MK-0646, Etoposide, and Cisplatin in Treating Patients With Extensive-Stage Small Cell Lung Cancer

OBJECTIVES:

• To determine the recommended phase II dose of MK-0646 in combination with a standard etoposide and cisplatin chemotherapy regimen in patients with extensive stage small cell lung cancer. (phase I)
• To assess the toxicity and tolerability of this regimen in these patients. (phases I and II)
• To evaluate the preliminary efficacy of this regimen in these patients. (phase I)
• To assess the efficacy of this regimen, in terms of objective response rate, as well as complete response rate in these patients. (phase II)
• To assess progression-free survival and overall survival of patients treated with this regimen. (phase II)
• To explore the predictive and prognostic impact of biomarkers in patients treated with this regimen. (phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of MK-0646 followed by a phase II study.

Patients receive MK-0646 IV over 1 hour on days 1, 8, and 15 and cisplatin IV and etoposide IV once daily on days 1-3. Treatment repeats every 3 weeks for 4 to 8 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients with complete response (CR) or partial response (PR) may continue MK-0646 in the absence of disease progression, with temporary discontinuation while undergoing prophylactic cranial irradiation or thoracic radiotherapy.

Blood samples are collected at baseline (pre-dose) and periodically for biomarker and pharmacogenetic correlative studies. Blood samples are analyzed for changes in expression of IGF biomarkers (e.g., IGF-1, IGF-2 and IGF-PB), haplotype tagging analysis of the IGF-1R, and evaluation of the immunoglobulin G fragment C receptor polymorphisms.

After completion of study therapy, patients are followed at 4 weeks. Patients with responding disease (i.e., CR, PR, or stable disease) are followed every 3 months until relapse or progression.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed small cell lung cancer (SCLC)

• Extensive stage disease that is incurable but amenable to treatment with platinum-based chemotherapy
• Small cell and variant histologies allowed
• No mixed tumors (i.e., small and large cell) or other neuroendocrine tumors of the lung
• Clinically and/or radiologically documented measurable disease, defined as ≥ 1 unidimensionally measurable site of disease ≥ 20 mm by chest x-ray, ≥ 15 mm by CT scan (lymph nodes), or ≥ 10 mm by CT scan or physical exam
• No uncontrolled or symptomatic CNS metastases

• Patients who have completed radiotherapy or have undergone complete resection of CNS metastases are allowed provided they are on stable (non-increasing) or decreasing doses of corticosteroids

PATIENT CHARACTERISTICS:

• Life expectancy ≥ 12 weeks
• ECOG performance status 0-2
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin ≤ upper limit of normal (ULN)
• AST and ALT ≤ 3 times ULN (≤ 5 times ULN if documented liver metastases)
• Serum creatinine ≤ ULN OR creatinine clearance ≥ 50 mL/min
• Not pregnant or lactating
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after completion of study therapy
• No other active cancer
• No untreated and/or uncontrolled cardiovascular or other comorbid conditions

• Patients with a significant cardiac history, even if controlled, should have a LVEF > 50%
• No uncontrolled diabetes
• Must be accessible for treatment and follow-up

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior cytotoxic chemotherapy or other IGF-1R targeting agents for SCLC
• At least 3 weeks since prior radiotherapy to neurological sites
• No prior radiotherapy to the lungs
• Prior surgery allowed provided that wound healing has occurred

• At least 14 days since prior major surgery
• No other concurrent investigational agents or therapy
• No other concurrent anticancer treatment
• No concurrent radiotherapy