Bevacizumab and Gemcitabine Combined With Either Cetuximab or Erlotinib in Treating Patients With Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying bevacizumab, gemcitabine, and cetuximab to see how well they work compared to bevacizumab, gemcitabine, and erlotinib in treating patients with advanced pancreatic cancer. Monoclonal antibodies, such as cetuximab and bevacizumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining bevacizumab and gemcitabine with either cetuximab or erlotinib may kill more tumor cells.

Detailed Description
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OBJECTIVES: I. Compare the objective response rate in patients with advanced adenocarcinoma of the pancreas treated with bevacizumab and gemcitabine with cetuximab vs erlotinib. II. Compare the toxicity of these regimens in these patients. III. Compare median progression-free and overall survival of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center (University of Chicago vs other) and ECOG performance status (0-1 vs 2). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, and 22; gemcitabine IV over 30 minutes on days 1, 8, and 15; and bevacizumab IV over 30-90 minutes on days 1 and 15. Arm II: Patients receive gemcitabine and bevacizumab as in arm I. Patients also receive oral erlotinib once daily on days 1-5, 8-12, and 15-26. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months. PROJECTED ACCRUAL: A total of 54-126 patients (27-63 per treatment arm) will be accrued for this study within 16 months.

Official Title
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A Randomized Phase II Study of Bevacizumab (NSC# 704865) and Gemcitabine in Combination With Either Cetuximab (NSC# 714692) or OSI-774 (NSC# 718781) in Patients With Advanced Pancreatic Cancer

Conditions
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Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage II Pancreatic Cancer, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the pancreas Advanced disease Patients with locally advanced disease must have disease that extends outside the boundaries of a standard radiation port Not amenable to curative surgery or radiotherapy Measurable disease At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan Pleural effusions and ascites are not considered measurable lesions No CNS disease, including primary brain tumors or brain metastasis No tumor invasion into the duodenum Performance status - ECOG 0-2 More than 3 months Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 WBC ≥ 3,000/mm^3 No history of bleeding diatheses Bilirubin ≤ 1.5 times upper limit of normal (ULN) SGOT and SGPT ≤ 2.5 times ULN (5 times ULN if liver metastases are present) INR ≤ 1.5 (≤ 3 for patients on warfarin) No esophageal varices Creatinine ≤ 1.5 mg/dL Creatinine clearance ≥ 60 mL/min Urine protein < 1+ 24-hour urine protein < 500 mg No history of a recent cerebrovascular accident No clinically significant cardiovascular disease No uncontrolled hypertension No New York Heart Association class II-IV congestive heart failure No serious cardiac arrhythmia requiring medication No peripheral vascular disease ≥ grade II None of the following arterial thromboembolic events within the past 6 months: Transient ischemic attack Cerebrovascular accident Unstable angina Myocardial infarction Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 3 months after study participation HIV negative No significant traumatic injury within the past 28 days No gastrointestinal tract disease resulting in an inability to take oral medication No allergic reactions to compounds similar to bevacizumab, cetuximab, or erlotinib (e.g., Chinese hamster ovary cell products or recombinant humanized antibodies) No serious or non-healing wound, ulcer, or bone fracture No active infection requiring antibiotics No other active malignancy within the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix No prior bevacizumab or cetuximab No other prior vascular endothelial growth factor inhibitors No prior gemcitabine No prior cytotoxic chemotherapy for metastatic disease At least 4 weeks since prior adjuvant chemotherapy (6 weeks for mitomycin or nitrosoureas) At least 4 weeks since prior radiotherapy Must have a site of measurable disease outside the radiation port No prior surgical procedure affecting absorption More than 28 days since prior major surgical procedure or open biopsy More than 7 days since prior core biopsy No concurrent major surgical procedures No prior erlotinib No other prior epidermal growth factor receptor inhibitors At least 30 days since prior investigational drugs More than 1 month since prior thrombolytic agents Concurrent warfarin or low molecular weight heparin allowed provided the following criteria are met: Currently therapeutic on a stable dose INR target range ≤ 3 Patients undergo weekly INR testing No evidence of active bleeding or pathological condition that carries high risk of bleeding (e.g., tumor invading adjacent organs or esophageal varices) No concurrent chronic daily therapy with aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory medications known to inhibit platelet function No other concurrent antiplatelet medications No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer therapies or agents No other concurrent investigational drugs

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (cetuximab, gemcitabine hydrochloride, bevacizumab)<br>Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, and 22; gemcitabine IV over 30 minutes on days 1, 8, and 15; and bevacizumab IV over 30-90 minutes on days 1 and 15. | Biological: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;|
| Experimental: Arm II (gemcitabine hydrochloride, bevacizumab, erlotinib)<br>Patients receive gemcitabine and bevacizumab as in arm I. Patients also receive oral erlotinib once daily on days 1-5, 8-12, and 15-26. | Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Drug: erlotinib hydrochloride<br>* Given orally<br>* Other names: OSI-774;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (Complete or Partial Response) Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) |  | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Median progression-free survival time (time from randomization to disease progression or death from any cause). Analyzed using the Kaplan-Meier (1958) estimator and their associated 95% confidence intervals determined using the method described in Brookmeyer and Crowley. | 36 months | 
| Overall Survival | Time from randomization until death from any cause. Analyzed using the Kaplan-Meier (1958) estimator and their associated 5% confidence intervals determined using the method described in Brookmeyer and Crowley. | 36 months |