Bevacizumab and Erlotinib or Sorafenib as First-Line Therapy in Treating Patients With Advanced 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. Erlotinib and sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab, erlotinib, and sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether giving bevacizumab together with erlotinib is more effective than giving sorafenib in treating patients with liver cancer. PURPOSE: This randomized phase II trial is studying how well giving bevacizumab together with erlotinib works compared with sorafenib as first-line therapy in treating patients with advanced liver cancer.

Detailed Description
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OBJECTIVES: Primary To estimate the overall survival in patients with advanced hepatocellular carcinoma treated with bevacizumab and erlotinib hydrochloride vs sorafenib tosylate. Secondary To estimate the event-free survival and tumor response rate of these patients. To evaluate the safety and tolerability of these regimens in these patients. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride once daily on days 1-28. 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. After completion of study treatment, patients are followed at 30 days and then every 3 months for 1 year.

Official Title
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A Randomized Open-Label Multi-Institution Phase II Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients With Advanced Hepatocellular Carcinoma (HCC)

Conditions
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Liver Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Pathologically confirmed advanced hepatocellular carcinoma (HCC) Childs-Pugh class A CLIP score ≤ 5 Not a candidate for curative surgical resection or loco-regional therapy Measurable disease as per RECIST 1.1 criteria, defined as ≥ 1 previously unirradiated, bidimensionally measurable lesion ≥ 20 mm by CT scan or MRI (triphasic spiral CT scan or MRI employing a liver protocol image capture technique required) Bone lesions, ascites, and pleural effusions are not considered measurable lesions No fibrolamellar HCC No known brain metastases No prior organ transplantation PATIENT CHARACTERISTICS: ECOG performance status 0-2 Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 75,000/mm³ Hemoglobin ≥ 9 g/dL Transaminases ≤ 5 times upper limit of normal (ULN) Total bilirubin ≤ 2.0 times ULN PT ≤ 1.8 times ULN Prolonged INR allowed for patients who require full dose anticoagulation Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 45 mL/min Urine protein < 2+ by urine dipstick OR urine protein ≤ 1 g by 24-hour urine collection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 12 weeks after completion of study treatment Able to take and absorb oral medication No active infection requiring parenteral therapy No known HIV or AIDS No uncontrolled blood pressure (BP), defined as systolic BP ≥ 150 mm Hg and/or diastolic BP ≥ 100 mm Hg No uncontrolled or significant cardiovascular disease, including any of the following: Myocardial infarction within the past 6 months Uncontrolled angina within the past 6 months New York Heart Association class II-IV congestive heart failure Grade 3 cardiac valve dysfunction Cardiac arrhythmia not controlled by medication Stroke or transient ischemic attack within the past 6 months Arterial thrombotic event of any type within the past 6 months No significant or symptomatic vascular disease (e.g., aortic aneurysm, aortic dissection, or peripheral vascular disease) within the past 6 months No decompensated liver disease as evidenced by clinically significant ascites refractory to diuretic therapy, hepatic encephalopathy, or coagulopathy not corrected by conservative measures No grade 3 bleeding esophageal or gastric varices within the past 2 months Prior variceal bleeding allowed provided patient has undergone banding or sclerotherapy and there has been no evidence of bleeding for 2 months No gastric varices ≥ grade 2 No hemoptysis (i.e., ≥ ½ teaspoon of bright red blood per episode) within the past month No evidence of bleeding diathesis or coagulopathy No concurrent uncontrolled illness, including, but not limited to, a history of or current evidence of unexplained nephrotic syndrome or other severe illness/disease that would preclude study participation No history of hypertensive crisis or hypertensive encephalopathy No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months No serious, non-healing wound, active ulcer, or untreated bone fracture No significant traumatic injury within the past 28 days No history of allergy to bevacizumab, erlotinib hydrochloride, sorafenib tosylate, or related compounds No other primary malignancy within the past 5 years, except carcinoma in situ of the cervix or urinary bladder or nonmelanoma skin cancer No mental incapacitation or psychiatric illness that would preclude study participation Not incarcerated or compulsorily detained (i.e., involuntarily incarcerated) for treatment of either a psychiatric or physical illness (e.g., infectious disease) PRIOR CONCURRENT THERAPY: Prior surgery, local ablation, trans-arterial hepatic artery embolization, or trans-arterial chemoembolization are allowed provided the lesion(s) have progressed since treatment OR there are additional measurable, untreated lesions present No prior systemic therapy for HCC No prior organ transplantation More than 7 days since prior minor surgical procedures, fine needle aspirations, or core biopsies (excluding placement of a vascular access device) More than 28 days since any prior therapy More than 28 days since prior and no concurrent major surgical procedure or open biopsy More than 28 days since prior and no concurrent participation in another experimental drug study No other concurrent anticancer or antitumor therapy, including chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy No other concurrent investigational agents No concurrent warfarin (other types of anticoagulation allowed)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 116 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 1: bevacizumab and erlotinib<br>Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride once daily on days 1-28. | Biological: bevacizumab<br>* Given IV<br>Drug: erlotinib hydrochloride<br>* Given orally<br>|
| Active Comparator: Arm 2: sorafenib tosylate<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 |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from treatment day 1 until death from any cause. Patients still alive at the end of follow up,patients who withdrew consent from the trial and patients who were lost to follow up will have their survival time censored at the last date of contact. | from date of day 1 until the date of death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | EFS is defined as the time from randomization to any of the following three types of events: 1 - progression; 2 - withdrawal due to excessive toxicity; 3 - any other clinical event requiring withdrawal from the study. | From the time of randomization until progression, withdrawal due to toxicity or any other clinical event requiring withdrawal from the study. | 
| Number of SAEs Experienced | The study will report the number of SAEs experienced in each arm. All patients who receive any study drug will be evaluable for toxicity. | From day 1 of drug administration until 30 days after the last dose of study drug. | 
| Response Rate | Secondary outcome measures include response rate as assessed on restaging imaging studies utilizing RECIST 1.1. | From day 1 drug administration until 30 days after the last dose of study drug. | 

 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, recurrent adult primary liver cancer