Pemetrexed Disodium Plus Gemcitabine in Treating Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer

A Phase II Clinical Trial Evaluating Three Schedules Of ALIMTA Plus Gemcitabine As Frontline Chemotherapy For Patients With Locally Advanced Or Metastatic Non-Small Cell Lung Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving more than one drug and giving the drugs in different ways may kill more tumor cells.

PURPOSE: Randomized phase II trial to compare the effectiveness of three different regimens of pemetrexed disodium plus gemcitabine in treating patients who have locally advanced or metastatic non-small cell lung cancer.

OBJECTIVES:

• Compare the tumor response rates in patients with locally advanced or metastatic non-small cell lung cancer treated with 3 different schedules of pemetrexed disodium and gemcitabine.
• Compare the duration of response, time to progressive disease, time to treatment failure, and survival time in patients treated with these regimens.
• Compare the quantitative and qualitative toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, open-label study. Patients are stratified according to stage of disease (IIIB vs IV) and ECOG performance status (0 vs 1). Patients are randomized to one of three treatment arms.

• Arm I: Patients receive pemetrexed disodium IV over 10 minutes on day 1 followed by gemcitabine IV over 30 minutes on days 1 and 8.
• Arm II: Patients receive gemcitabine IV over 30 minutes on days 1 and 8 followed by pemetrexed disodium IV over 10 minutes on day 1.
• Arm III: Patients receive gemcitabine IV over 30 minutes on day 1 and pemetrexed disodium IV over 10 minutes followed by gemcitabine IV over 30 minutes on day 8.

Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease may receive up to 6 additional courses of therapy.

Patients are followed every 2 months for 1 year and then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 180 patients (60 per treatment arm) will be accrued for this study within 20 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer

  • Stage IIIB disease that is ineligible for combined modality therapy OR
  • Stage IV disease

• Measurable disease

• No clinically detectable (by physical exam) third-space fluid collection (e.g., ascites or pleural effusions) that cannot be controlled by drainage or other procedures

• No brain metastases (even if treated)

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

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 and 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)

Renal:

• Creatinine clearance at least 45 mL/min

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to take folic acid or cyanocobalamin (vitamin B12) supplementation
• No uncontrolled infection
• No concurrent chronic debilitating disease
• No weight loss of 10% or more within the past 6 weeks
• No other prior malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or noninvasive carcinoma

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic or genetic therapy for lung cancer
• No concurrent immunomodulating agents

Chemotherapy:

• No prior chemotherapy for lung cancer

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 4 weeks since prior radiotherapy to a different site and recovered
• No prior radiotherapy to 25% or more of bone marrow
• No prior radiotherapy to whole pelvis
• No prior radiotherapy for primary disease
• No concurrent radiotherapy

Surgery:

• More than 4 weeks since prior major surgery

Other:

• No aspirin or nonsteroidal anti-inflammatory agents 2 days before, during, and for 2 days after pemetrexed disodium administration (5 days for long-acting agents such as piroxicam, naproxen, diflunisal, or nabumetone)
• No other concurrent cytostatic or cytotoxic therapy