of randomization up to 42 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) - Arm B	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.	From date of randomization up to 57 months
Objective Response Rate (ORR) Per Investigator	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.	From date of randomization up to 57 months
Duration of Response (DoR) Per Investigator	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.	From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)
Duration of Response (DoR) Per Blinded Independent Central Review (BICR)	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.	From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)
Time to Objective Response (TTR) Per Investigator	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.	From date of randomization to date of first confirmed response (CR or PR) (Up to 57 months)
Time to Objective Response (TTR) Per Blinded Independent Central Review (BICR)	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.	From date of randomization to date of first confirmed response (CR or PR) (Up to 57 months)
Clinical Benefit Rate (CBR) Per Investigator	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 lesions	From date of randomization up to 57 months
Clinical Benefit Rate (CBR) Per Blinded Independent Central Review (BICR)	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 lesions	From date of randomization up to 57 months
Progression Free Survival (PFS) Per Investigator	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.	From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)
Progression Free Survival (PFS) Per Blinded Independent Central Review (BICR)	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.	From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)
Overall Survival (OS)	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.	From date of randomization to date of death (Up to 57 months)
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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 exclusive	From first dose to 30 days post last dose (Up to 25 months)
Number of Participants With On-Treatment Laboratory Parameters	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	From first dose to 30 days post last dose (Up to 25 months)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2018
• Primary Completion (Actual): May 3, 2022
• Study Completion (Actual): August 2, 2023

Study Registration Dates

• First Submitted: September 11, 2018
• First Submitted That Met QC Criteria: September 11, 2018
• First Posted (Actual): September 12, 2018

Study Record Updates

• Last Update Posted (Actual): August 28, 2024
• Last Update Submitted That Met QC Criteria: July 31, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: TMB-H
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: CA209-848; 2016-002898-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No