Nivolumab and Yttrium Y 90 Glass Microspheres in Treating Patients With Advanced Liver Cancer
|ClinicalTrials.gov Identifier: NCT02837029|
Recruitment Status : Active, not recruiting
First Posted : July 19, 2016
Results First Posted : August 11, 2020
Last Update Posted : August 11, 2020
|Condition or disease||Intervention/treatment||Phase|
|Stage IIIA Hepatocellular Carcinoma Stage IIIB Hepatocellular Carcinoma Stage IIIC Hepatocellular Carcinoma Stage IVA Hepatocellular Carcinoma Stage IVB Hepatocellular Carcinoma||Other: Laboratory Biomarker Analysis Biological: Nivolumab Radiation: Yttrium Y 90 Glass Microspheres||Phase 1|
I. To identify MTD of nivolumab for combination treatment of nivolumab and Y-90 in this population.
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.
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 (Clinical Trial)|
|Actual Enrollment :||27 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I/Ib Study of Nivolumab in Combination With Therasphere (Yttrium-90) in Patients With Advanced Hepatocellular Carcinoma|
|Study Start Date :||July 2016|
|Actual Primary Completion Date :||July 17, 2019|
|Estimated Study Completion Date :||July 2023|
Experimental: Treatment (yttrium Y 90 glass microspheres, nivolumab)
Patients receive yttrium Y 90 glass microspheres IA. Approximately 4 weeks after yttrium Y 90 glass microspheres treatment, patients receive nivolumab IV over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Radiation: Yttrium Y 90 Glass Microspheres
Other Name: TheraSphere
- Maximum Tolerated Dose (MTD) [ Time Frame: The first cycle of treatment with nivolumab (28 days) ]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).
- Phase IB: Objective Response Rate (ORR) [ Time Frame: At baseline and every 8 weeks for the first 13 months and then every 12 weeks up to 2 years ]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.
- Incidence of Adverse Events [ Time Frame: Up to 100 days following the last administration of study drug ]Evaluate the toxicities (according to the NCCN CTCAE v4.03) and tolerability of nivolumab and y-90 in patients with advanced hepatocellular carcinoma.
- Progression Free Survival (PFS) [ Time Frame: Up to 24 weeks ]Evaluate the proportion of patients alive and progression free at 24 weeks.
- Disease Control Rate (DCR) [ Time Frame: At 24 months ]DCR will be determined at 24 months from the start of nivolumab treatment by the sum of complete response, partial response and stable response according to measurement of target and non-target lesions.
- PD-L1 Protein Expression [ Time Frame: At baseline ]Tumor tissue will be used to examine expression of PD-L1 protein on tumor cells.
- Expression Level of Biomarker of Inflammatory/Immune Signature [ Time Frame: Up to 2 years ]Evaluate biomarker expression level using immunohistochemistry or flow cytometry.
- Circulating Free DNA (cfDNA) Mutation Analyses [ Time Frame: Every 8 weeks for the first 24 weeks then every 16 weeks up to 2 years ]Change in clonal burden landscape will be analyzed to investigate its correlation with treatment response or development of resistance to treatment.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02837029
|United States, Illinois|
|Chicago, Illinois, United States, 60611|
|Principal Investigator:||Aparna Kalyan, MBBS, FRACP||Northwestern University|