A Study of Safety, Tolerability and Pharmacokinetics of Nivolumab in Chinese Subjects With Previously Treated Advanced or Recurrent Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to determine whether nivolumab is safe and effective in the treatment of advanced or recurrent solid tumors in Chinese subjects.

Official Title
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A Phase 1/2, Open-Label Study of Nivolumab (BMS-936558) in Chinese Subjects With Previously Treated Advanced or Recurrent Solid Tumors (CheckMate 077: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 077)

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chinese subjects with advanced or recurrent solid tumors Exclusion Criteria: Subjects with brain metastases are excluded unless clinically stable for more than 2 weeks at the time of enrollment as determined by the investigator Subjects with carcinomatous meningitis are excluded

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab monotherapy<br>Nivolumab specified dose on specified days | Drug: Nivolumab<br> <br> |
| Experimental: Cohort Expansion<br>Nivolumab specified dose on specified days | Drug: Nivolumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants Experiencing Drug-Related Grade 3-4 Adverse Events (AEs) | A drug related 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 drug that has a causal relationship with the treatment. AEs are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03) (NCI CTCAE) guidelines where Grade 3= Severe and Grade 4= Life-threatening. | From first dose to 100 days after last dose (up to approximately 28 months) | 
| The Number of Participants Experiencing Drug-Related Grade 3-4 Serious Adverse Events (SAEs) | A drug related serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death; is life-threatening; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event that has a casual relationship with the treatment. SAEs are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03) (NCI CTCAE) guidelines where Grade 3= Severe and Grade 4= Life-threatening. | From first dose to 100 days after last dose (up to approximately 28 months) | 
| The Number of Participants Experiencing Abnormal Hepatic Laboratory Test Results | The number of participants with the following laboratory abnormalities from the following on-treatment evaluations: ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN Total bilirubin > 2 x ULN Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN | From first dose to 100 days after last dose (up to approximately 28 months) | 
| The Number of Participants Experiencing Toxicity Grade 3-4 Laboratory Test Results | The number of participants with Grade 3-4 laboratory results according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Note: Grade 4 Toxicities not included in the below table if there were no participants that experienced Grade 4 in that category. Grade 3: prolonged recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae [e.g., renal impairment, pulmonary infiltrates]. Grade 4: Life-threatening; pressor or ventilatory support indicated. | From first dose to 100 days after last dose (up to approximately 28 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) | Best overall response (BOR) was assessed by the investigator using Response Evaluation Criteria in Solid Tumor (RECIST v1.1). Complete Response (CR) is defined as a disappearance of all target lesions. Partial Response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). | From first dose up to approximately 28 months | 
| Duration of Response (DOR) | Duration of response is defined as the time from the date of first response (CR or PR) to the date of the first documented tumor progression as determined using RECIST 1.1 or death due to any cause, whichever occurs first. Participants who remain alive and have not progressed will be censored on the date of their last tumor assessment. Participants who started subsequent therapy without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent anticancer therapy. Complete response (CR) is defined as a disappearance of all target lesions and partial response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Other tumor types include: gastric, melanoma, neuroblastoma, colorectal cancer, cervical cancer, duodenal papillary carcinoma, and gallbladder carcinoma. | From the date of first response (CR or PR) to the date of the first documented tumor progression or death due to any cause, whichever occurs first. (Up to approximately 28 months) | 
| Objective Response Rate (ORR) | Objective response rate (ORR) is defined as the percentage of all treated participants whose best overall response (BOR) is either a complete response (CR) or partial response (PR) by investigator using Response Evaluation Criteria in Solid Tumor (RECIST v1.1). Complete response (CR) is defined as a disappearance of all target lesions and partial response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Other tumor types include: gastric, melanoma, neuroblastoma, colorectal cancer, cervical cancer, duodenal papillary carcinoma, and gallbladder carcinoma. | From first dose up to approximately 28 months | 
