Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage III Pancreatic Cancer, Stage II Pancreatic Cancer, Stage IV Pancreatic Cancer
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALcetuximab
Given IV
DRUGgemcitabine hydrochloride
Given IV
BIOLOGICALbevacizumab
Given IV
DRUGerlotinib hydrochloride
Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Objective Response Rate (Complete or Partial Response) Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) | Up to 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 36 months | 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. |
| Overall Survival | 36 months | 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. |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled at sixteen sites between September 2004 and February 2007.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Cetuximab, Gemcitabine Hydrochloride, Bevacizumab) 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. | 71 |
| Arm II (Gemcitabine Hydrochloride, Bevacizumab, Erlotinib) 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. | 68 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Patient deemed non eligible-never receiv | 1 | 0 |
| Overall Study | Patient withdrew and never received trea | 0 | 2 |
| Overall Study | Unknown-never received treatment | 0 | 1 |
Baseline characteristics
| Characteristic | Arm I (Cetuximab, Gemcitabine Hydrochloride, Bevacizumab) | Arm II (Gemcitabine Hydrochloride, Bevacizumab, Erlotinib) | Total |
|---|---|---|---|
| Age, Continuous | 63 years | 63 years | 63 years |
| ECOG Performance Status 0 | 26 Participants | 32 Participants | 58 Participants |
| ECOG Performance Status 1 | 40 Participants | 32 Participants | 72 Participants |
| ECOG Performance Status 2 | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Female | 37 Participants | 19 Participants | 56 Participants |
| Sex: Female, Male Male | 34 Participants | 49 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 57 / 71 | 44 / 68 |
| serious Total, serious adverse events | 21 / 71 | 17 / 68 |
Outcome results
Primary
Objective Response Rate (Complete or Partial Response) Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST)
Time frame: Up to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Cetuximab, Gemcitabine Hydrochloride, Bevacizumab) | Objective Response Rate (Complete or Partial Response) Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) | 21 percentage of participants |
| Arm II (Gemcitabine Hydrochloride, Bevacizumab, Erlotinib) | Objective Response Rate (Complete or Partial Response) Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) | 21 percentage of participants |
p-value: 0.2295% CI: [-13, 14]Chi-squared
Secondary
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.
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Cetuximab, Gemcitabine Hydrochloride, Bevacizumab) | Overall Survival | 7.9 Months |
| Arm II (Gemcitabine Hydrochloride, Bevacizumab, Erlotinib) | Overall Survival | 7.1 Months |
p-value: 0.86Log Rank
Secondary
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.
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Cetuximab, Gemcitabine Hydrochloride, Bevacizumab) | Progression-free Survival | 5.0 months |
| Arm II (Gemcitabine Hydrochloride, Bevacizumab, Erlotinib) | Progression-free Survival | 5.1 months |
p-value: 0.95Log Rank