Bevacizumab and Erlotinib Hydrochloride in Treating Patients With Metastatic or Unresectable Biliary Tumors

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 hydrochloride works in treating patients with metastatic or unresectable biliary tumors. 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 hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and erlotinib hydrochloride may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with erlotinib hydrochloride may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Evaluate the objective response rate in patients with metastatic or unresectable cholangiocarcinoma treated with bevacizumab and erlotinib hydrochloride. SECONDARY OBJECTIVES: I. Evaluate time to progression in these patients. II. Evaluate overall and progression-free survival of these patients. III. Evaluate the adverse events associated with this regimen. OUTLINE: This is an open-label, multicenter study. Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. After completion of study therapy, patients are followed periodically for up to 3 years.

Official Title
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A Phase II Trial of Bevacizumab and Erlotinib in Patients With Advanced Biliary Tumors

Conditions
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Cholangiocarcinoma of the Extrahepatic Bile Duct, Cholangiocarcinoma of the Gallbladder, Gastrointestinal Cancer, Recurrent Extrahepatic Bile Duct Cancer, Recurrent Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Cancer, Unresectable Gallbladder Cancer

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


Participation Criteria
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Eligibility Criteria
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Criteria: Absolute neutrophil count >= 1,500/mm3 Histologically or cytologically confirmed cholangiocarcinoma or gallbladder carcinoma: Metastatic or surgically unresectable disease Measurable disease, defined as >= 1 lesion whose longest diameter can be accurately measured as >= 2.0 cm with conventional techniques or as > 1.0 cm with spiral CT scan: Spiral CT scan imaging must be used for pre- and post-treatment tumor measurements of lesions measuring >= 1.0 cm to < 2.0 cm Clinical lesions will only be considered measurable when they are superficial Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung No ampulla of Vater tumors No evidence of CNS disease Life expectancy >= 3 months ECOG performance status 0-2 Platelet count >= 75,000/mm3 Total bilirubin =< 2 times ULN ALT and AST =< 2.5 times ULN Creatinine =< 2 mg/dL Albumin >= 2.5 g/dL Alkaline phosphatase =< 5 times ULN Urine protein:creatinine ratio < 1.0 OR 24-hour urine protein < 1000 mg No concurrent illness or medical condition, including any of the following: Impairment of gastrointestinal (GI) function or disease that may significantly alter the absorption of erlotinib hydrochloride Requirement for IV alimentation No concurrent illness or medical condition, including any of the following: Active peptic ulcer disease; Serious or nonhealing wound, ulcer, or bone fracture; GI bleed that required procedural intervention within the past 3 months No concurrent illness or medical condition, including any of the following: Abdominal fistula, GI perforation, or intra-abdominal abscess within the past 28 days Ongoing or active infection Symptomatic congestive heart failure Psychiatric illness or social situation that would limit study compliance No other malignancy within the past 3 years No abnormalities of the cornea Not pregnant or nursing Fertile patients must use effective contraception No clinically significant cardiovascular disease More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered No significant traumatic injury within the past 28 days No prior systemic anticancer therapy for metastatic gallbladder or bile duct cancer More than 28 days since prior major surgery [Note: Insertion of a vascular access device is not considered major/minor surgery] More than 2 weeks since prior minor surgery [Note: Insertion of a vascular access device is not considered major/minor surgery] More than 7 days since prior core biopsy No concurrent major surgery No other concurrent chemotherapy, immunotherapy, radiotherapy, or any other therapy or supportive care considered investigational No concurrent enzyme-inducing antiepileptic drugs or any other CYP3A4 inducer, such as rifampin or Hypericum perforatum No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational agents or other concurrent anticancer therapies No concurrent prophylactic hematopoietic colony-stimulating factors Concurrent full-dose anticoagulants allowed provided PT/INR is > 1.5 and both of the following criteria are met: In-range INR 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 ulcerations, or known varices)

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: Bevacizumab and Erlotinib Hydrochloride<br>Patients receive 5 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15 and 150 mg oral erlotinib hydrochloride daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Tumor tissue and blood specimens are collected periodically for correlative studies. Specimens are examined by immunohistochemistry for epidermal growth factor receptor (EGFR) and P-EGFR protein levels; AKT p-AKT, mitogen-activated protein kinase (MAPK) and P-MAPK protein levels; and vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2 protein levels. EGFR mutations are detected by laser capture microdissection. Enzyme-linked immunosorbent assay is used to measure total and free serum VEGF levels. | Drug: erlotinib hydrochloride<br>* Given orally, 150 mg, once daily.<br>* Other names: OSI-774;Biological: bevacizumab<br>* Given IV, 5mg/kg on days 1 and 15 every cycle<br>* Other names: rhuMAb VEGF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Confirmed Tumor Responses. | Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the target lesions. A confirmed tumor response is defined to be either a Complete Response or a Partial Response noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Confirmed tumor responses will be evaluated using the first 6 cycles of treatment. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment and had one post-baseline disease assessment will be evaluable for response. Forty-nine of the 53 eligible patients had at least one post-baseline disease assessment and were evaluable for this endpoint. | After 6 courses of treatment. Each course lasts 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Time | Estimated using the method of Kaplan-Meier (1958). | From registration to death due to any cause, assessed up to 3 years | 
| Time to Disease Progression | Estimated using the method of Kaplan-Meier (1958). | From registration to documentation of disease progression, assessed up to 3 years | 
| Duration of Response | Point estimates and 95% confidence intervals were calculated using the method of Duffy and Santner (1987). | From 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, assessed up to 3 years |