| Response Rate at 24 Weeks | Response rate at 24 weeks is defined as the percentage of all treated participants who have CR or PR by 24 weeks. Complete response (CR) is defined as a disappearance of all target lesions and partial response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Other tumor types include: gastric, melanoma, neuroblastoma, colorectal cancer, cervical cancer, duodenal papillary carcinoma, and gallbladder carcinoma. | Week 24 | 
| Disease Control Rate (DCR) at 24 Weeks | Disease control rate (DCR) at 24 weeks is defined as the percentage of all treated participants who have CR, PR or SD by 24 weeks. Complete Response (CR) is defined as a disappearance of all target lesions. Partial Response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Other tumor types include: gastric, melanoma, neuroblastoma, cervical cancer, duodenal papillary carcinoma, and gallbladder carcinoma. | Week 24 | 
| The Number of Participants With Positive Anti Drug Antibody (ADA) Assessments at Baseline and Positive or Negative ADA Samples After Treatment | The number of participants with the following anti-drug responses: Baseline ADA positive: all participants with baseline ADA positive samples. ADA Positive: participants that have at least one ADA positive sample relative to baseline at any time after initiation of treatment. ADA negative: participants that have no ADA positive samples after the initiation of treatment. | From pre-dose on day 1 Cycle 1 up to participants end of study (up to approximately 28 months) | 
| Cmax - Maximum Observed Serum Concentration | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. Cmax is the maximum observed serum concentration over time. | Day 1 Cycle 1, 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| Tmax - Time of Maximum Observed Serum Concentration | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. Tmax is the time of maximum observed serum concentration. | Day 1 Cycle 1, 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| AUC (0-T)-Area Under the Plasma Concentration-Time Curve | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. AUC (0-T) is the area under the plasma concentration-time curve from time zero to the last time of the last quantifiable concentration. | Day 1 Cycle 1, 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| AUC(TAU) - Area Under the Concentration-Time Curve in One Dosing Interval | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. AUC (TAU) is the area under the plasma concentration-time curve in one dosing interval. | Day 1 Cycle 1, 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| Ceoinf - Serum Concentration Achieved at the End of Study Drug Infusion | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. Ceoinf is the serum concentration achieved at the end of study drug infusion. | End of infusion on Day 1 of Cycle 1, 3, 5, 6 | 
| Ctrough - Trough Observed Serum Concentration at the End of Dosing Interval | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. Ctrough is the trough observed serum concentration at the end of dosing interval. | Day 1 Cycle 3, 5, 6 (168 hours post dose [Cohort A-B], 336 hours post dose [Cohort C-D]) | 
| Ctau - Concentration at the End of Dosing Interval | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. Ctau is the concentration at the end of dosing interval. | Day 1 Cycle 1, 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| T-HALFeff - Effective Elimination Half-Life | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. T-HALFeff is the effective elimination half-life that explains the degree of observed AUC accumulation calculated based on ratio of an exposure measure at steady state to that after the first dose (exposure measure includes AUC(TAU), Cmax and Ctau). | Day 1 Cycle 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| CLT - Total Body Clearance | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. CLT is the total body clearance. | Day 1 Cycle 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| AI - Accumulation Index (Cmax) | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. AI of Cmax refers to the accumulation index calculated based on ratio of an exposure measure of Cmax at steady state to that after the first dose. | Day 1 Cycle 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| AI - Accumulation Index (Ctau) | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. AI of Ctau refers to the accumulation index calculated based on ratio of an exposure measure of Ctau at steady state to that after the first dose. | Day 1 Cycle 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) | 
| AI - Accumulation Index (AUC) | Nivolumab pharmacokinetic parameters are derived from serum concentration versus time data. AI of AUC refers to the accumulation index calculated based on ratio of an exposure measure of AUC at steady state to that after the first dose. | Day 1 Cycle 3, 5, 6 (pre-dose, 0.5, 4, 8, 24, 48, 96, 168, hours post dose. Cohort C-D includes also 336 hours post dose) |