This phase II trial studies the best dose and side effects of sorafenib tosylate and nivolumab in treating patients with liver cancer that cannot be removed by surgery (unresectable), has spread to nearby tissues or lymph nodes (locally advanced) or to other places in the body (metastatic). Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sorafenib tosylate and nivolumab may work better in treating patients with liver cancer.
PRIMARY OBJECTIVES: I. Maximum tolerated dose (MTD) of sorafenib tosylate (sorafenib) in combination with standard dose nivolumab with Child Pugh A-B7 liver function. (Part 1: Escalation Cohort). II. Safety in participants with Child-Pugh B liver function. (Part 2: Child-Pugh B Escalation Cohort) SECONDARY OBJECTIVES: I. Safety and tolerability of combination overall. (Parts 1 and 2). II. Rate of immune-related adverse event (irAE) for combination overall and in participants with Child-Pugh B liver function. (Parts 1 and 2). III. Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in participants with Child-Pugh B liver function. (Parts 1 and 2). IV. Duration of response (DOR), progression free survival (PFS), and overall survival (OS) for escalation cohort and Child-Pugh B expansion cohort and overall. (Parts 1 and 2). EXPLORATORY OBJECTIVES: I. Relationship between peripheral blood mononuclear cell (PBMC) immune cell subset frequencies, baseline liver function, and clinical outcomes. II. Relationship between PBMC T cell receptor (TCR) clonotype frequency and diversity, baseline liver function, and clinical outcomes. III. Tumor tissue immune cell subsets and TCR clonotype frequency and diversity in pre-treatment archival tumor tissue samples. IV. Tumor and immune cell programmed death-ligand 1 (PD-L1) status in pre-treatment archival tumor tissue samples and relationship to clinical outcomes. V. Changes in hepatitis B virus (HBV) and/or hepatitis C virus (HCV) viral load on treatment. VI. Alpha-fetoprotein (AFP) changes on treatment and relationship to clinical outcomes. VII. Relationship between clinical outcomes and clinicopathologic features including race/ethnicity, etiology of liver disease including HBV/HCV status, baseline liver function, presence of cirrhosis, macrovessel invasion, extrahepatic spread, site(s) of metastatic disease, prior treatment history including prior radiation and arterial therapies. OUTLINE: This is a dose-escalation and expansion study of sorafenib tosylate. DOSE-ESCALATION (Part 1): Between 3-12 participants will be enrolled in Part 1. Participants receive sorafenib tosylate orally (PO) once daily (QD) or twice daily (BID) on days 1-28, and nivolumab intravenously (IV) over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. EXPANSION COHORT (Part 2). Participants receive nivolumab IV over 30 minutes on days 1 and 15, and sorafenib tosylate once daily (QD) or twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 30 and 100 days, then every 3 months for up to 2 years after the last dose.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
16
University of California, Davis
Sacramento, California, United States
University of California, San Francisco
San Francisco, California, United States
Maximum Tolerated Dose (MTD) (Part 1 Only)
MTD is defined as the dose in which 1 or more dose limiting toxicities (DLT) is reported by study participants in Part 1 within the first cycle of treatment. Participants in Part 1 must receive at least 2 doses of nivolumab and at least 75% of sorafenib doses within 28 days (1 cycle), or experience a qualifying DLT event to be evaluable.
Time frame: 28 days
Proportion of Participants With Grade 3 or Higher Treatment-related Adverse Events (Part 2 Only)
All adverse event (AE) will be summarized based on proportion of total participants in Part 2 to evaluate the safety of the treatment combination in participants with Child-Pugh B7-9 liver function as measured by proportion of participants with an AE of toxicity grade \>=3 as graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and assessed as at least possibly related to sorafenib, nivolumab, or the combination of therapies.
Time frame: Up to 2 years
Proportion of Participants With Treatment-related Adverse Events
Overall rates of AE and serious adverse events (SAE) as classified by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 assessed as at least possibly related to sorafenib, nivolumab, or the combination of therapies will be reported as the proportion of participants in each arm. .
Time frame: Up to 2 years
Proportion of Participants Reporting Immune-related Adverse Event (irAE) (Part 1 and Part 2 Combined)
Safety events for all participants assessed by treating investigator and/or Study Chair as being at least possibly immune-related while on nivolumab (irAE) will be summarized based on proportion of total participants across all treatment groups combined.
