Paclitaxel + Carboplatin With/ut BMS-275291 in Advanced or Metastatic Non-small Cell Lung Cancer

OBJECTIVES:

• Compare the overall survival of patients with advanced or metastatic non-small cell lung cancer treated with paclitaxel and carboplatin with or without BMS-275291.
• Compare the incidence of grade 2 or higher drug related arthritis, arthralgia and/or myalgia in patients treated with these regimens. (Phase II only)
• Compare the objective tumor response rate, time to response, and response duration in patients treated with these regimens.
• Compare the nature, severity, and frequency of toxic effects of these regimens in these patients.
• Compare the progression free survival of patients treated with these regimens. (Phase III only)
• Correlate the expression of serum/plasma and tissue matrix metalloproteinases (MMP) levels and other markers with outcomes and response in patients treated with these regimens.
• Compare quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, double blind, placebo controlled, multicenter study. Patients are stratified according to center, disease stage (IIIB vs IV), and ECOG performance status (0-1 vs 2). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1 plus oral BMS-275291 daily on days 1-21.
• Arm II: Patients receive paclitaxel and carboplatin as in arm I plus oral placebo daily on days 1-21.

Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. BMS-275291 or placebo continues beyond 8 courses in the absence of disease progression.

Quality of life is assessed.

Patients are followed every 3 months for 2 years and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 776 patients will be accrued for this study within 27 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed stage IIIB or IV non-small cell lung cancer (NSCLC)

• Local or metastatic failure after surgery and/or radiotherapy allowed
• Phase II only:

• At least one measurable lesion

• At least 20 mm by conventional techniques OR 10 mm by spiral CT scan
• No known CNS metastases unless asymptomatic and at least 4 weeks since prior corticosteroid therapy

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• At least 12 weeks

Hematopoietic:

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• ALT no greater than 2 times ULN (5 times ULN for liver metastases)

Renal:

• Creatinine no greater than 1.5 times ULN

Cardiovascular:

• No significant cardiac disease
• No uncontrolled high blood pressure, unstable angina, congestive heart failure, second or third degree atrioventricular conduction defects, or ventricular arrhythmias requiring medication
• No myocardial infarction within the past year

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergic reaction to drugs containing Cremophor EL
• No serious active infection or other underlying medical condition that would preclude study participation
• No peripheral neuropathy
• No condition (e.g., psychological, geographical) that would preclude study participation
• No prior breast cancer or melanoma
• No other prior malignancy within the past 5 years except carcinoma in situ, basal cell or squamous cell skin cancer, or other cancer that has been curatively treated surgically

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior immunotherapy
• No prior biological response modifiers
• No other concurrent biologic therapy or immunotherapy

Chemotherapy:

• No prior antineoplastic chemotherapy, including intrapleural chemotherapy

Endocrine therapy:

• See Disease Characteristics

Radiotherapy:

• See Disease Characteristics
• No prior radiotherapy to study lesion (unless evidence of disease progression) or to 30% or greater of marrow bearing bones
• At least 1 week since prior radiotherapy and recovered
• No concurrent radiotherapy

Surgery:

• See Disease Characteristics
• At least 2 weeks since prior major surgery
• No concurrent surgery

Other:

• At least 2 weeks since prior investigational drugs
• No other concurrent cytotoxic anticancer therapy
• No other investigational drugs during and for 30 days after study