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A Randomized Phase III Trial Of Gemcitabine Plus Bevacizumab (NSC#704865 IND#7621) Versus Gemcitabine Plus Placebo In Patients With Advanced Pancreatic Cancer

Phase 3
18 Years
Not Enrolling
Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage II Pancreatic Cancer, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

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Trial Information

A Randomized Phase III Trial Of Gemcitabine Plus Bevacizumab (NSC#704865 IND#7621) Versus Gemcitabine Plus Placebo In Patients With Advanced Pancreatic Cancer


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.


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

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.

Inclusion Criteria:

- 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

- 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

- Anticipation of need for major surgical procedures during the course of the

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Overall survival (OS)

Outcome Description:

Based on the stratified logrank test.

Outcome Time Frame:

From trial entry until death, assessed up to 7 years

Safety Issue:


Principal Investigator

Hedy Kindler

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer and Leukemia Group B


United States: Food and Drug Administration

Study ID:




Start Date:

June 2004

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Pancreas
  • Recurrent Pancreatic Cancer
  • Stage II Pancreatic Cancer
  • Stage III Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms



Cancer and Leukemia Group B Chicago, Illinois  60606