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Trial record 1 of 1 for:    I 238913
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Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02072486
Recruitment Status : Completed
First Posted : February 26, 2014
Last Update Posted : July 29, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Tracking Information
First Submitted Date  ICMJE February 24, 2014
First Posted Date  ICMJE February 26, 2014
Last Update Posted Date July 29, 2020
Actual Study Start Date  ICMJE November 18, 2013
Actual Primary Completion Date July 19, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 25, 2015)
  • Granzyme B levels [ Time Frame: Up to 35 days ]
    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) [ Time Frame: Time between start of first treatment and death, assessed up to 6 months ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 24, 2014)
  • Overall survival (OS) [ Time Frame: Time between start of first treatment and death, assessed up to 6 months ]
    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.
  • Granzyme B levels [ Time Frame: Up to day 35 ]
    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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 25, 2015)
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 [ Time Frame: Up to 30 days ]
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2014)
Granzyme B level variations by presence of grade 3 or higher adverse events (AE), characterized using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) severity grade [ Time Frame: Up to 30 days ]
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.
Current Other Pre-specified Outcome Measures
 (submitted: September 25, 2015)
  • Change in granzyme B levels after sorafenib tosylate treatment [ Time Frame: Baseline to up to 35 days ]
    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.
  • Proportion of cluster of differentiation (CD)8+ T cells expressing granzyme B [ Time Frame: Up to 24 weeks ]
Original Other Pre-specified Outcome Measures
 (submitted: February 24, 2014)
  • Proportion of cluster of differentiation (CD)8+ T cells expressing granzyme B [ Time Frame: Up to day 35 ]
  • Change in granzyme B levels after sorafenib tosylate treatment [ Time Frame: Baseline to up to 35 days ]
    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.
 
Descriptive Information
Brief Title  ICMJE Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery
Official Title  ICMJE Granzyme B Production as a Biomarker for the Immunomodulatory Activity of Sorafenib in HCC
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Sorafenib Tosylate
    Given PO
    Other Names:
    • BAY 43-9006 Tosylate
    • BAY 54-9085
    • Nexavar
    • sorafenib
Study Arms  ICMJE Experimental: Treatment (sorafenib tosylate)
Patients receive sorafenib tosylate PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Drug: Sorafenib Tosylate
Publications * Kalathil SG, Hutson A, Barbi J, Iyer R, Thanavala Y. Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy. JCI Insight. 2019 Aug 8;4(15). pii: 130116. doi: 10.1172/jci.insight.130116. eCollection 2019 Aug 8.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 24, 2014)
30
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 19, 2020
Actual Primary Completion Date July 19, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02072486
Other Study ID Numbers  ICMJE I 238913
NCI-2014-00180 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 238913 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Roswell Park Cancer Institute
Study Sponsor  ICMJE Roswell Park Cancer Institute
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Renuka Iyer Roswell Park Cancer Institute
PRS Account Roswell Park Cancer Institute
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP