Sorafenib Tosylate With or Without Stereotactic Body Radiation Therapy in Treating Patients With Liver Cancer

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01730937
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 193
• Locations: 51
• Arms: 2
• Duration (Months): 146
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase III trial studies sorafenib tosylate and stereotactic body radiation therapy to see how well they work compared to sorafenib tosylate alone in treating patients with liver cancer. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stereotactic body radiation therapy may be able to send the radiation dose directly to the tumor and cause less damage to normal tissue. Giving sorafenib tosylate together with stereotactic body radiation therapy may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer	Drug: sorafenib tosylate; Radiation: stereotactic body radiation therapy	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. To determine if stereotactic body radiation therapy (SBRT) improves overall survival in hepatocellular carcinoma (HCC) patients treated with sorafenib (sorafenib tosylate).

SECONDARY OBJECTIVES:

1. To determine the difference in time to progression (TTP) and progression-free survival (PFS) in HCC patients treated with sorafenib compared to SBRT followed by sorafenib.

2. To measure differences in toxicity in HCC patients treated with sorafenib versus SBRT followed by sorafenib.

3. To measure vascular thrombosis response post sorafenib versus SBRT followed by sorafenib.

4. To measure differences in health related quality of life (QOL) and quality-adjusted survival in HCC patients treated with sorafenib compared to SBRT followed by sorafenib.

5. Collection of biospecimens for future correlative studies to investigate differences in potential biomarkers in patients treated with sorafenib versus SBRT followed by sorafenib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM 1: Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

ARM 2: Patients undergo SBRT every 24-72 hours for a total of 5 fractions over 5 to 15 days. Within 1-5 days post-SBRT, patients receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Patients are followed weekly during SBRT, monthly during sorafenib tosylate and on the following schedule as a whole from study entry: every 3 months for 3 years, then every 6 months for 2 years and then annually.

Study Design

• Study Type: Interventional
• Actual Enrollment: 193 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Phase III Study of Sorafenib Versus Stereotactic Body Radiation Therapy Followed by Sorafenib in Hepatocellular Carcinoma
• Study Start Date: Apr 1, 2013
• Anticipated Primary Completion Date: Jun 1, 2024
• Anticipated Study Completion Date: Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 (sorafenib tosylate) Patients receive sorafenib tosylate orally PO BID on days 1-28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.	Drug: sorafenib tosylate; Given PO; Other Names: BAY 43-9006 BAY 43-9006 Tosylate Salt BAY 54-9085 Nexavar SFN
Experimental: Arm 2 (SBRT and sorafenib tosylate) Patients undergo SBRT every 24-72 hours for a total of 5 fractions over 5 to 15 days. Within 1-5 days post-SBRT, patients receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.	Drug: sorafenib tosylate; Given PO; Other Names: BAY 43-9006 BAY 43-9006 Tosylate Salt BAY 54-9085 Nexavar SFN ; Radiation: stereotactic body radiation therapy; Undergo SBRT; Other Names: SBRT stereotactic radiation therapy stereotactic radiotherapy

Outcome Measures

Primary Outcome Measures

1. Overall survival (OS) [From the date of randomization to the date of death or last follow-up. Analysis occurs after 227 deaths have been reported.]

   Will be estimated by the Kaplan-Meier method. The distribution of OS estimates between the 2 arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with OS.

Secondary Outcome Measures

1. TTP [From the date of randomization to the date of first failure or last follow-up.]

   Will be estimated by the cumulative incidence method. The distribution of TTP estimates between the 2 arms will be compared using Gray's test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with TTP.

2. PFS [From the date of randomization to the date of first failure or last follow-up.]

   Will be estimated by the Kaplan-Meier method. The distribution of PFS estimates between the 2 arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with PFS.

3. Grade 4 or 5 hepatic adverse events, grade 4 or 5 gastrointestinal AEs, grade 4 thrombocytopenia associated with any bleeding or grade 5 thrombocytopenia. All AEs must be definitely or probably related to protocol treatment and use CTCAE version 4.0 [From the start of treatment to to 90 days.]

   A 90% power will be provided to detect an increase in the rate of specified adverse events from 10% to at least 30% with a 1-sided alpha of 0.05, using a Chi-squared test for difference in proportions.

4. Health related quality of life assessments measured by the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) [Change from baseline to 6 months.]

