The purpose of this study is to identify maximum tolerated dose (MTD), that is, the highest dose of the study drug nivolumab that does not cause unacceptable side effects, for combination treatment of nivolumab and yttrium Y 90 glass microspheres (Y-90). Also, to evaluate the efficacy (the effect of drug on your tumor) and the tolerability (the effect of the drug on your body) of nivolumab, when given with standard of care Y-90 (Therasphere). Nivolumab is currently Food and Drug Administration (FDA) approved for other cancers, but has not yet been investigated in advanced or refractory hepatocellular carcinoma. Nivolumab is an antibody (a human protein that sticks to a part of the tumor and/or immune cells) designed to allow the body's immune system to work against tumor cells. Y-90 is currently FDA approved for the treatment of hepatocellular carcinomas, but has not yet been investigated in combination with nivolumab for this disease.
PRIMARY OBJECTIVES: I. To identify MTD of nivolumab for combination treatment of nivolumab and Y-90 in this population. SECONDARY OBJECTIVES: I. To evaluate the proportion of patients with objective response rate (ORR) (according to Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria) to the combination treatment of nivolumab with Y-90. II. To evaluate the proportion of patients alive and progression free at 24 weeks in the described population. III. To evaluate the toxicities (according to the National Comprehensive Cancer Network \[NCCN\] Common Terminology Criteria for Adverse Events \[CTCAE\] version (v)4.03) and tolerability of nivolumab and Y-90 in patients with advanced hepatocellular carcinoma IV. To determine the disease control rate (DCR) to the combination of nivolumab and Y-90 at 24 months from the start of nivolumab treatment. TERTIARY OBJECTIVES: I. Programmed cell death 1 ligand 1 (PD-L1) protein on tumor cells and the expression levels of other markers of inflammatory/immune signature that may include but not be limited to programmed cell death protein 1 (PD-1), tumor necrosis factor receptor superfamily, member 4 (OX40), cluster of differentiation (CD) 73, CD39, T cell immunoglobulin and T-cell immunoglobulin and mucin-domain containing-3 (TIM3), glucocorticoid-induced tumour necrosis factor receptor (GITRL), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD3, CD4, CD8, CD45RO, forkhead box P3 (FOXP3), and granzyme by immunohistochemistry (IHC) and/or flow cytometry will be evaluated. II. Whole exome sequencing and computational analyses will be performed to assess mutanome and immunome (subpopulations of immune cells). III. Change in clonal burden landscape of various mutanome and immunome will be analyzed to investigate its correlation with treatment response or development of resistance to treatment. OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase Ib study. Patients receive yttrium Y 90 glass microspheres intraarterially (IA). Approximately 7-14 days after Y-90 administration. A delay of 4 weeks will be permitted in case of toxicity. After yttrium Y 90 glass microspheres treatment, nivolumab will be administered intravenously (IV) over approximately 60 minutes every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. After completion of study treatment, patients are followed up 30 days after the last dose of nivolumab and again at 100 days after discontinuing study drug.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Northwestern University
Chicago, Illinois, United States
Maximum Tolerated Dose (MTD)
To identify maximum tolerated dose (MTD) of nivolumab for combination treatment of nivolumab following Y-90 in patients with advanced hepatocellular carcinoma. The MTD will be defined as the highest dose of nivolumab that causes dose limiting toxicities (DLTs) in \<2 of 6 patients. The Phase I portion of the study follows a 3+3 dose escalation design. Nivolumab has two dose levels: Level 1: 80mg IV every 2 weeks, Level 2: 240mg IV every 2 weeks. Toxicity will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03. A DLT is defined as an Adverse Event (AE) or abnormal laboratory value assessed as at least possibly related to the study medication, occurs ≤ 28 days (1 cycle) following the first dose of nivolumab and meets any of the criteria listed in the Protocol (Section 4.3.1).
Time frame: The first cycle of treatment with nivolumab (28 days)
Phase IB: Objective Response Rate (ORR)
Evaluate tumor response by assessing the proportion of patients with Objective response rate (ORR) (according to RECIST v. 1.1 criteria) to the combination treatment of nivolumab with Y-90 by examining imaging scans. Per RECIST v. 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: At baseline and every 8 weeks for the first 13 months and then every 12 weeks up to 2 years
Number of Patients Who Experience Adverse Events
Safety and tolerability of toxicities (according to the NCCN CTCAE v4.03) and tolerability of nivolumab and y-90 in patients with advanced hepatocellular carcinoma as graded using CTCAE 4.03 that are grade 3 - 5 for patients determined to be evaluable for other endpoints. In general the following severity definitions are true: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death.
Time frame: During treatment where (1 Cycle = 28 days) the range of cycles attempted was 1-14 and up to 100 days following the last administration of study drug
Progression Free Survival (PFS) at 24 Weeks (6 Months)
Evaluate the percentage of patients alive and progression free at 24 weeks. PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression assessment will be performed by investigator each time the patients has a radiologic evaluation after 8 weeks of treatment. In general Progressive Disease (PD) will be assessed using RECIST v1.1 and defined as: 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 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is also considered progression).
Time frame: Up to 24 weeks (6 months)
Disease Control Rate (DCR)
DCR will be determined at 24 weeks from the start of nivolumab treatment by the sum of complete response (CR), partial response (PR) and stable disease (SD) according to measurement of target and non-target lesions as assessed by RECIST v1.1 where generally the following definitions are true: CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.
Time frame: At 24 weeks (6 months)
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