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)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT03668119 |
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Recruitment Status :
Active, not recruiting
First Posted : September 12, 2018
Results First Posted : May 18, 2023
Last Update Posted : May 23, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Pan Tumor | Biological: Nivolumab Biological: Ipilimumab | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 212 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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) |
| Actual Study Start Date : | October 31, 2018 |
| Actual Primary Completion Date : | May 3, 2022 |
| Estimated Study Completion Date : | October 31, 2023 |
| Arm | Intervention/treatment |
|---|---|
| Experimental: Nivolumab + Ipilimumab Combination |
Biological: Nivolumab
Specified dose on specified days
Other Names:
Biological: Ipilimumab Specified dose on specified days
Other Names:
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| Experimental: Nivolumab Monotherapy |
Biological: Nivolumab
Specified dose on specified days
Other Names:
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- Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) - Arm A [ Time Frame: 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.
- Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) - Arm B [ Time Frame: 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.
- Objective Response Rate (ORR) Per Investigator [ Time Frame: 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 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.
- Duration of Response (DoR) Per Investigator [ Time Frame: From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 42 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.
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) [ Time Frame: From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 42 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.
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 [ Time Frame: From date of randomization to date of first confirmed response (CR or PR) (Up to 42 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.
- Time to Objective Response (TTR) Per Blinded Independent Central Review (BICR) [ Time Frame: From date of randomization to date of first confirmed response (CR or PR) (Up to 42 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 Investigator [ Time Frame: From date of randomization up to 42 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 lesions
- Clinical Benefit Rate (CBR) Per Blinded Independent Central Review (BICR) [ Time Frame: From date of randomization up to 42 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 lesions
- Progression Free Survival (PFS) Per Investigator [ Time Frame: From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 42 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.
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.
- Progression Free Survival (PFS) Per Blinded Independent Central Review (BICR) [ Time Frame: From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 42 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.
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) [ Time Frame: From date of randomization to date of death (Up to 42 months) ]OS is defined as the time between the date of randomization and the date of death due to any cause. Participants who do not have a date of death will be censored on the last date for which a participant was known to be alive.
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose to 30 days post last dose (Up to 39 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 exclusive
- Number of Participants With On-Treatment Laboratory Parameters [ Time Frame: From first dose to 30 days post last dose (Up to 39 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 12 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03668119
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| Study Director: | Bristol-Myers Squibb | Bristol-Myers Squibb |
Documents provided by Bristol-Myers Squibb:
| Responsible Party: | Bristol-Myers Squibb |
| ClinicalTrials.gov Identifier: | NCT03668119 |
| Other Study ID Numbers: |
CA209-848 2016-002898-35 ( EudraCT Number ) |
| First Posted: | September 12, 2018 Key Record Dates |
| Results First Posted: | May 18, 2023 |
| Last Update Posted: | May 23, 2023 |
| Last Verified: | May 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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TMB-H |
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Neoplasms Nivolumab Ipilimumab Antineoplastic Agents, Immunological |
Antineoplastic Agents Immune Checkpoint Inhibitors Molecular Mechanisms of Pharmacological Action |