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About
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.
Full 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.
Enrollment
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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)
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
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
Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
Patients must have adequate organ function within 14 days prior to registration as determined by:
Renal
Hepatic
Serum electrolytes
Potassium, sodium, magnesium, and calcium (corrected for serum albumin) =< grade 1 or within the institutional ranges of normal; if clinically appropriate, electrolytes may be corrected and values reassessed prior to enrollment
Females of childbearing potential (FOCBP), and non-sterilized males who are sexually active must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective; they must also refrain from egg and/or sperm cell donation and breastfeeding for 90 days after the final dose of investigational product(s)
FOCBP must have a negative pregnancy test within 7 days prior to registration
Subjects must provide archived tumor specimens for correlative biomarker studies if sufficient tissue is available; a fresh biopsy is not required
Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study
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:
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:
Patients with renal failure currently requiring dialysis of any kind are not eligible
Patients with untreated central nervous system (CNS) metastatic disease (including spinal cord and leptomeningeal disease) are excluded
Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study, is excluded
Receipt of any investigational therapy is not permitted within 28 days prior to the first dose of nivolumab
Any concurrent chemotherapy, biologic or hormonal therapy for cancer treatment is not permitted within 28 days of registration
Patients with exposure to prior immunotherapy are not eligible
Patients are ineligible if they have unresolved toxicities from prior anticancer therapy, defined as having not resolved to National Cancer Institute (NCI) CTCAE version 4.03 grade 0 or 1 with the exception of alopecia and laboratory values listed per the inclusion criteria
Radiation therapy is not permitted within 14 days of registration
Live vaccines are not permitted within 28 days of study registration
No systemic glucocorticoids will be permitted within 48 hours prior to study registration
Patients with cardiac disease defined as one of the following are not eligible:
Patients with cardiac ventricular arrhythmias requiring anti-arrhythmic therapy are not eligible
Patients with known human immunodeficiency virus (HIV) infection are not eligible
Patients must not have elevated lung shunting precluding treatment with Y-90
Patients who have had major surgery within 4 weeks prior to registration are not eligible
Patients who have active clinically serious infection > CTCAE grade 2 are not eligible
Patients with a history of gastrointestinal bleeding (GIB) within 6 weeks prior to registration are not eligible
Patients with prior transplant of any kind are not eligible
Known or suspected allergy to nivolumab or any agent given in the course of this trial is not permitted
Patients may not be pregnant or lactating at study registration
Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:
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27 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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