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

A Phase II/III Double Blind Randomized Trial of BMS-275291 vs. Placebo in Patients Receiving Paclitaxel/Carboplatin Chemotherapy for the Treatment of 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. It is not yet known whether paclitaxel and carboplatin are more effective with or without BMS-275291 for non-small cell lung cancer.

PURPOSE: Randomized phase II/III trial to compare the effectiveness of paclitaxel and carboplatin with or without BMS-275291 in treating patients who have 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