Bevacizumab and Sorafenib as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Liver Cancer

Study Overview
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Brief Summary
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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)

Detailed Description
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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.

Official Title
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Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients With Locally Advanced or Metastatic Hepatocellular Carcinoma

Conditions
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Liver Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed hepatocellular carcinoma Locally advanced or metastatic disease that is not amenable to treatment with surgery or to orthotopic liver transplant Child Pugh class A or B7 disease Measurable disease No mixed cholangiocarcinoma/hepatocellular carcinoma No current or previously resected brain metastases PATIENT CHARACTERISTICS: ECOG performance status 0-1 Life expectancy ≥ 3 months ANC ≥ 1,200/mm³ Platelet count ≥ 75,000/mm³ Hemoglobin ≥ 9.0 g/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST ≤ 5 times ULN Alkaline phosphatase ≤ 5 times ULN Urine protein ≤ 1+ by urine protein:creatinine ratio OR 24-hour urine protein < 1 g QTc interval ≤ 500 msec on baseline EKG Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 2 weeks after sorafenib tosylate and 6 months after bevacizumab None of the following risk factors for decreased LVEF: Prior treatment with anthracyclines History of myocardial infarction within the past 12 months No uncontrolled hypertension (defined as systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical management No New York Heart Association class III-IV congestive heart failure No cardiac ventricular arrhythmias requiring antiarrhythmic therapy No history of hypertensive crisis or hypertensive encephalopathy No cardiac ventricular arrhythmia requiring anti-arrhythmic therapy within the past 6 months None of the following within the past 6 months: Transient ischemic attack Cerebrovascular accident Unstable angina or angina Clinically significant peripheral artery disease (i.e., claudication in less than one block) or any other arterial thrombotic event Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis No active or recent history of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within the past 30 days No evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation) No significant traumatic injury within the past 4 weeks No serious or non-healing wound, ulcer, or bone fracture No uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements No other active malignancy within the past 3 years, except nonmelanotic skin cancer or carcinoma in situ of the cervix No comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab or sorafenib tosylate PRIOR CONCURRENT THERAPY: No prior systemic chemotherapy regimens for hepatocellular carcinoma No prior external beam radiation to the primary site No prior central thoracic radiation therapy (RT), including RT to the heart No prior radiation (if given for another malignancy) to ≥ 25% of the bone marrow At least 6 weeks since prior chemoembolization, radioembolization, radiofrequency ablation, or other local ablative therapies More than 4 weeks since prior biologic, hormonal, or immune therapy More than 4 weeks since prior and no concurrent major surgical procedure or open biopsy More than 7 days since prior core biopsy or other minor surgical procedure (placement of a vascular access device allowed) No concurrent investigational agent which would be considered as a treatment for the primary neoplasm No concurrent anticoagulants, except low-dose warfarin or heparin for deep venous thrombosis prophylaxis No other concurrent treatment for prior malignancy (other than hormonal therapy)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (Phase II)<br>Patients receive oral sorafenib tosylate on days 1-28 twice daily and bevacizumab IV on days 1 and 15. | Biological: bevacizumab<br>* Given IV<br>Drug: sorafenib tosylate<br>* Given orally<br>|
| Experimental: Arm II (Phase II)<br>Patients receive oral sorafenib tosylate twice daily on days 1-28. | Drug: sorafenib tosylate<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | From baseline up to 3 years post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult primary hepatocellular carcinoma, advanced adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer