Bevacizumab and Sorafenib as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Liver Cancer | NCT00867321 | Trialant

Bevacizumab and Sorafenib as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Liver Cancer | NCT00867321 | Trialant

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

Ages Eligible for Study: Adult (18-64)Older Adult (65+)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Eligibility Criteria: 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)