Neoplasms

All Conditions

Digestive System Diseases

Heart and Blood Diseases

Carcinoma

Carcinoma, Hepatocellular

Liver Neoplasms

Hyperemia

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Chlorotrianisene

Liver Extracts

Patients undergo SBRT on day 1 and TACE on day 2.

Laboratory Biomarker Analysis

Stereotactic Body Radiation Therapy

Transarterial Chemoembolization

Terence Williams, MD, PhD

This pilot clinical trial studies stereotactic body radiation therapy (SBRT) and transarterial chemoembolization (TACE) in treating patients with liver cancer that cannot be removed by surgery. SBRT is a specialized radiation therapy that delivers a high dose of radiation directly to the tumor and may kill more tumor cells and cause less damage to normal tissue. Chemoembolization kills tumor cells by carrying drugs directly into blood vessels near the tumors and then blocking the blood flow to allow a higher concentration of the drug to reach the tumor for a longer period of time. SBRT may make TACE more beneficial by increasing blood flow to the tumor, which may allow more of the TACE chemotherapy to enter the tumor. Giving SBRT with TACE may work better in treating patients with liver cancer that cannot be removed by surgery.

PRIMARY OBJECTIVES:

I. To establish the feasibility of completing SBRT followed by TACE in a 2 day time period.

SECONDARY OBJECTIVES:

I. To determine acute tumor perfusion changes after SBRT using functional magnetic resonance imaging (MRI) (magnetic resonance \[MR\]-dynamic contrast enhanced \[DCE\]/perfusion weighted imaging \[PWI\], MR-diffusion, blood oxygen level dependent \[BOLD\] sequences).

II. To establish safety and tolerability of this regimen. III. To determine overall response rates (using modified Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria), including objective response rate (partial response \[PR\] + complete response \[CR\]) and clinical benefit rate (stable disease \[SD\] + PR + CR) at 1, 3, and 6 months after TACE.

IV. To evaluate local control, progression-free survival, and overall survival at 1, 3, 6, 9, and 12 months after a single-dose of SBRT followed by TACE.

V. To correlate micro ribonucleic acid (miRNA) biomarkers with response and toxicity.

OUTLINE: This is a dose-escalation study of SBRT.

Patients undergo SBRT on day 1 and TACE on day 2.

After completion of study treatment, patients are followed up at 1-2 weeks and at 1, 3, 6, 9, 12, 18, and 24 months.

Stereotactic Body Radiation Therapy and Transarterial Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

A Pilot Trial of Stereotactic Body Radiation Therapy (SBRT) to Induce Tumor Hyperemia in Combination With Transarterial Chemoembolization (TACE) for Unresectable Hepatocellular Carcinoma

Determined on the intent-to-treat principle. Any treatment delivery difficulties that arise that could impede successful delivery of this therapy sequence will be evaluated. The capability of the Ohio State University (OSU) system and communication between departments will be analyzed and deemed effective if it facilitates the successful treatment completion of all patients.

Tested by comparing mean values pre- and post-SBRT using a paired t-test. Should there be concern for outliers, the median for each metric will be determined and compared using a corresponding non-parametric procedure.

Includes measurement of grade 2-5 gastrointestinal symptoms, such as nausea, abdominal pain, hepatitis, enteritis, gastritis, bowel perforation, and fistula, as defined by Common Terminology Criteria for Adverse Events version 4.03.

Calculated using standard clinical follow-up with MRI imaging and labs.

Calculated using standard clinical follow-up with MRI imaging and labs. Estimated using Kaplan-Meier analysis.

Varian Medical Systems

Ohio State University Comprehensive Cancer Center

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

Yttrium Y 90 Glass Microspheres

Aparna Kalyan, MBBS, FRACP

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.

Nivolumab and Yttrium Y 90 Glass Microspheres in Treating Patients With Advanced Liver Cancer

Phase I/Ib Study of Nivolumab in Combination With Therasphere (Yttrium-90) in Patients With Advanced Hepatocellular Carcinoma

Tumor tissue will be used to examine expression of PD-L1 protein on tumor cells.

Evaluate biomarker expression level using immunohistochemistry or flow cytometry.

Change in clonal burden landscape will be analyzed to investigate its correlation with treatment response or development of resistance to treatment.

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).

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.

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.

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).

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.

