Phase I/Ib Study of Nivolumab in Combination With Therasphere (Yttrium-90) in Patients With Advanced Hepatocellular Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Stage IIIA Hepatocellular Carcinoma
- Sponsor
- Northwestern University
- Enrollment
- 27
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have a diagnosis of hepatocellular carcinoma (HCC) confirmed by American Association for Study of Liver Diseases (AASLD) guidelines with a Childs-Pugh score of A or B (but, =\< Childs score B8)
- •NOTE: If the patient does not have histological confirmation of disease by biopsy, diagnosis of HCC must be documented with approval by a tumor board or other multidisciplinary conference
- •Patients must have at least 1 lesion that is measurable using RECIST guidelines.
- •NOTE: A previously irradiated lesion can be considered a target lesion if the lesion is well defined, measurable per RECIST, and has clearly progressed.
- •NOTE: For patients with infiltrative disease, evaluable disease needs to be confirmed by pathology if RECIST measurements cannot be made.
- •Patients must have advanced disease that is not amenable to transplant or resection
- •Patients may be treatment naive or have received any number of prior therapies
- •NOTE: Prior immunotherapy is contraindicated and not permitted
- •Patients with chronic hepatitis B are eligible as long as they have evidence of ongoing viral replication (detectable hepatitis B surface antigen \[HBsAg\], hepatitis B envelope antigen \[HBeAg\], or hepatitis B virus \[HBV\] deoxyribonucleic acid \[DNA\]); they must have HBV DNA viral load \< 100 IU/mL at screening; in addition, they must be on antiviral therapy per regional standard of care guidelines prior to initiation of study therapy; if not on antiviral therapy at screening, then the subject must initiate treatment per regional standard of care guidelines at the time of consent; both HBeAg positive and negative patients will be included
- •Patients positive for hepatitis C are permitted if controlled with medication, in the opinion of the investigator
Exclusion Criteria
- •Patients must not have had prior treatment with nivolumab or any other PDL1 or PD-1 antagonists
- •Patients must not have a history of severe allergic reactions (i.e., grade 4 allergy, anaphylactic reaction from which the subject did not recover within 6 hours of institution of supportive care) to any unknown allergens or any components of the nivolumab formulations
- •Patients diagnosed or treated for malignancy other than HCC are not eligible unless they meet one of the following exceptions:
- •Malignancy treated with curative intent and with no known active disease present for \>= 3 years before registration and felt to be at low risk for recurrence by the treating physician.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- •Adequately treated cervical carcinoma in situ without evidence of disease
- •Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded; these include but are not limited to patients with a history of:
- •Immune related neurologic disease
- •Multiple sclerosis
- •Autoimmune (demyelinating) neuropathy
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- Progression Free Survival (PFS) at 24 Weeks (6 Months)(Up to 24 weeks (6 months))
- Number of Patients Who Experience Adverse Events(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)
- Disease Control Rate (DCR)(At 24 weeks (6 months))