RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and sorafenib may also stop the growth of liver cancer by blocking blood flow to the tumor. PURPOSE: This randomized phase I/II trial is studying the best dose of bevacizumab when given together with sorafenib as first-line therapy in treating patients with locally advanced or metastatic liver cancer.(Phase I closed to accrual as of 11/03/2010)
OBJECTIVES: Primary * Determine the maximum tolerated dose of bevacizumab in combination with sorafenib tosylate in patients with locally advanced or metastatic hepatocellular carcinoma. (Phase I closed to accrual as of 11/03/2010) * Determine time to progression in these patients. (Phase II) Secondary * Determine the safety of this regimen in these patients. (Phase I closed to accrual as of 11/03/2010) * Assess tolerability of this regimen in these patients. (Phase I closed to accrual as of 11/03/2010) * Determine overall survival of these patients. (Phase II) * Determine tumor response (at 6 months) in patients treated with this regimen. (Phase II) * Determine progression-free survival of these patients. (Phase II) * Determine response rate in patients treated with this regimen. (Phase II) * Assess the occurrence of adverse events in these patients. (Phase II) Tertiary * Determine the relationship between tumor biomarkers and circulating biomarkers of vascular response and clinical outcome in patients treated with this regimen. OUTLINE: This is a phase I, dose escalation study followed by a randomized phase II study. * Phase I (closed to accrual as of 11/03/2010): Patients receive oral sorafenib tosylate twice daily on days 1-28 and bevacizumab IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. * Phase II: Patients are stratified according to gender (female vs male), ECOG performance status (0 vs 1), and Child-Pugh class (A vs B7). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral sorafenib tosylate on days 1-28 twice daily and bevacizumab IV on days 1 and 15. * Arm II: Patients receive oral sorafenib tosylate twice daily on days 1-28. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for analysis of circulating endothelial cells and circulating endothelial progenitor cells and angiogenic proteins in plasma by ELISA. After completion of study treatment, patients are followed for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Given IV
Given orally
Mayo Clinic Scottsdale
Scottsdale, Arizona, United States
Aurora Presbyterian Hospital
Aurora, Colorado, United States
Boulder Community Hospital
Boulder, Colorado, United States
Penrose Cancer Center at Penrose Hospital
Colorado Springs, Colorado, United States
St. Anthony Central Hospital
Denver, Colorado, United States
Maximum Tolerated Dose (Phase I)
MTD is defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients). If dose level (-1) is not tolerable, but dose (-3) or (-2) is below or at MTD, testing of alternate dose levels (-2a, -3a, -3b) will occur as outlined in the table. The number of dose limiting toxicities will be reported here.
Time frame: From baseline up to 3 years post treatment
Time to Progression (TTP) (Phase II)
Time to progression is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Kaplan-Meier survival curves will be used to estimate the distribution of TTP.
Time frame: From baseline up to 3 years post treatment
Overall Survival
Overall survival (OS) is defined as the length of time from date of registration to a) date of death due to any cause or b) last follow-up. Kaplan-Meier survival curves will be used to estimate the distribution of OS.
Time frame: Up to 3 years post treatment
Tumor Response at 6 Months
Tumor response (at 6 months) is defined as the number of responses (complete or partial response per Section 11) over the number of eligible patients observed for at least 6 months. Tumor response will be evaluated using simple estimates of proportions.
Time frame: 6 months
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