Gemcitabine With Or Without Bevacizumab In Treating Patients With Locally Advanced Or Metastatic Pancreatic Cancer

Study Overview

Gemcitabine With or Without Bevacizumab in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer

This randomized phase III trial is studying gemcitabine and bevacizumab to see how well they work compared to gemcitabine alone in treating patients with locally advanced or metastatic pancreatic cancer. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as bevacizumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Bevacizumab may also stop the growth of tumor cells by stopping blood flow to the tumor. Combining gemcitabine with bevacizumab may kill more tumor cells. It is not yet known whether gemcitabine is more effective with or without bevacizumab in treating pancreatic cancer.

PRIMARY OBJECTIVES: I. To determine if combination chemotherapy with gemcitabine and bevacizumab achieves superior survival compared to gemcitabine and placebo in patients with previously untreated advanced pancreatic cancer. SECONDARY OBJECTIVES: I. To compare the objective response rates, duration of response, progression free survival, and toxicity of these two regimens in patients with advanced pancreatic cancer. II. To measure baseline levels of VEGF and correlate with treatment outcome. III. To measure baseline and on treatment levels of additional growth factors that may be co- or counter- regulated with VEGF and correlate with response to treatment. IV. To measure baseline and on treatment levels of coagulation and endothelial cell activation markers that may predict for thrombotic or bleeding risks related to treatment. V. To generate protein expression profiles using a MALDI-TOF based platform from serum samples. To analyze and compare protein expression profiles to elucidate ion peaks that differentiate patients who respond to therapy from patients who do not respond. To identify proteins responsible for the differentially expressed ion peaks. To develop quantitative assays for each of these proteins. VI. To assess any differences in overall survival within the treatment arm (gemcitabine + bevacizumab), between the two VEGF genotypic groups: Group 1 denoted by individuals with CT or TT genotypes and Group 2 consisting of individuals with CC genotypes. VII. To conduct an exploratory analysis of gene-toxicity, gene-response, and gene-survival relationships for the various polymorphisms described in the genes implicated in gemcitabine pharmacology (CDA, DCK, DCTD, SLC29A1, SLC28A1, SLC29A2). An exploratory quantitative interaction between the genotypes (group 1 or 2) and the treatment arms (gemcitabine + bevacizumab or gemcitabine + placebo) in predicting overall survival will also be evaluated. VIII. To identify specific SNPs and genetic variation that are associated with differences among patients in the risk of toxicity. IX. To compare the effects of gemcitabine + bevacizumab versus gemcitabine + placebo on resource utilization, cost, and utilities, and if applicable, to make estimates of marginal cost-utility. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to ECOG performance status (0-1 vs 2), disease extent (metastatic vs locally advanced), and prior radiotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive 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 IV as in arm I and placebo IV over 30-90 minutes on days 1 and 15. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year and then every 6 months for 3 years. PROJECTED ACCRUAL: A total of 590 patients (295 per treatment arm) will be accrued for this study within 26.8 months.

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

DRUG: gemcitabine hydrochloride
BIOLOGICAL: bevacizumab
OTHER: placebo
OTHER: laboratory biomarker analysis
OTHER: pharmacogenomic studies
OTHER: pharmacological study

NCI-2012-02960
CALGB-80303
CDR0000377542
U10CA031946 (U.S. NIH Grant/Contract)

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 2004-08-04	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2013-06-04
First Submitted that Met QC Criteria 2004-08-04	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2013-06-05
First Posted (ESTIMATED) 2004-08-05	Results First Posted N/A	Last Verified 2013-06

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:
Randomized

Interventional Model:
Parallel

Masking:
Double

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm I (gemcitabine hydrochloride, bevacizumab) Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15.	DRUG: gemcitabine hydrochloride Given IV BIOLOGICAL: bevacizumab Given IV OTHER: laboratory biomarker analysis Correlative studies OTHER: pharmacogenomic studies Correlative studies OTHER: pharmacological study Correlative studies
ACTIVE_COMPARATOR: Arm II (gemcitabine hydrochloride, placebo) Patients receive gemcitabine IV as in arm I and placebo IV over 30-90 minutes on days 1 and 15.	DRUG: gemcitabine hydrochloride Given IV OTHER: placebo Given IV OTHER: laboratory biomarker analysis Correlative studies OTHER: pharmacogenomic studies Correlative studies OTHER: pharmacological study Correlative studies

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Arm I (gemcitabine hydrochloride, bevacizumab)

Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15.

DRUG: gemcitabine hydrochloride

Given IV

BIOLOGICAL: bevacizumab

Given IV

OTHER: laboratory biomarker analysis

Correlative studies

OTHER: pharmacogenomic studies

Correlative studies

OTHER: pharmacological study

Correlative studies

ACTIVE_COMPARATOR: Arm II (gemcitabine hydrochloride, placebo)

Patients receive gemcitabine IV as in arm I and placebo IV over 30-90 minutes on days 1 and 15.