   Distributions of QOL data collection patterns over all collection points in each treatment arm will be described. Chi-squared tests will be used to test the null hypothesis that the proportion of patients categorized as "improved" will be the same for the 2 treatment arms, versus the alternative hypothesis that the proportion of patients categorized as "improved" is higher for the SBRT+sorafenib arm.

5. Quality adjusted survival defined as the weighted sum of different time in different health states added up to a total quality-adjusted survival time using EuroQol (EQ-5D) [Combining survival with changed in EQ-5D from start of treatment to 6 and 12 months.]

   To examine trade-offs between the survival time and QOL. They will be combined for each patient into a single measurement: quality-adjusted life years (QALY). If (and only if) the primary endpoint hypothesis is substantiated, a quality-adjusted survival analysis will be conducted. The quality adjusted survival analysis will not be done until after the primary endpoint results are published.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have a diagnosis of HCC by at least one criterion listed below within 360 days prior to study entry:

• Pathologically (histologically or cytologically) proven diagnosis of HCC,(biopsies are recommended, and are to be submitted for research evaluation if patients consent)

• At least one solid liver lesion or vascular tumor thrombosis (involving portal vein, inferior vena cava [IVC] and/or hepatic vein) > 1 cm with arterial enhancement and delayed washout on multi-phasic computerized tomography (CT) or magnetic resonance imaging (MRI) in the setting of cirrhosis or chronic hepatitis B or C without cirrhosis.

• For patients whose CURRENT disease is vascular only: enhancing vascular thrombosis (involving portal vein, IVC and/or hepatic vein) demonstrating early arterial enhancement and delayed washout on multi-phasic CT or MRI in a patient with known HCC (diagnosed previously <720 days) using the above criteria.

• Measureable hepatic disease and/or presence of vascular tumor thrombosis (involving portal vein, IVC and/or hepatic vein) which may not be measureable as per Response Evaluation Criteria in Solid Tumors (RECIST) on liver CT or MRI, within 28 days of registration

• Appropriate for protocol entry based upon the following minimum diagnostic workup:

• History/physical examination including examination for encephalopathy, ascites, weight, height, and blood pressure within 14 days prior to study entry

• Assessment by radiation oncologist and medical oncologist or hepatologist who specializes in treatment of HCC within 28 days prior to study entry

• Pre-randomization Scan (REQUIRED for All Patients): CT scan chest/abdomen/pelvis or PET CT chest/abdomen/pelvis with multiphasic liver CT or multiphasic liver MR scan within 28 days prior to study entry. MRI of abdomen and pelvis with contrast with chest CT is permitted.

• Zubrod performance status 0-2 within 28 days prior to study entry

• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

• Platelets >= 60,000 cells/mm^3

• Hemoglobin >= 8.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 6 times upper limit of normal (ULN)

• Serum creatinine =< 2 x ULN or creatinine clearance >= 60 mL/min

• Barcelona Clinic Liver Cancer (BCLC) stage: intermediate (B) or advanced (C) within 28 days prior to study entry

• Child-Pugh score A within 14 days prior to study entry

• Women of childbearing potential and male participants must agree to practice adequate contraception while on study and for at least 6 months following the last dose of radiation therapy (RT) and for at least 28 days following the last dose of sorafenib (whichever is later)

• Unsuitable for resection or transplant or radiofrequency ablation (RFA)

• Unsuitable for or refractory to transarterial hepatic chemo-embolization (TACE) or drug eluting beads (DEB) for any of the following reasons, as described by Raoul et al (2011):

• Technical contraindications: arteriovenous fistula, including, surgical portosystemic shunt or spontaneous portosystemic shunt

• Severe reduction in portal vein flow: due to tumor portal vein, IVC or atrial invasion or bland portal vein occlusion

• Medical contraindications including congestive heart failure, angina, severe peripheral vascular disease

• Presence of extrahepatic disease

• No response post TACE (or DEB) or progressive HCC despite TACE; prior TACE or DEB is allowed but must be > 28 days from study entry

• Serious toxicity following prior TACE (or DEB); prior TACE or DEB must be > 28 days from study entry

• Other medical comorbidities making TACE (or DEB) unsafe and/or risky (e.g. combination of relative contraindications including age > 80 years, tumor > 10 cm, > 50% replacement of the liver by HCC, extensive multinodular bilobar HCC, biliary drainage)

