Gemcitabine, Bevacizumab, And Abdominal Radiation Therapy In Treating Patients With Localized Pancreatic Cancer

Study Overview

Gemcitabine, Bevacizumab, and Abdominal Radiation Therapy in Treating Patients With Localized Pancreatic Cancer

RATIONALE: Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Bevacizumab may also stop the tumor growth by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Gemcitabine and bevacizumab may make tumor cells more sensitive to radiation therapy. Giving gemcitabine together with bevacizumab and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving gemcitabine together with bevacizumab and abdominal radiation therapy works in treating patients with localized pancreatic cancer.

OBJECTIVES: Primary * Determine the objective response rate in patients treated with concurrent bevacizumab, gemcitabine hydrochloride, and abdominal radiotherapy. Secondary * Determine the quantitative toxicity associated with the delivery of this regimen in these patients. * Determine the 1-year and median survival of patients treated with this regimen. * Determine the time to progression in patients treated with this regimen. * Determine the patterns of recurrence in the entire population of patients treated with this regimen and in the subgroup that is resected for cure. * Determine the safety of this regimen in these patients. * Evaluate the surgical experience of patients who undergo surgical resection after completion of protocol-directed therapy. * Evaluate the toxicity associated with surgical resection in these patients. OUTLINE: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 of courses 1 and 3 and on days 1, 8, and 15 of course 2. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15 of course 1, on days 8 and 22 of course 2, and on day 8 of course 3. Treatment repeats every 3-4 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of the second course of chemotherapy, patients undergo concurrent abdominal radiotherapy once daily, five days a week, for 3 weeks. Patients are evaluated at week 10. Patients whose disease deemed resectable after study treatment undergo standard pancreatic resection at least 6 weeks after completion of bevacizumab. Patients who remain unresectable and have not progressed after completion of chemoradiotherapy may begin maintenance therapy comprising gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment with gemcitabine hydrochloride and bevacizumab repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed periodically for up to 10 years. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Pancreatic Cancer

BIOLOGICAL: bevacizumab
DRUG: gemcitabine
PROCEDURE: conventional surgery
RADIATION: radiation therapy

NU 04I6
NU-04I6
STU00006774 (OTHER Identifier) (OTHER: Northwestern University IRB)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2007-04-11	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2018-10-25
First Submitted that Met QC Criteria 2007-04-11	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2018-10-29
First Posted (ACTUAL) 2007-04-13	Results First Posted N/A	Last Verified 2018-10

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment Arm Concurrent gemcitabine, bevacizumab, and radiation therapy	BIOLOGICAL: bevacizumab 10 mg/kg every 2 weeks as an intravenous infusion after gemcitabine and before radiation DRUG: gemcitabine 1000 mg/m2, 30 minute intravenous infusion, cycle 1 (weeks 1, 2), cycle 2 (weeks 4, 5, 6) and cycle 3 (weeks 8 and 9). During cycle 2, gemcitabine will be delivered prior to radiation therapy PROCEDURE: conventional surgery If resectable, patients will undergo surgery no less than 6 weeks following last dose of bevacizumab. Unresectable patients will not undergo surgery. RADIATION: radiation therapy 2.4 Gy fractions, 5 fractions/week during cycle 2 only (weeks 4, 5, 6). Total dose 36 Gy.

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment Arm

Concurrent gemcitabine, bevacizumab, and radiation therapy

BIOLOGICAL: bevacizumab

10 mg/kg every 2 weeks as an intravenous infusion after gemcitabine and before radiation

DRUG: gemcitabine

1000 mg/m2, 30 minute intravenous infusion, cycle 1 (weeks 1, 2), cycle 2 (weeks 4, 5, 6) and cycle 3 (weeks 8 and 9). During cycle 2, gemcitabine will be delivered prior to radiation therapy

PROCEDURE: conventional surgery

If resectable, patients will undergo surgery no less than 6 weeks following last dose of bevacizumab. Unresectable patients will not undergo surgery.

