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

Primary Purpose

Advanced Adult Hepatocellular Carcinoma, Localized Non-Resectable Adult Hepatocellular Carcinoma, Stage III Childhood Hepatocellular Carcinoma

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Laboratory Biomarker Analysis

Sorafenib Tosylate

About this trial

This is an interventional basic science trial for Advanced Adult Hepatocellular Carcinoma

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
Outpatients with histologically/cytologically documented or radiographically diagnosed unresectable hepatocellular carcinoma (HCC) who are candidates for systemic therapy and for whom a decision to treat with sorafenib has been made; radiographic diagnosis needs typical findings of HCC by a radiographic method, i.e. on multi-dimensional dynamic computed tomography (CT), CT hepatic arteriography (CTHA)/CT arterial portography (CTAP) or magnetic resonance imaging (MRI)
Patients must have a life expectancy of at least 8 weeks
Patients must not have any evidence of bleeding diathesis or active gastrointestinal bleeding

Exclusion Criteria:

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant or nursing female subjects
Unwilling or unable to follow protocol requirements
Any condition which in the investigator's opinion deems the subject an unsuitable candidate to receive study drug
Patients who have had prior anti-angiogenic therapy, including but not limited to sorafenib, brivanib, bevacizumab, or sunitinib; prior treatment with liver directed, ablative or surgical therapies will be permitted as long as there is documented progression justifying the need for starting sorafenib therapy
No known contraindications to anti-angiogenics such as severe coronary artery disease, recent myocardial infarction or stroke within 6 months, bleeding peptic ulcer or varices within last 3 months, and any other major illness that may jeopardize study treatment or follow up

Sites / Locations

Roswell Park Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (sorafenib tosylate)

Arm Description

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

Outcomes

Primary Outcome Measures

Granzyme B levels

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.

Overall survival (OS)

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.

Secondary Outcome Measures

Granzyme B level variations by presence of grade 3 or higher AE, characterized using National Cancer Institute Common Terminology Criteria for Adverse Events severity grade

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.

Full Information

NCT ID

NCT02072486

First Posted

February 24, 2014

Last Updated

July 20, 2022

Sponsor

Roswell Park Cancer Institute

Collaborators

National Comprehensive Cancer Network

1. Study Identification

Unique Protocol Identification Number

NCT02072486

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Completed

Study Start Date

November 18, 2013 (Actual)

Primary Completion Date

July 19, 2019 (Actual)

Study Completion Date

July 19, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Roswell Park Cancer Institute

Collaborators

National Comprehensive Cancer Network

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Advanced Adult Hepatocellular Carcinoma, Localized Non-Resectable Adult Hepatocellular Carcinoma, Stage III Childhood Hepatocellular Carcinoma, Stage IIIA Hepatocellular Carcinoma, Stage IIIB Hepatocellular Carcinoma, Stage IIIC Hepatocellular Carcinoma, Stage IV Childhood Hepatocellular Carcinoma, Stage IVA Hepatocellular Carcinoma, Stage IVB Hepatocellular Carcinoma

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (sorafenib tosylate)

Arm Type

Experimental

Arm Description

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

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Drug

Intervention Name(s)

Sorafenib Tosylate

Other Intervention Name(s)

BAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenib

Intervention Description

Given PO

Primary Outcome Measure Information:

Title

Granzyme B levels

Description

Time Frame

Up to 35 days

Title

Overall survival (OS)

Description

Time Frame

Time between start of first treatment and death, assessed up to 6 months

Secondary Outcome Measure Information:

Title

Granzyme B level variations by presence of grade 3 or higher AE, characterized using National Cancer Institute Common Terminology Criteria for Adverse Events severity grade

Description

Time Frame

Up to 30 days

Other Pre-specified Outcome Measures:

Title

Change in granzyme B levels after sorafenib tosylate treatment

Description

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.

Time Frame

Baseline to up to 35 days

Title

Proportion of cluster of differentiation (CD)8+ T cells expressing granzyme B

Time Frame

Up to 24 weeks

10. Eligibility

Sex

All

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure Outpatients with histologically/cytologically documented or radiographically diagnosed unresectable hepatocellular carcinoma (HCC) who are candidates for systemic therapy and for whom a decision to treat with sorafenib has been made; radiographic diagnosis needs typical findings of HCC by a radiographic method, i.e. on multi-dimensional dynamic computed tomography (CT), CT hepatic arteriography (CTHA)/CT arterial portography (CTAP) or magnetic resonance imaging (MRI) Patients must have a life expectancy of at least 8 weeks Patients must not have any evidence of bleeding diathesis or active gastrointestinal bleeding Exclusion Criteria: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or nursing female subjects Unwilling or unable to follow protocol requirements Any condition which in the investigator's opinion deems the subject an unsuitable candidate to receive study drug Patients who have had prior anti-angiogenic therapy, including but not limited to sorafenib, brivanib, bevacizumab, or sunitinib; prior treatment with liver directed, ablative or surgical therapies will be permitted as long as there is documented progression justifying the need for starting sorafenib therapy No known contraindications to anti-angiogenics such as severe coronary artery disease, recent myocardial infarction or stroke within 6 months, bleeding peptic ulcer or varices within last 3 months, and any other major illness that may jeopardize study treatment or follow up

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Renuka Iyer

Organizational Affiliation

Roswell Park Cancer Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Roswell Park Cancer Institute

City

Buffalo

State/Province

New York

ZIP/Postal Code

14263

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

31391334

Citation

Kalathil SG, Hutson A, Barbi J, Iyer R, Thanavala Y. Augmentation of IFN-gamma+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy. JCI Insight. 2019 Aug 8;4(15):e130116. doi: 10.1172/jci.insight.130116. eCollection 2019 Aug 8.

Results Reference

derived

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

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