Bristol-Myers Squibb

National Cancer Institute (NCI)

Northwestern University

Patients who signed consent/did not initiate treatment are included as at risk for SAE but not at risk for other AEs due to 1 out of 10 screenfail patients experiencing an SAE. All cause mortality and other adverse events are assessed from first dose of study treatment. Only patients that received at least 1 dose of study drug are included in all cause mortality and other adverse events. SAEs are assessed from patient signing consent.

Nivolumab was administered at 80mg as an intravenous infusion over 30 minutes (-5 minutes / +15 minutes) every 2 weeks (Day 1 \& 15 of each cycle, 1 Cycle = 28 days). Courses repeated every cycle in the absence of disease progression or unacceptable toxicity.

Correlatives studies: Peripheral lymphocyte analysis, and analysis for PD-K1, PD-1, CD8+, and CD4+ tumor infiltrating lymphocytes.

Phase I, Nivolumab Dose Lvl 1 (80mg IV Every 2 Weeks)

Nivolumab was administered at 240mg as an intravenous infusion over 30 minutes (-5 minutes / +15 minutes) every 2 weeks (Day 1 \& 15 of each cycle, 1 Cycle = 28 days). Courses repeated every cycle in the absence of disease progression or unacceptable toxicity.

Correlatives studies: Peripheral lymphocyte analysis, and analysis for PD-K1, PD-1, CD8+, and CD4+ tumor infiltrating lymphocytes.

Phase I, Nivolumab Dose Lvl 2 (240mg IV Every 2 Weeks)

The maximum tolerated dose of nivolumab was planned to be administered in patients recruited to Phase 1b, as an intravenous infusion over 30 minutes (-5 minutes / +15 minutes) every 2 weeks (Day 1 \& 15 of each cycle, 1 Cycle = 28 days). Courses would repeat every cycle in the absence of disease progression or unacceptable toxicity.

Correlatives studies: Peripheral lymphocyte analysis, and analysis for PD-K1, PD-1, CD8+, and CD4+ tumor infiltrating lymphocytes.

Phase 1b never opened to accrual due to funding issues.

Phase 1b at Nivolumab MTD (240mg IV, Every 2 Weeks)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Although the MTD was determined at dose level 2 (240 IV every 2 weeks), Phase 1b never opened for accrual due to funding issues. In Phase I dose lvl 1, 7 patients failed screening. In Phase I does lvl 2, 3 patients failed screening. Included here patients that were treated on study. 10 patients were screen fails (not treated) and not included here.

The total accrual goal of 40 patients was not met. Due to funding issues, Phase 1b of the study never opened to accrual.

Patients in Phase I 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. Phase I follows a 3+3 dose escalation design. There are two dose levels of nivolumab, Level 1: 80mg IV every 2 weeks, and Level 2: 240mg IV every 2 weeks.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Yttrium Y 90 Glass Microspheres: Given IA

Phase I (Yttrium Y 90 Glass Microspheres, Nivolumab)

Maximum Tolerated Dose (MTD)

Due to funding issues, Phase 1b of the study never opened to accrual.

Phase IB: Objective Response Rate (ORR)

Lymphocyte count decreased

Abdominal pain

Blood bilirubin increased

Alkaline phosphatase increased

Keratitis

Thromboembolic event

Aspartate aminotransferase increased

Hyperglycemia

Creatinine increased

Investigations (other)

Number of Patients Who Experience Adverse Events

Progression Free Survival (PFS) at 24 Weeks (6 Months)

Disease Control Rate (DCR)

PD-L1 Protein Expression

Expression Level of Biomarker of Inflammatory/Immune Signature

Circulating Free DNA (cfDNA) Mutation Analyses

OS is defined as the duration of time from start of treatment to time of death and is summarized using Kaplan-Meier product limit curve and estimates.

Overall Survival (OS)

Screening

Induction Treatment With Y90

Cycle 1 (DLT Monitoring Period)

Cycle 2 and Beyond

2 Year Follow-up

Rare Diseases

Childhood Hepatocellular Carcinoma

Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive sorafenib tosylate PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.

Sorafenib Tosylate

Renuka Iyer

This clinical trial studies sorafenib tosylate in treating patients with liver cancer that cannot be removed by surgery. Sorafenib tosylate may block some of the enzymes needed for tumor cell growth. Blocking these enzymes may also help the immune system work better. Granzyme B is a biomarker that can be used to measure how well the immune system is working. A biomarker is a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. Studying granzyme B levels in patients receiving sorafenib tosylate may help doctors learn more about the effects of sorafenib tosylate on the immune system and may help to predict how well sorafenib tosylate will work in treating patients with liver cancer.