Time frame: Up to 2 years
Proportion of Participants With Child-Pugh B (CPB) Reporting Immune-related Adverse Event (irAE) (Parts 1 and 2 Combined)
Safety events for all CPB participants assessed by treating investigator and/or Study Chair as being at least possibly immune-related while on nivolumab (irAE) will be summarized based on proportion of total CPB participants across all treatment groups combined.
Time frame: Up to 2 years
Proportion of Participants With Dose Delays Due to Toxicity
Delays in dosing due to adverse events will be summarized as proportion of participants by each arm.
Time frame: Up to 2 years
Proportion of Participants With Dose Reductions Due to Toxicity
Dose reductions due to adverse events will be summarized as proportion of participants in each arm.
Time frame: Up to 2 years
Proportion of Participants Who Discontinued Treatment Due to Toxicity
Treatment discontinuations due to adverse events will be summarized as proportion of participants in each arm.
Time frame: Up to 2 years
Proportion of Participants With an Objective Response (Part 1 and Part 2 Combined)
Objective response is defined as the proportion of participants assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with measurable disease at study entry who have an evaluated complete response (CR) or partial response (PR) at any time during the main study. Participants with measurable disease at study entry who have unknown or missing response information will be treated as non-responders.
Time frame: Up to 2 years
Proportion of Participants With an Objective Response by Part
Objective response will be based on assessments using RECIST 1.15 using local radiographic review and analyzed for Part 1 and Part 2 individually. Objective response is defined as the proportion of subjects with RECIST 1.1-measurable disease at study entry who have a CR or PR at any time during the main study. Participants with measurable disease at study entry who have unknown or missing response information will be treated as non-responders.
Time frame: Up to 2 years
Median Duration of Response (DOR) (Part 1 and Part 2 Combined)
DOR is defined as the median time in months from first documented evidence of complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) until the first documented sign of disease progression or death for all participant who received any treatment during the course of the study.
Time frame: Up to 2 years
Median Duration of Response (DOR) by Treatment Group
DOR is defined as the median time in months from first documented evidence of CR or PR assessed by Response Evaluation Criteria in Solid Tumors (RECIST) until the first documented sign of disease progression or death by treatment group for all participants who received treatment during the course of the study.
Time frame: Up to 2 years
Median Progression-Free Survival (PFS) (Part 1 and Part 2 Combined)
PFS will be calculated as the median time in months from date of first dose of protocol therapy to date of first documented radiographic and/or clinical disease progression or death from any cause for all participants who received treatment during the course of the study. For participants who discontinued from study for other reasons than progression or death, PFS will be censored at the date last date known to be progression-free for up to 2 years following the last dose of protocol therapy.
Time frame: Up to 3.5 years
Median Progression-free Survival (PFS) by Child-Pugh Group
PFS will be calculated as the median time in months from date of first dose of protocol therapy to date of first documented radiographic and/or clinical disease progression or death from any cause for participants grouped by Child-Pugh Group (Class A and Class B). For participants discontinued from study for other reasons than progression or death, PFS will be censored at the date last known to be progression-free for up to 2 years following the last dose of protocol therapy.
Time frame: Up to 3.5 years
Median Overall Survival (OS) (Part 1 and Part 2 Combined)
OS is defined as the median time in months from the date of first dose of protocol therapy to the date of death due to any cause for up to 2 years following the last dose of protocol therapy. Censoring will be performed using the date of last known contact for those who are alive at the time of analysis. If data warrant, Kaplan-Meier estimates along with the 95% confidence intervals (CI) or full range will be reported.
Time frame: Up to 3.5 years
Overall Survival (OS) by Child-Pugh Group
OS is defined as the median time in months from the date of first dose of protocol therapy to the date of death due to any cause for up to 2 years following the last dose of protocol therapy and will be reported for each of the Child-Pugh groups separately. Censoring will be performed using the date of last known contact for those who are alive at the time of analysis. If data warrant, Kaplan-Meier estimates along with the 95% confidence intervals (CI) or full range will be reported.
Time frame: Up to 3.5 years
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