The first part of the study is the Dose Escalation Phase designed to establish the safety of nivolumab at different dose levels for each of the three cohorts (uninfected hepatocellular carcinoma (HCC) subjects, hepatitis C virus (HCV)-infected HCC subjects, and hepatitis B virus (HBV)-infected subjects). The second part of the study is the Expansion Phase designed to generate additional clinical data at specified doses for each of the 3 cohorts. A third cohort has been added in this study to compare the efficacy of nivolumab and sorafenib in the treatment of Advanced HCC. A fourth cohort will generate data on the safety and efficacy of the combination nivolumab plus ipilimumab in the treatment of Advanced HCC. In the fifth cohort, additional clinical data will be generated for Child-Pugh B subjects. A Cabozantinib Combination Cohort has been added to evaluate the safety and tolerability of nivolumab in combination with cabozantinib and nivolumab with ipilimumab in combination with cabozantinib.
Study Classification: Pharmacokinetics/Pharmacodynamics
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
657
Local Institution - 0008
Los Angeles, California, United States
Local Institution - 0048
Washington D.C., District of Columbia, United States
Local Institution - 0053
Pensacola, Florida, United States
Local Institution - 0047
Atlanta, Georgia, United States
Local Institution - 0025
Boston, Massachusetts, United States
Number of Participants With Adverse Events (AEs)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of Participants With Serious Adverse Events (SAEs)
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, and requires inpatient hospitalization or causes prolongation of existing hospitalization.
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of Participants With Adverse Events Leading to Discontinuation
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of Participants Who Died
Number of participants who died during the study.
Time frame: From first dose of study medication until study closure (Up to approximately 144 months)
Number of Participants With Laboratory Abnormalities in Specific Liver Tests
Participants with abnormalities in liver function tests related to potential drug-induced liver injury. Blood samples were collected and analyzed for liver function parameters, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Abnormalities were assessed relative to the upper limit of normal (ULN) for each parameter. Abbreviations: ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase; ULN = Upper Limit of Normal.
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests
Number of participants with thyroid-related laboratory abnormalities during the study. Blood samples were collected and analyzed for thyroid function markers (FT3, FT4). Abnormalities were assessed against LLN and ULN for each parameter. Abbreviations: FT3 = Free T3; FT4 = Free T4; LLN = Lower Limit of Normal; ULN = Upper Limit of Normal; TSH = Thyroid Stimulating Hormone
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 2
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Time frame: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Objective Response Rate (ORR) by Investigator for Cohorts 3, 4, 5, and 6
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 1
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Time frame: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Number of Participants With Complete Response (CR) Assessed by Blinded Independent Central Review (BICR)
The number of participants whose best overall response (BOR) is CR in the population of interest. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm.
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to approximately 144 months after first dose
Disease Control Rate (DCR) Assessed by Blinded Independent Central Review (BICR)
The percentage of participants whose best overall response (BOR) is CR, PR or SD in the population of interest. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Failure to meet criteria for complete or partial response, in the absence of progressive disease. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
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Local Institution - 0002
Ann Arbor, Michigan, United States
Local Institution - 0054
Hackensack, New Jersey, United States
Local Institution - 0067
Paterson, New Jersey, United States
Local Institution - 0001
Portland, Oregon, United States
The University Of Texas MD Anderson Cancer Center
Houston, Texas, United States
...and 50 more locations
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Duration of Response (DOR) Assessed by Blinded Independent Central Review (BICR)
DOR is defined as the time from the first documented objective response (either complete or partial response) until the date of disease progression or death from any cause, whichever occurs first. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Time frame: From first documented response to first documented progression or death, whichever occurs first (Up to approximately 144 months)
Time to Response (TTR) Assessed by Blinded Independent Central Review (BICR)
Time to Response (TTR) defined as the time from randomization to the date of the first confirmed CR or PR for Cohort 3, 4 and 6, and from the first dosing date of study medication to the date of the first confirmed CR or PR for cohort 1, 2 and 5. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) to the date of attainment of complete response (CR) or partial response (PR) (up to approximately 144 months)
Time to Progression (TTP) Assessed by Blinded Independent Central Review (BICR)
Time to Progression (TTP) is defined from the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) to the date of the first objectively documented disease progression. Participants who have not progressed as assessed by radiography will be censored at the last tumor assessment date prior to subsequent anti-cancer therapy. Participants who have no on-study tumor assessments were censored at the date of randomization. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Time to Progression (TTP) Rate Assessed by Blinded Independent Central Review (BICR)
TTP rate is defined as the percentage of participants without disease progression at select time points (milestones) during the study. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Time frame: At 6 and 12 months
Progression Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR)
PFS is defined as the time from randomization date or first dosing date of study medication to the date of the first objectively documented tumor progression or death due to any cause. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last tumor assessment. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to documented disease progression or death, whichever occurs first (up to approximately 144 months)
Overall Survival (OS)
OS is defined as the time from randomization date or first dosing date of study medication to the date of death (due to any cause). Participants who were alive were censored at the last known alive dates.
Time frame: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of death or date last known alive (up to approximately 144 months)
Overall Survival (OS) Rate
OS rate is defined as the percentage of participants who are still alive at certain time points during the study.
Time frame: At 6, 12, 24, 48 and 60 months
Maximum Observed Serum Concentration (Cmax)
Cmax is the maximum observed serum concentration.
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Time of Maximum Observed Serum Concentration (Tmax)
Tmax is the time taken to reach the maximum observed serum concentration (Cmax).
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Area Under the Serum Concentration Time Curve in the Dosing Interval [AUC(TAU)]
AUC (TAU) is the area measured under the concentration-time curve taken over the dosing interval.
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Serum Concentration Achieved at the End of Dosing Interval (Trough Concentration) (Ctrough)
Ctrough is the lowest observed serum concentration.
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Serum Concentration Achieved at the End of the Infusion (Ceoinf)
Serum Concentration Achieved at the End of the Infusion (Ceoinf) refers to the amount of drug present in the blood (serum) immediately after the completion of an infusion. It represents the concentration measured at the exact time the infusion ends, before any significant elimination or distribution occurs.
Time frame: At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Ratio of an Exposure Measure at Steady State to That After the First Dose (Exposure Measure Includes Cmax) (AI_Cmax)
AI\_Cmax is ratio of an exposure measure at steady state to that after the first dose (exposure measure includes Cmax)
Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Accumulation Index Ratio of AUC at Steady State to That After the First Dose (AI_AUC)
AI\_AUC is accumulation index ratio of AUC at steady state to that after the first dose
Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Effective T-Half (T-HALF)
Effective half-life is defined as the time it takes for the amount of a drug in the body to decrease by half.
Time frame: At Cycle 3 Day 1 (Each Cycle = 2 Weeks)
Number of Participants With Anti-drug Antibodies (ADA)
Baseline ADA Positive: Participant with baseline ADA-positive sample ADA Positive: Participant with at least one ADA-positive sample relative to baseline Persistent Positive (PP): ADA-positive sample at 2 or more consecutive timepoints Not PP-Last Sample Positive: Not persistent but with ADA-positive sample at the last sampling timepoint Other Positive: Not persistent but some ADA-positive samples with the last sample being negative ADA Negative: Participant with no ADA-positive sample after initiation of treatment
Time frame: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)