PRIMARY OBJECTIVES:

I. To determine whether the proportion of cytotoxic T lymphocytes that are producing granzyme B (denoted pGrzB) as measured \~28-35 days after initiation of sorafenib (sorafenib tosylate) therapy correlates with overall survival, defined as the number of months between the start of sorafenib treatment and death from any cause.

SECONDARY OBJECTIVES:

I. To determine whether higher pGrzB levels will correlate with better sorafenib tolerance, manifested by fewer dose reductions, dose interruptions and adverse events.

II. To determine whether improved immune function may also result in greater recognition of hepatitis viral antigens.

OUTLINE:

Patients receive sorafenib tosylate orally (PO) twice daily (BID). Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study, patients are followed up for 30 days or after the 6 month time point if continuing sorafenib tosylate and then periodically thereafter.

Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

Granzyme B Production as a Biomarker for the Immunomodulatory Activity of Sorafenib in HCC

The hypotheses of immediate (HI) and sustained improvement (HS) of immune function will be tested using a fixed-sequence procedure. Each hypothesis uses a permutation paired t-test with an upper 1-sided 0.05 significance threshold. HI considers a pGrzB increase between days 0 \& \~28-35. If the HI test finds no short-term pGrzB improvement, the HS test will not be done. If HI indicates a short-time pGrzB improvement, HS considers a pGrzB increase between days 0 and 24 weeks (± 1 week). If both tests indicate improvements it will be concluded improved \& sustained pGrzB response follows sorafenib.

The pGrzB hazard ratio (per 10 percentage point increase) and the associated 95% confidence interval will be estimated using a Cox PH model. Whether pGrzB measurements vary by presence of grade 3+ adverse events (AEs) will be assessed using permutation independent sample t-tests. Descriptive statistics include the pGrzB mean, standard deviations and ranges within AE or patient characteristics.

The hazard ratio and 95% confidence interval for the effect of day \~28-35 pGrzB (in 10 percentage point increments) on OS will be estimated using proportional hazards (PH) models. The pGrzB functional form will be assessed using generalized additive models. Possible confounding from sorafenib dose differences and baseline characteristics will be assessed by including other covariates (or perhaps frailty terms) in the model.

These differences will be assessed using permutation independent sample t-tests. For an AE observed in 15 (50%) of the patients and two-sided statistical significance threshold = 0.05, this test has 80% power to detect a 1.0 standard difference in mean pGrzB. 95% confidence limits for the difference in mean pGrzB will also be provided. Descriptive statistics include the pGrzB mean, standard deviations and ranges within AE or patient characteristics.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Stereotactic Body Radiation Therapy and Transarterial Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery	NCT02507765	Child-Pugh Clas... Child-Pugh Clas... Stage IIIA Hepa... Stage IIIB Hepa... Stage IIIC Hepa... Stage IVA Hepat... Stage IVB Hepat...	Laboratory Biom... Stereotactic Bo... Transarterial C...	18 Years -	Ohio State University Comprehensive Cancer Center
Nivolumab and Yttrium Y 90 Glass Microspheres in Treating Patients With Advanced Liver Cancer	NCT02837029	Stage IIIA Hepa... Stage IIIB Hepa... Stage IIIC Hepa... Stage IVA Hepat... Stage IVB Hepat...	Laboratory Biom... Nivolumab Yttrium Y 90 Gl...	18 Years -	Northwestern University
Nivolumab and Yttrium Y 90 Glass Microspheres in Treating Patients With Advanced Liver Cancer	NCT02837029	Stage IIIA Hepa... Stage IIIB Hepa... Stage IIIC Hepa... Stage IVA Hepat... Stage IVB Hepat...	Laboratory Biom... Nivolumab Yttrium Y 90 Gl...	18 Years -	Northwestern University
Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery	NCT02072486	Advanced Adult ... Localized Non-R... Stage III Child... Stage IIIA Hepa... Stage IIIB Hepa... Stage IIIC Hepa... Stage IV Childh... Stage IVA Hepat... Stage IVB Hepat...	Laboratory Biom... Sorafenib Tosyl...	-	Roswell Park Cancer Institute

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