Bevacizumab and Erlotinib in Treating Patients With Advanced Liver Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving bevacizumab together with erlotinib works in treating patients with advanced liver cancer. 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 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and erlotinib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with erlotinib may kill more tumor cells

Detailed Description
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PRIMARY OBJECTIVES: I. Evaluate the objective response rate in patients with advanced hepatocellular carcinoma treated with bevacizumab and erlotinib. SECONDARY OBJECTIVES: I. Evaluate the time to progression in patients treated with this regimen. II. Evaluate the overall and progression-free survival of patients treated with this regimen. III. Evaluate the adverse events in patients treated with this regimen. TERTIARY OBJECTIVES: I. Determine the presence of epidermal growth factor receptor (EGFR) mutations in tumor tissue and correlate this with response rate, progression, and survival in patients treated with this regimen. II. Evaluate the expression of molecules involved in EGFR signal transduction, including EGFR, phosphorylated-EGFR, Akt, phosphorylated-Akt, mitogen-activated protein kinase (MAPK), phosphorylated-MAPK, and HER2/neu by immunohistochemistry (from tumor tissue) and correlate these with patient outcome measures. III. Determine the levels of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor tissue as well as baseline plasma VEGF levels and correlate these with patient outcome measures. OUTLINE: This is a multicenter study. Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo laboratory studies to determine epidermal growth factor receptor (EGFR) and phosphorylated-EGFR protein levels using initial diagnostic biopsy specimens by immunohistochemistry (IHC) for correlation with clinical outcome. Levels of proteins through which EGFR signals, including Akt, phosphorylated-Akt, mitogen-activated protein kinase (MAPK), and phosphorylated-MAPK, are also determined using initial diagnostic biopsy specimens by IHC and correlated with clinical outcome. Total and free serum vascular endothelial growth factor levels are determined at the start of study and prior to course 3 by enzyme-linked immunosorbent assays (ELISA). After completion of study treatment, patients are followed periodically for up to 3 years.

Official Title
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Phase II Study of Bevacizumab Plus Erlotinib in Patients With Advanced Hepatocellular Cancer (HCC)

