RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Pemetrexed disodium may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. It is not yet known whether gemcitabine is more effective with or without pemetrexed disodium in treating pancreatic cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of gemcitabine combined with pemetrexed disodium to that of gemcitabine alone in treating patients who have unresectable stage II, stage III, or stage IV pancreatic cancer.

Condition	Treatment or Intervention	Phase
stage II pancreatic cancer stage III pancreatic cancer stage IVB pancreatic cancer stage IVA pancreatic cancer adenocarcinoma of the pancreas	Drug: cyanocobalamin  Drug: folic acid  Drug: gemcitabine  Drug: pemetrexed disodium  Procedure: chemotherapy  Procedure: drug modulation  Procedure: enzyme inhibitor therapy	Phase III

Further Study Details: 

OBJECTIVES:

• Compare the overall survival of patients with stage II, III, or IV unresectable pancreatic cancer treated with gemcitabine with or without pemetrexed disodium.
• Compare the progression-free survival of patients treated with these regimens.
• Compare the time to treatment failure and duration of response in patients treated with these regimens.
• Compare tumor response rate in patients treated with these regimens.
• Compare the effects of these regimens on health-related quality of life in these patients.
• Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, open-label, parallel, multicenter study. Patients are stratified according to baseline ECOG performance status (0-1 vs 2), disease stage (II or III vs IV), baseline homocysteine level (at least 12 µmol/L vs less than 12 µmol/L), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive gemcitabine IV over 30-60 minutes on days 1 and 8 and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral folic acid and cyanocobalamin intramuscularly every 9 weeks beginning 1-2 weeks before day 1 and continuing until 3 weeks after end of study therapy.
• Arm II: Patients receive gemcitabine IV over 30-60 minutes on days 1, 8, and 15. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, at the end of each course, and then every 3 months thereafter.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 520 patients (260 per treatment arm) will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the pancreas
• Stage II, III, or IV disease that is not amenable to resection with curative intent
• At least 1 bidimensionally measurable lesion with clearly defined margins by CT scan or MRI or by palpation with both diameters at least 2 cm
• No clinically significant third-space fluid collection (e.g., ascites or pleural effusions) NOTE: Fluid collections may be drained
• No documented brain metastases

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST/ALT no greater than 3 times ULN (5 times ULN if liver metastases present)
• Alkaline phosphatase no greater than 3 times ULN (5 times ULN if liver metastases present)
• Endoscopic or radiologic stenting allowed for biliary obstructions (bilirubin must meet study requirements and AST/ALT and alkaline phosphatase must be no greater than 5 times ULN)

Renal

• Creatinine clearance at least 45 mL/min

Cardiovascular

• No unstable angina pectoris

Pulmonary

• See Disease Characteristics

Other

• No other malignancy within the past 5 years except carcinoma in situ of the cervix or adequately treated nonmelanoma skin cancer
• No active infection
• No other serious concurrent systemic disorders that would preclude study
• No uncontrolled diabetes mellitus
• No weight loss of 10% or more within the past 6 weeks
• No inability or unwillingness to take folic acid or vitamin B12 supplementation
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 3 months after study

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prior immunotherapy
• No prior biological therapy for pancreatic cancer
• No concurrent immunotherapy
• No concurrent routine colony-stimulating factors
• No concurrent stimulators of thrombopoiesis

Chemotherapy

• No prior chemotherapy for pancreatic cancer
• No prior fluorouracil for pancreatic cancer (including as a radiosensitizer)
• No other concurrent chemotherapy

Endocrine therapy

• No prior hormonal therapy for pancreatic cancer
• No concurrent hormonal therapy for cancer

Radiotherapy

• No prior radiation to whole pelvis
• Prior radiotherapy to less than 25% of bone marrow allowed
• At least 4 weeks since prior radiotherapy and recovered
• Concurrent palliative radiotherapy for small, painful metastases allowed

Surgery

• No concurrent surgery for cancer

Other

• At least 30 days since prior investigational agents or devices
• No other concurrent experimental medications (except thymidine)
• No other concurrent antitumor therapy
• No concurrent aspirin, salicylates, or other nonsteroidal anti-inflammatory drugs for 2-5 days before, during, and for 2 days after each dose of pemetrexed disodium

Ohio
      Ireland Cancer Center, Cleveland,  Ohio,  44106-1714,  United States

Study chairs or principal investigators

Joanna M. Brell, MD,  Study Chair,  Ireland Cancer Center   

Study ID Numbers:  CDR0000258097; CWRU-010224M; NCI-G02-2125; LILLY-H3E-MC-JMES; LILLY-LILY-1201
Record last reviewed:  April 2003
Last Updated:  October 13, 2004
Record first received:  November 12, 2002
ClinicalTrials.gov Identifier:  NCT00049426
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08