RADIATION: radiation therapy

2.4 Gy fractions, 5 fractions/week during cycle 2 only (weeks 4, 5, 6). Total dose 36 Gy.

Primary Outcome Measures	Measure Description	Time Frame
Response rate	Response will be measured by CT scans using Recist and defined as Complete Response, Partial Response, Stable disease/no response, Progressive Disease.	After 10 weeks of concurrent therapy

Secondary Outcome Measures	Measure Description	Time Frame
Toxicity profile of bevacizumab and gemcitabine with radiation therapy	Toxicities will be measured using National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). Adverse events (AE)are graded: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE	After every cycle of therapy (cycle = 3-4 weeks), then every 3 months for 2 years, then every 6 months for 3 years, then yearly up to 10 years or until disease progression.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Diagnosis of localized pancreatic cancer

No metastatic disease
Resectable or unresectable tumor based on spiral CT with both oral and intravenous contrast enhancement, defined by the following National Comprehensive Cancer Network (NCCN) criteria for resectability*:

Resectable tumors meeting the following criteria:

No distant metastases
Clear fat plane around celiac and superior mesenteric arteries
Patent superior mesenteric vein/portal vein
Tumors considered borderline resectable according to NCCN criteria, including any of the following, are considered unresectable for the purpose of this study:

Severe unilateral superior mesenteric vein/portal impingement
Tumor abutment on the superior mesenteric artery
Gastroduodenal artery encasement up to the origin at the hepatic artery
Colon invasion NOTE: *Determination of resectability must be made prior to study entry based on NCCN criteria
Patients with biliary or gastroduodenal obstruction must have drainage or surgical bypass prior to starting chemoradiotherapy
Radiographically assessable disease

Malignant disease must be encompassable within a single irradiation field
No gross duodenal invasion noted on endoscopy
No CNS or brain metastases

ECOG performance status 0-1
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for up to 3 months after completion of study therapy
Bilirubin ≤ 2.0 mg/dL
AST or ALT ≤ 2.5 times upper limit of normal
Urine protein:creatinine ratio < 1.0
Proteinuria < 2+ by dipstick urinalysis OR baseline protein ≤ 1 g/24-hour urine collection
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 9.0 g/dL (transfusion or epoetin alfa support allowed)
INR ≤ 1.5
No other malignancy within the past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix, uterus, or bladder
No concurrent significant infection or other medical condition that would preclude protocol treatment
No history of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that would contraindicate use of an investigational drug, affect the interpretation of the results of the study, or render the patient at high risk for treatment complications
No clinically significant cardiac disease, including any of the following:

Uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg despite antihypertensive medication)
Myocardial infarction within the past year
Unstable angina
New York Heart Association class II-IV congestive heart failure
Unstable symptomatic arrhythmia requiring medication

Chronic atrial arrhythmia (i.e., atrial fibrillation or paroxysmal supraventricular tachycardia) allowed
No clinically significant peripheral vascular disease
No evidence of bleeding diathesis or coagulopathy
No significant traumatic injury within the past 28 days
No serious, nonhealing wound or ulcer, or concurrent healing fracture
No history of aneurysm, stroke, transient ischemic attack, or arteriovenous malformation
No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

See Disease Characteristics
No prior treatment for pancreatic cancer
More than 5 years since prior chemotherapy for malignancies other than pancreatic cancer
No prior radiotherapy to the target volume
More than 28 days since prior major surgical procedure or open biopsy
At least 28 days since prior surgical bypass
More than 7 days since prior fine-needle aspiration or core biopsy
No prior organ transplant
At least 4 weeks since prior sorivudine or brivudine
At least 30 days since prior cimetidine
No concurrent major surgical procedure

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

STUDY_CHAIR: William Small, MD, Robert H. Lurie Cancer Center

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Small W Jr, Mulcahy M, Benson A, et al.: A phase II trial of weekly gemcitabine and bevacizumab in combination with abdominal radiation therapy in patients with localized pancreatic cancer. [Abstract] J Clin Oncol 25 (Suppl 18): A-15043, 637s, 2007.
Rezai P, Yaghmai V, Tochetto SM, Galizia MS, Miller FH, Mulcahy MF, Small W Jr. Change in the growth rate of localized pancreatic adenocarcinoma in response to gemcitabine, bevacizumab, and radiation therapy on MDCT. Int J Radiat Oncol Biol Phys. 2011 Oct 1;81(2):452-9. doi: 10.1016/j.ijrobp.2010.05.060. Epub 2011 May 11.

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