Conditions
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Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Absolute neutrophil count >= 1,500/mm^3 Creatinine =< 2 mg/dL Albumin >= 2.5 g/dL Total bilirubin =< upper limit of normal (ULN) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times ULN Alkaline phosphatase =< 5 times ULN Urine protein:creatinine ratio < 1.0 OR 24-hour urine protein < 1,000 mg Not pregnant or nursing: No nursing for >= 6 months after completion of study treatment Negative pregnancy test Fertile patients must use effective contraception during study and for >= 6 months after completion of study treatment No history of allergic reactions attributed to compounds of similar chemical or biological composition to bevacizumab or erlotinib hydrochloride No abnormalities of the cornea, including any of the following: History of dry eye syndrome or Sjögren's syndrome; Congenital abnormality (e.g., Fuch's dystrophy); Abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose); Abnormal corneal sensitivity test (e.g., Schirmer test or similar tear production test) No stroke or transient ischemic attack within the past 6 months No uncontrolled high blood pressure, history of labile hypertension, or history of poor compliance with an antihypertensive regimen No unstable angina pectoris within the past 6 months No symptomatic congestive heart failure No myocardial infarction within the past 6 months No serious uncontrolled cardiac arrhythmias No uncontrolled diabetes mellitus No active or uncontrolled infection No impaired GI function or disease that may significantly alter the absorption of erlotinib hydrochloride (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or bowel obstruction) Able to swallow tablets No psychiatric illness or social situation that would limit compliance with study requirements No history of nephrotic-range protein No history of bleeding diathesis No encephalopathy No serious nonhealing wounds, skin ulcers, or bone fractures No clinically significant peripheral vascular disease No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No history of a GI bleed that required procedural intervention (e.g., variceal banding, surgical shunt, transvenous intrahepatic porto-systemic shunt [TIPS]) within the past 3 months No significant traumatic injury within the past 28 days No other prior malignancy within the past 5 years except for the following: Adequately treated basal cell or squamous cell skin cancer; Adequately treated in situ cervical cancer; Stage I or II cancer from which the patient is currently in complete remission; Stage I chronic lymphocytic leukemia Recovered from all therapy-related toxicities No more than 1 prior systemic or liver directed drug therapy including transarterial chemoembolization (TACE) (multiple TACEs will count as 1 prior regimen irrespective of their total numbers) that were used for HCC No chemotherapy for HCC within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C) No biological therapy or immunotherapy for HCC within the past 4 weeks Prior surgery, regional therapy (e.g., transarterial embolization), liver transplantation, or other liver-directed ablative therapies of discrete lesions allowed provided any related progressive or recurrent disease is documented No cryotherapy, radiofrequency ablation, ethanol injection, or photodynamic therapy within the past 6 weeks: Indicator lesions must be outside the area of prior treatment OR if the lesion is inside the area of prior treatment, there must be clear evidence of disease progression associated with that lesion No core biopsy within the past 7 days No radiotherapy within the past 4 weeks No prior antiangiogenesis agent or antiepidermal growth factor receptor drug No prior treatment with hepatic arterial infusion with chemotherapy or yttrium Y 90-labeled microspheres No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer therapy Concurrent full-dose anticoagulants (e.g., warfarin) with international normalized ratio (INR) > 1.2 allowed provided the following criteria are met: An in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant (or on a stable dose of low molecular weight heparin) AND (continued from above) No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels, gastrointestinal [GI] ulceration, or known varices) No concurrent major surgical procedures Histologically confirmed hepatocellular carcinoma (HCC): No fibrolamellar subtype HCC Advanced disease Not a candidate for surgical resection or liver transplantation Measurable disease: Edges of the indicator lesion must be clearly distinct on CT scan Lesions that measure at least 1 cm but less than 2 cm only must use spiral CT imaging for both pre- and post-treatment tumor assessments Child's Pugh classification A or B No primary brain tumor, brain metastasis, or other central nervous system (CNS) diseases Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Platelet count >= 75,000/mm^3 No major surgery (e.g., laparotomy), open biopsy, or minor surgery (e.g., insertion of a vascular access device) within the past 4 weeks No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 28 days No concurrent prophylactic hematopoietic colony-stimulating factors

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (monoclonal antibody, enzyme inhibitor)<br>Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo laboratory studies to determine EGFR and phosphorylated-EGFR protein levels using initial diagnostic biopsy specimens by IHC for correlation with clinical outcome. Levels of proteins through which EGFR signals, including Akt, phosphorylated-Akt, MAPK, and phosphorylated-MAPK, are also determined using initial diagnostic biopsy specimens by IHC and correlated with clinical outcome. Total and free serum vascular endothelial growth factor levels are determined at the start of study and prior to course 3 by ELISA. | Biological: bevacizumab<br>* Given IV, 10 mg/kg, days 1 and 15 in every cycle<br>* Other names: rhuMAb VEGF;Drug: erlotinib hydrochloride<br>* Given orally, 150 mg, every day during each cycle.<br>* Other names: OSI-774;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Confirmed Tumor Response Defined to be Either a Complete Response (CR) or Partial Response (PR). | Responses to erlotinib and bevacizumab treatment were evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). A Complete Response (CR) is defined as the disappearance of all target lesions. A Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of the longest diameters. | Patients were able to continue treatment indefinitely and were evaluated every cycle until discontinued treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Time | Survival time is defined as the time from registration to death due to any cause. Estimated using the method of Kaplan-Meier. | From registration to death due to any cause, patients are followed up to 3 years after treatment | 
| Time to Disease Progression | Time to disease progression is defined as the time from registration to documentation of disease progression. Estimated using the method of Kaplan-Meier. | From registration to documentation of disease progression, up to 3 years after treatment. | 
| Duration of Response | Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented. | The date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented. | 
| Time to Treatment Failure | Time to treatment failure is defined to be the time from the date of randomization to the date at which the patient is removed from treatment due to progression, toxicity, or refusal. | From the date of randomization to the date at which the patient is removed from treatment due to progression, toxicity, or refusal. |