Combination Chemotherapy and Imatinib Mesylate in Treating Patients With Extensive-Stage Small Cell Lung Cancer

OBJECTIVES:

• Determine the maximum tolerated dose of imatinib mesylate when administered with cisplatin and irinotecan in patients with extensive stage small cell lung cancer.
• Determine the recommended phase II dose of imatinib mesylate in patients treated with this regimen.
• Determine the response rate, median duration of response, progression-free survival, median survival, and overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of imatinib mesylate.

Patients receive cisplatin IV over 1 hour on day 1 and irinotecan IV over 60 minutes on days 1, 8, and 15. Treatment repeats every 28 days for a maximum of 4 courses. Patients also receive oral imatinib mesylate daily continually for one week prior to, during, and after chemotherapy in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of imatinib mesylate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional patients are treated at the recommended phase II dose (one dose level below the MTD).

PROJECTED ACCRUAL: A total of 12-24 patients will be accrued for this study within 1-2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed extensive stage small cell lung cancer

• Incurable but amenable to treatment with chemotherapy
• c-kit positive by immunohistochemistry of original biopsy or other metastatic site
• At least one unidimensionally measurable lesion

• > 20 mm by conventional techniques or > 10 mm by spiral CT scan
• No prior radiotherapy to target measurable lesion(s), unless there is documented disease progression
• No known brain metastases

PATIENT CHARACTERISTICS:

Age

• Not specified

Performance status

• ECOG 0-1 OR
• Karnofsky 70-100%

Life expectancy

• More than 6 weeks

Hematopoietic

• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin normal
• AST and/or ALT ≤ 2.5 times upper limit of normal

Renal

• Creatinine normal OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Gastrointestinal

• No concurrent untreated upper gastrointestinal bleeding that has not been fully investigated
• No gastrointestinal disease that would impair drug absorption

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception prior to, during, and for 3 months after study participation
• No history of ototoxicity
• No history of peripheral neuropathy
• No traumatic injury within the past 21 days
• No ongoing or active infection
• No other concurrent significant medical condition that would preclude study participation
• No concurrent psychiatric condition or social situation that would preclude study compliance
• No other malignancy within the past 5 years except treated nonmelanoma skin cancer, carcinoma in situ, or stage A prostate cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics
• No prior chemotherapy
• No other concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics
• More than 4 weeks since prior radiotherapy
• No prior radiotherapy to more than 25% of marrow

Surgery

• More than 3 weeks since prior major surgery
• No prior surgical procedure impairing absorption

Other

• No prior c-kit-targeted therapy
• No concurrent therapeutic dose of warfarin

• Mini-dose warfarin for prophylaxis and low-molecular weight heparin allowed
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No concurrent amifostine
• No other concurrent anticancer therapy