Phase II Study of Bevacizumab, FDR Gemcitabine, & Rapid Fractionation Radiotherapy in Preoperative Treatment of Potentially Resectable Pancreatic Cancer

Condition(s) targeted: Pancreatic Cancer

Intervention: Bevacizumab (Drug); Gemcitabine (Drug); Radiotherapy (Procedure)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of Pittsburgh

Official(s) and/or principal investigator(s):
Arthur J Moser, MD, Principal Investigator, Affiliation: University of Pittsburgh

Overall contact:
Amy Schmotzer, RN, BSN, Phone: 412-647-6205, Email: schmotzerar@upmc.edu

This is a 2 stage phase II study of bevacizumab (10 mg/kg) and fixed dose rate (FDR) gemcitabine (1500 mg/m2 at 10 mg/kg/min) in combination with sequential rapid fractionation radiotherapy (30 Gy total) in the preoperative treatment of potentially-resectable subjects with adenocarcinoma of the pancreas. The purpose of this study is to determine the rate of margin negative surgical resection (R0 resection rate) and the rate of complete pathological response in patients with resected pancreas cancer. The overall goal of this study is to determine the merit of this novel regimen for further study in a Phase III trial examining time to progression and overall survival. Based on the need for 48 evaluable subjects to evaluate the primary endpoints, the study will be opened with a target accrual of 60 subjects given an expected 20% rate of attrition observed in prior studies of subjects with pancreas cancer at UPCI.

Official title: Phase II Study of the Anti-Vascular Endothelial Growth Factor (Anti-VEGF) Monoclonal Antibody Bevacizumab in Combination With Fixed Dose Rate (FDR) Gemcitabine and Rapid-Fractionation Radiotherapy in the Preoperative Treatment of Potentially Resectable Pancreatic Cancer (UPCI 06-035)

Study design: Interventional, Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Efficacy Study

Primary outcome:

To determine the rate of margin negative surgical resection (R0 resection rate), and

To establish the rate of complete pathologic response in resected pancreas cancer after neoadjuvant treatment.

Secondary outcome:

Rate of surgical resection

Rate of treatment failure due to unexpected metastasis and locally-advanced disease

Rate of treatment drop-out due to toxicity

Radiographic tumor response (RECIST criteria)

Biomarker response (Ca 19-9)

First site of tumor recurrence

Overall and disease-free survival

Pre- to post-treatment change in tumor expression of VEGF and its downstream markers

Detailed description: Potentially-resectable pancreatic adenocarcinoma staged by traditional surgical criteria based on high-quality helical abdominal computed tomography; i. e. no portomesenteric venous occlusion or suspected hepatic or mesenteric arterial involvement.

No evidence of hepatic or pulmonary metastatic disease on staging pretreatment helical CT scans and chest radiographs; additional imaging studies will be performed to exclude metastatic disease if the clinical presentation warrants (i. e. head CT for suspected central nervous system involvement or bone scan for symptomatic bone metastasis).

Pretreatment histologic confirmation of adenocarcinoma by fine-needle aspiration at the time of endoscopic ultrasound (EUS FNA) or percutaneous needle biopsy as required.

No evidence of gastric outlet obstruction or duodenal invasion during pretreatment upper endoscopy at the time of EUS FNA.

Biliary stent placement to relieve obstructive jaundice and maintain total bilirubin <= 1. 5x upper limit of normal and AST/ALT < 2. 5x normal.

Fixed-dose rate gemcitabine infusion (1500 mg/m2 at 10 mg/m2/min) on days 1, 15, 29 with toxicity monitoring and flexible dose modification as required.

Concurrent infusion of bevacizumab at 10 mg/kg on days 1, 15, 29, and 43. Radiation therapy to a total dose of 30 Gy (3 Gy/fraction Monday-Friday for 10 days) beginning on day 43 and coinciding with the final dose of bevacizumab.

Proton pump inhibitor (pantoprazole or equivalent, 40 mg. p. o. daily.) administered beginning 3 days prior to the start of protocol treatment and continued for 28 days after the last dose of bevacizumab.

Weekly reexamination including vital signs, physical examination, CBC with differential and platelets, serum chemistries, and liver function tests.

Urinalysis for protein every two weeks prior to bevacizumab infusion.

Restaging with arterial phase helical computed tomography of the abdomen, PA and lateral chest radiographs, and EUS as clinically indicated within two to four weeks of completion of therapy.

