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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03668119
Registration number
NCT03668119
Ethics application status
Date submitted
11/09/2018
Date registered
12/09/2018
Date last updated
1/09/2023
Titles & IDs
Public title
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)
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Scientific 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)
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Secondary ID [1]
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0
2016-002898-35
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Secondary ID [2]
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CA209-848
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Universal Trial Number (UTN)
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Trial acronym
CheckMate 848
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Pan Tumor
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0
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Condition category
Condition code
Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Nivolumab
Other interventions - Ipilimumab
Experimental: Nivolumab + Ipilimumab Combination -
Experimental: Nivolumab Monotherapy -
Other interventions: Nivolumab
Specified dose on specified days
Other interventions: Ipilimumab
Specified dose on specified days
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Intervention code [1]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) - Arm A
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Assessment method [1]
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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.
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Timepoint [1]
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From date of randomization up to 42 months
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Secondary outcome [1]
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Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) - Arm B
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Assessment method [1]
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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.
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Timepoint [1]
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From date of randomization up to 42 months
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Secondary outcome [2]
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Objective Response Rate (ORR) Per Investigator
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Assessment method [2]
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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.
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Timepoint [2]
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From date of randomization up to 42 months
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Secondary outcome [3]
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Duration of Response (DoR) Per Investigator
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Assessment method [3]
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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.
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Timepoint [3]
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From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 42 months)
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Secondary outcome [4]
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Duration of Response (DoR) Per Blinded Independent Central Review (BICR)
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Assessment method [4]
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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.
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Timepoint [4]
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From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 42 months)
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Secondary outcome [5]
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Time to Objective Response (TTR) Per Investigator
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Assessment method [5]
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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.
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Timepoint [5]
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From date of randomization to date of first confirmed response (CR or PR) (Up to 42 months)
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Secondary outcome [6]
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Time to Objective Response (TTR) Per Blinded Independent Central Review (BICR)
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Assessment method [6]
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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.
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Timepoint [6]
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From date of randomization to date of first confirmed response (CR or PR) (Up to 42 months)
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Secondary outcome [7]
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Clinical Benefit Rate (CBR) Per Investigator
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Assessment method [7]
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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
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Timepoint [7]
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From date of randomization up to 42 months
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Secondary outcome [8]
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Clinical Benefit Rate (CBR) Per Blinded Independent Central Review (BICR)
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Assessment method [8]
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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
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Timepoint [8]
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From date of randomization up to 42 months
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Secondary outcome [9]
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Progression Free Survival (PFS) Per Investigator
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Assessment method [9]
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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.
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Timepoint [9]
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From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 42 months)
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Secondary outcome [10]
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Progression Free Survival (PFS) Per Blinded Independent Central Review (BICR)
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Assessment method [10]
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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.
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Timepoint [10]
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From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 42 months)
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Secondary outcome [11]
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Overall Survival (OS)
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Assessment method [11]
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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.
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Timepoint [11]
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From date of randomization to date of death (Up to 42 months)
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Secondary outcome [12]
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Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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Assessment method [12]
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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
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Timepoint [12]
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From first dose to 30 days post last dose (Up to 39 months)
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Secondary outcome [13]
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Number of Participants With On-Treatment Laboratory Parameters
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Assessment method [13]
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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
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Timepoint [13]
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From first dose to 30 days post last dose (Up to 39 months)
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Eligibility
Key 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
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Minimum age
12
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
31/10/2018
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
2/08/2023
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Sample size
Target
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Accrual to date
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Final
212
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Recruitment in Australia
Recruitment state(s)
NSW,QLD
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Recruitment hospital [1]
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Local Institution - 0118 - St Leonards
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Recruitment hospital [2]
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Local Institution - 0062 - Sydney
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Recruitment hospital [3]
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Local Institution - 0117 - Woolloongabba
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Recruitment postcode(s) [1]
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2065 - St Leonards
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Recruitment postcode(s) [2]
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2010 - Sydney
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Recruitment postcode(s) [3]
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4102 - Woolloongabba
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Recruitment outside Australia
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United States of America
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State/province [1]
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California
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United States of America
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Colorado
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United States of America
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Minnesota
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United States of America
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New York
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United States of America
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North Carolina
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United States of America
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Oregon
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United States of America
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Texas
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Argentina
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Buenos Aires
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Argentina
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Caba
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Argentina
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Cordoba
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Belgium
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Brussels
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Belgium
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Bruxelles
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Belgium
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Leuven
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Canada
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Alberta
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Canada
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Ontario
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Canada
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Quebec
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Chile
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Metropolitana
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Denmark
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Copenhagen
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Denmark
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Herlev
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France
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Lyon Cedex 08
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France
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Marseille Cedex 9
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France
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Paris Cedex 5
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France
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Toulouse
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France
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Villejuif
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Germany
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Berlin
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Germany
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Bonn
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Germany
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Dresden
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Germany
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Essen
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Germany
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Wuerzburg
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Italy
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Genova
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Italy
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Milano
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Italy
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Napoli
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Italy
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Siena
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Zuid-Holland
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Netherlands
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Amsterdam
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Poland
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Mazowieckie
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Poland
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Gdansk
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Puerto Rico
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San Juan
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Romania
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Cluj
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Romania
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Bucuresti
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Romania
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Craiova
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Romania
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Floresti
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Romania
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Timisoara, Timis
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Singapore
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Singapore
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Spain
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Barcelona
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Spain
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Madrid
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Spain
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Pamplona
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United Kingdom
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Greater London
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United Kingdom
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State/province [49]
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Preston
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Bristol-Myers Squibb
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03668119
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Bristol-Myers Squibb
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Address
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Bristol-Myers Squibb
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03668119
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