Avastin, Fluorouracil, Doxorubicin and Streptozocin in Locally Advanced and Metastatic Pancreatic Endocrine Tumors

Study Overview
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Brief Summary
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Open label, single-arm phase II study of avastin combined with fluorouracil, doxorubicin and streptozocin administered in 28-day cycles. Treatment will continue until progression of disease, or until withdrawal due to toxicity, or up to a maximum of 12 cycles (48 weeks). In order to reduce the risk of cardiac toxicity, doxorubicin will be administered for a maximum of 8 cycles. If disease has not progressed after 12 cycles of treatment, avastin monotherapy will continue until disease progression or withdrawal due to toxicity.

Detailed Description
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Patients will need to come for 24 study visits in all. Most study visits will take about 2 hours. At some of these study visits, the doctor Will do a physical exam Will take blood for routine lab tests Will do a urinalysis Will administer study medication Some study visits may be longer because patient will have a CT scan or an MRI. At patient's last visit, they will have a CT scan or MRI. After treatment starts, patient will: Have their blood pressure monitored with every dose of Avastin® (about every 2 weeks). Have a history and physical with every chemotherapy cycle (about every 4 weeks). Have their blood taken for routine blood tests with every chemotherapy cycle (about every 4 weeks). Have a CT scan or MRI during every other cycle (about every 8 weeks). Have a MUGA scan during every 4 cycles (about 16 weeks). Have blood taken for tumor markers during every cycle only if their markers were high at baseline. Patients will receive study medication to treat their cancer: Fluorouracil on days 1 through 5 of each cycle through cycle 12 Doxorubicin on day 1 of each cycle through cycle 8 Streptozocin on days 1 through 5 of each cycle through cycle 12 Avastin® on days 1 and 15 of each cycle through cycle 12

Official Title
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Phase II Study of Avastin, Fluorouracil, Doxorubicin and Streptozocin in Locally Advanced and Metastatic Pancreatic Endocrine Tumors

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Avastin
* Drug: Fluorouracil
* Drug: Doxorubicin
* Drug: Streptozocin
* Drug: Dexamethasone
* Drug: Ondansetron


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have locally advanced (unresectable) or metastatic, well or moderately differentiated pancreatic endocrine tumors. Measurable disease on CT scan or MRI. Age ≥ 18 years and ≤ 80 years. Use of effective means of contraception (men and women) in subjects of child-bearing potential Adequate renal function (serum creatinine ≤1.5, urine protein:creatinine ratio <1.0 or urine dipstick for proteinuria < 2+ (patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours to be eligible). Adequate hepatic function (bilirubin ≤2.0, AST and ALT ≤ 3x ULN. Adequate hematologic function (WBC ≥ 3,000, ANC ≥ 1500, platelets ≥ 100,000) Exclusion Criteria: Prior therapy with fluorouracil, doxorubicin, streptozocin or avastin Ejection fraction on MUGA <50% ECOG performance status > 2 Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored avastin cancer study Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications) Any prior history of hypertensive crisis or hypertensive encephalopathy Unstable angina New York Heart Association (NYHA) Grade II or greater congestive heart failure History of myocardial infarction or unstable angina within 6 months prior to study enrollment History of stroke or transient ischemic attack within 6 months prior to study enrollment Significant vascular disease (e.g., aortic aneurysm, aortic dissection) Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy Presence of central nervous system or brain metastases Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential Proteinuria at screening as demonstrated by either Urine protein: creatinine (UPC) ratio ≥ 1.0 at screening OR Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible). History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0 Evidence of duodenal invasion on CT scan, MRI, or endoscopy Known hypersensitivity to any component of avastin Serious, non-healing wound, ulcer, or bone fracture Inability to comply with study and/or follow-up procedures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Protocol Specified Chemotherapy<br>Protocol Specified Chemotherapy Every 28 Days: Avastin, Fluorouracil, Doxorubicin, Streptozocin. Premedications: Dexamethasone, Ondansetron | Drug: Avastin<br>* Every 28 Days: Avastin 5mg/kg iv days 1 and 15<br>* Other names: bevacizumab;Drug: Fluorouracil<br>* Every 28 Days: Fluorouracil 400mg/m^2 iv bolus daily days 1-5<br>* Other names: Efudex;Drug: Doxorubicin<br>* Every 28 Days: Doxorubicin 40mg/m^2 iv bolus day 1<br>* Other names: Adriamycin®;Drug: Streptozocin<br>* Every 28 Days: Streptozocin 400mg/m2 iv bolus daily days 1-5<br>* Other names: Zanosar®;Drug: Dexamethasone<br>* Premedication: Dexamethasone 20mg intravenously days 1-5<br>* Other names: Decadron;Drug: Ondansetron<br>* Premedication: Ondansetron 16mg intravenously days 1-5<br>* Other names: Zofran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression Free Survival (PFS) at 12 Months | We planned to calculate the One Year Progression Free Survival rate. The event for PFS analyses was the first occurrence of disease progression or death and patients who did not progress or died would be censored at the date of last tumor evaluation (e.g. one-year). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Radiographic Response | Objective Radiographic Response Rate (ORR). We planned to calculate the sum of complete response (CR) and partial response (PR) in target lesions. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced, unresectable, metastatic, endocrine, tumors