DRUG: gemcitabine hydrochloride

Given IV

OTHER: placebo

Given IV

OTHER: laboratory biomarker analysis

Correlative studies

OTHER: pharmacogenomic studies

Correlative studies

OTHER: pharmacological study

Correlative studies

Primary Outcome Measures	Measure Description	Time Frame
Overall survival (OS)	Based on the stratified logrank test.	From trial entry until death, assessed up to 7 years
Discrepancies in the response rate between the two genotypic groups (CT/TT or CC) (Pharmacogenetics portion)	This analysis will be done in the context of a two-way multiplicative logistic model with genotype and treatment as the two factors.	Up to 7 years
Grade 3-4 neutropenia in terms of specific single-nucleotide polymorphisms (SNPs) and/or copy number variations that are associated with the prevalence of these events (Clinical endpoint)		Up to 7 years

Secondary Outcome Measures	Measure Description	Time Frame
Objective response (complete or partial [CR/PR])		Up to 7 years
Duration of response		Time from the first tumor assessment that supports the patient's response to the time of disease progression or death from any cause, assessed up to 7 years
Progression-free survival (PFS)	The two-way multiplicative Cox model will be used.	From study entry until documented progression of disease or death from any cause, assessed up to 7 years
Toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0	The two-way multiplicative Cox model will be used.	Up to 7 years
Quantitative interaction between the genotypes (group 1 or 2) and the treatment arm (gemcitabine or gemcitabine + bevacizumab) in modeling response (Pharmacogenetics portion)		Up to 7 years
Objective response (PR/CR versus stable disease [SD]/progressive disease [PD]) (Clinical endpoint)		Up to 7 years
Disease-control (PR/CR/SD versus PD) (Clinical endpoint)		Up to 7 years
OS (Clinical endpoint)	This endpoint will be analyzed in the framework of a 3x6 singly ordered contingency table.	Up to 7 years

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:

Histologic or cytologic documentation of adenocarcinoma of the pancreas; documentation of disease extent by CT scan is required; radiologically measurable disease is not required; patients with documented invasion of adjacent organs (e.g., duodenum, stomach) by CT scan are not eligible
No prior chemotherapy for metastatic disease
If the patient received adjuvant therapy, it must have been completed at least 4 weeks prior to enrollment on this study; the patient must have recovered from all treatment related toxicities and must have evidence of disease progression following adjuvant treatment
Prior radiation therapy, with or without a radiosensitizing dose of fluoropyrimidines, is allowed provided the patient has disease outside of the radiation port; at least 4 weeks must have elapsed from completion of the radiation therapy and all signs of toxicity must have resolved
No prior treatment with gemcitabine or bevacizumab in the adjuvant or metastatic setting
No current or recent (within 1 month) use of a thrombolytic agent
Patients may not have had prior therapy with other VEGF inhibitors
No recent invasive surgical procedures; this includes:

Major surgical procedure (e.g. exploratory laparotomy or laparoscopy), open biopsy, or significant traumatic injury within 28 days prior to registration
Fine needle aspirations or venous access device within 7 days prior to registration
Anticipation of need for major surgical procedures during the course of the study
No clinically significant cardiovascular disease; this includes:

Uncontrolled hypertension (blood pressure > 150/90 on medication)
New York Heart Association grade II or greater congestive heart failure
Serious cardiac arrhythmia requiring medication
No recent (within 6 months) arterial thrombotic events, including transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina, or myocardial infarction (MI); patients with clinically significant peripheral artery disease (i.e., claudication on less than one block) are also ineligible
No evidence of CNS disease, including primary brain tumor, or any brain metastasis
No serious or non-healing wound, ulcer or bone fracture
No serious active infection (viral, fungal bacterial); no infection requiring parenteral antibiotics at time of registration
Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies are not eligible
Patients with a "currently active" second malignancy other than non-melanoma skin cancers are not to be registered; patients are not considered to have a "currently active" malignancy if they have completed therapy and considered by their physician to be at less than 30% risk of relapse
Women must be non-pregnant and non-breast feeding
ECOG Performance status of 0, 1 or 2
Granulocytes ≥ 1,500/μl
Platelet count ≥ 100,000/μl
Creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/min
Total bilirubin ≤ 1 x upper limit of normal
SGOT(AST) ≤ 2.5 x upper limit of normal
PT INR =< 1.5, unless patient is on full dose warfarin
Urine protein; for ≥ 1+ proteinuria, 24 hour urine collection must demonstrate < 1 gm of protein/24 hours
Required diagnostic procedures:

CT of the abdomen
Chest x-ray

Collaborators and Investigators

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

Investigators

PRINCIPAL_INVESTIGATOR: Hedy Kindler, Cancer and Leukemia Group B

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

Quintanilha JCF, Wang J, Sibley AB, Jiang C, Etheridge AS, Shen F, Jiang G, Mulkey F, Patel JN, Hertz DL, Dees EC, McLeod HL, Bertagnolli M, Rugo H, Kindler HL, Kelly WK, Ratain MJ, Kroetz DL, Owzar K, Schneider BP, Lin D, Innocenti F. Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients. Br J Cancer. 2022 Feb;126(2):265-274. doi: 10.1038/s41416-021-01557-w. Epub 2021 Oct 6.
Quintanilha JCF, Liu Y, Etheridge AS, Yazdani A, Kindler HL, Kelly WK, Nixon AB, Innocenti F. Plasma levels of angiopoietin-2, VEGF-A, and VCAM-1 as markers of bevacizumab-induced hypertension: CALGB 80303 and 90401 (Alliance). Angiogenesis. 2022 Feb;25(1):47-55. doi: 10.1007/s10456-021-09799-1. Epub 2021 May 24.

Learn

Resources

PatientS

Caregivers

Clinical Trial Record