Surgical intervention after day 71 (28 days after last Bevacizumab dose) including exploratory laparoscopy and pancreatic resection where indicated.

Adjuvant chemotherapy may be administered to surgically-resected subjects who received protocol treatment at the discretion of the treating physician.

A boost of radiation may be administered postoperatively to resected subjects with positive surgical margins who received protocol therapy.

Physical examination and follow-up studies every 3 months for the first 12 months and then every 6 months for five years (CT scan (abdomen and pelvis), PA and lateral chest radiographs, CBC with differential and platelets, PT and PTT, CA 19-9, liver and renal functions (total bilirubin, AST, ALT, alkaline phosphatase, LDH, BUN, creatinine, electrolytes).

Minimum age: 18 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

• Histologic or cytologic proof of pancreatic adenocarcinoma.

• Subjects with biopsy-proven adenocarcinoma of the pancreas which is potentially resectable by preoperative imaging.

- if imaging detects no evidence of extrapancreatic disease;

- no evidence of tumor extension to the superior mesenteric artery (SMA) or celiac axis,

- patent superior mesenteric-portal vein confluence.

• Subjects who have been previously denied operation may be included so long as CT/EUS criteria for resectability are fulfilled, and medical comorbidities do not preclude an attempt at surgical resection after therapy.

• Karnofsky performance status >= 80.

• No active second malignancy except for basal cell carcinoma of the skin

• Normal renal, hepatic, and hematologic function at the time of enrollment.

- Serum creatinine level ≤1. 6 mg/dl ( Calculated Creat clearance >50)

- Serum total bilirubin level <2 mg/dl

- Urine protein excretion ≤ 1+ by urine dipstick

- White blood cell count >= 3. 5x109/ml per ml and platelet count > 100x109 per ml

• Age >18 years.

• For subjects with obstructive jaundice, the biliary tract must be drained with a temporary plastic or a short permanent metallic biliary stent.

Exclusion Criteria:

• Tumor involvement of major blood vessels.

• Subjects who have received chemotherapy within 12 months prior to study entry.

• Prior use of radiotherapy or investigational agents for pancreatic cancer.

• Subjects who have undergone prior surgery for pancreas cancer within 6 weeks

• Any evidence of metastasis to distant organs (liver, lung, peritoneum) or regional lymph nodes (celiac, periaortic, mediastinal) outside the anticipated field of surgical resection.

• Symptomatic or endoscopic evidence of gastric outlet obstruction

• Endoscopic findings suggesting tumor erosion into the gastrointestinal mucosa.

• Concurrent malignancies with evidence of active or measurable disease except basal cell carcinoma of the skin.

• Inability to adhere to study and/or follow-up procedures

• History of allergic reactions or hypersensitivity to the study drugs (bevacizumab and gemcitabine).

• Planned participation in any experimental drug study

• Because subjects with immune deficiency are at increased risk for lethal infections when treated with marrow-suppressive therapy, HIV-positive subjects receiving combination anti-retroviral therapy are excluded from the study.

• Subjects who have had recent surgery (prior 6 weeks)

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment

• Subjects with the following co-morbid medical conditions:

- History of myocardial infarction or unstable angina within 12 months prior to study enrollment.

- Ascites

- Pregnancy/lactation

- Regular aspirin use > 325 mg per day

- Regular NSAID use

- Bleeding diathesis, coagulopathy, or need for full-dose anticoagulation

- Known central nervous system metastasis

- Previous cerebrovascular accident, transient ischemic attack, or seizure ( within 6 months)

- Serious non-healing wound, ulcer, or bone fracture

- History of abdominal fistula, gastrointestinal perforation, diverticulitis, or intra-abdominal abscess within 6 months prior to study enrollment.

- Recent hemoptysis,

- Uncontrolled 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

- New York Heart Association (NYHA) grade 2 or greater congestive heart failure (see Appendix I)

- Prior deep venous thrombosis or pulmonary embolism

- Urine protein excretion 2+ or >= 1 g per 24 hours

- Peripheral vascular disease such as lower extremity claudication and rest pain or prior lower extremity vascular surgery for arterial insufficiency

- Dyspnea

Amy Schmotzer, RN, BSN, Phone: 412-647-6205, Email: schmotzerar@upmc.edu

UPMC Cancer Centers, Western and Central, Pennsylvania, United States; Recruiting

UPMC Cancer Centers

Starting date: January 2007
Ending date: January 2007
Last updated: January 29, 2007