• Patients treated with prior surgery are eligible for this study if they otherwise meet eligibility criteria

• Patient must be able to provide study-specific informed consent prior to study entry

Exclusion Criteria:

• Prior invasive malignancy (except non-melanomatous skin cancer and T1 renal cell carcinoma) unless disease free for a minimum of 2 years (note that carcinoma in situ of the breast, oral cavity, or cervix are all permissible)

• Prior sorafenib use > 60 days and/or grade 3 or 4 sorafenib related toxicity. Note that prior chemotherapy for HCC or a different cancer is allowable

• Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields

• Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months PRIOR TO registration

• Transmural myocardial infarction within the last 6 months prior to study entry

• Unstable ventricular arrhythmia within the last 6 months prior to study entry

• Acute bacterial or fungal infection requiring intravenous antibiotics within 28 days prior to study entry

• Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or variceal bleed within 28 days prior to study entry

• Bleeding within 28 days prior to study entry due to any cause, requiring transfusion

• Thrombolytic therapy within 28 days prior to study entry. Subcutaneous heparin is permitted.

• Known bleeding or clotting disorder

• Uncontrolled psychotic disorder

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic

• Maximal diameter of any one hepatocellular carcinoma > 15 cm

• Total sum of maximum diameters of each definite parenchymal hepatocellular carcinoma within the liver or maximum diameter of a single conglomerate HCC > 20 cm

• More than 5 discrete intrahepatic parenchymal foci of HCC

• Direct tumor extension into the stomach, duodenum, small bowel or large bowel

• Measureable common or main branch biliary duct involvement with HCC

• Extrahepatic metastases or malignant nodes (that enhance with typical features of HCC)

3.0 cm, in sum of maximal diameters (e.g. presence of one 3.4 cm metastatic lymph node or two 2 cm lung lesions); note that benign non-enhancing periportal lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if the sum of enlarged nodes is > 2.0 cm

• Prior liver transplant

• HIV positive with CD4 count < (350) cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ (350) cells/microliter, and no known detectable viral load, at the time of study entry. Note also that HIV testing is not required for eligibility for this protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California	United States	94704
2	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	UCSF Medical Center-Mount Zion	San Francisco	California	United States	94115
4	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
5	University of Colorado Hospital	Aurora	Colorado	United States	80045
6	Saint Vincent's Medical Center	Bridgeport	Connecticut	United States	06606
7	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
8	Queen's Medical Center	Honolulu	Hawaii	United States	96813
9	Northwestern University	Chicago	Illinois	United States	60611
10	University of Illinois	Chicago	Illinois	United States	60612
11	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
12	Loyola University Medical Center	Maywood	Illinois	United States	60153
13	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
14	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
15	Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
16	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
17	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
18	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
19	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
20	Boston Medical Center	Boston	Massachusetts	United States	02118
21	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
22	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
23	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
24	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
25	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
26	Columbia University/Herbert Irving Cancer Center	New York	New York	United States	10032
27	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
28	University of Rochester	Rochester	New York	United States	14642
29	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
30	Case Western Reserve University	Cleveland	Ohio	United States	44106
31	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
32	Providence Portland Medical Center	Portland	Oregon	United States	97213
33	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
34	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
35	M D Anderson Cancer Center	Houston	Texas	United States	77030
36	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
37	University of Vermont Medical Center	Burlington	Vermont	United States	05401
38	Hunter Holmes McGuire Veterans Administration Medical Center	Richmond	Virginia	United States	23249
39	ProCure Proton Therapy Center-Seattle	Seattle	Washington	United States	98133
40	University of Washington Medical Center	Seattle	Washington	United States	98195
41	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
42	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
43	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
44	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8V 5C2
45	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
46	University Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
47	CHUM - Hopital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
48	CHUM - Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec	Canada	H2X 3E4
49	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec	Canada	H3H 2R9
50	Pamela Youde Nethersole Eastern Hospital	Chai Wan		Hong Kong
51	Samsung Medical Center	Seoul	Korea	Korea, Republic of	135-710

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Laura Dawson, Radiation Therapy Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT01730937
• Other Study ID Numbers: RTOG-1112; NCI-2012-02057; U10CA021661
• First Posted: Nov 21, 2012
• Last Update Posted: Apr 8, 2022
• Last Verified: Apr 1, 2022

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Sorafenib

Study Results

No Results Posted as of Apr 8, 2022