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

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as MK-0646, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as etoposide and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase I/II trial is studying the side effects and best dose of MK-0646 when given together with etoposide and cisplatin and to see how well it works in treating patients with extensive-stage small cell lung cancer.

Detailed Description
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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.

Official Title
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A Phase I-II Trial of MK-0646, a Monoclonal Antibody Against Insulin-Like Growth Factor-1 Receptor, in Combination With Etoposide and Cisplatin in Extensive Stage Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Biological: anti-IGF-1R recombinant monoclonal antibody MK-0646
* Drug: cisplatin
* Drug: etoposide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>MK-0646, a monoclonial antibody in combination with etoposide and cisplatin. | Biological: anti-IGF-1R recombinant monoclonal antibody MK-0646<br>* MK-0646 should be given 1st followed within 30-60 minutes by cisplatin and then etoposide for cycles which include both MK-0646 and chemotherapy. Cycles are 21 days<br>Drug: cisplatin<br>* MK-0646 should be given 1st followed within 30-60 minutes by cisplatin and then etoposide for cycles which include both MK-0646 and chemotherapy. Cycles are 21 days<br>Drug: etoposide<br>* MK-0646 should be given 1st followed within 30-60 minutes by cisplatin and then etoposide for cycles which include both MK-0646 and chemotherapy. Cycles are 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose of MK-0646 in combination with standard etoposide and cisplatin chemotherapy | Evaluate safety, tolerability in combination with standard chemotherapy. | Each dose level | 
| Toxicity and tolerability according to NCI CTCAE v3.0 | Look at toxicity and tolerability of MK0646 in combination with standard therapy. | Phase 1, each dose level and Phase II | 
| Preliminary efficacy | Look for evidence of response | Phase 1 dose levels, evey other cycle | 
| Objective response rate | Determine objective response rate including complete response rate, progression free survival and overall survival. | Phase II portion, every other cycle | 
| Predictive and prognostic impact of biomarkers | Blood samples will be collected and analyzed for occurrence of human-anti-humanized antibody response to MK0646 as well as IGF-1R analysis. | Each cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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combined type small cell lung cancer, fusiform type small cell lung cancer, polygonal type small cell lung cancer, lymphocyte-like type small cell lung cancer, extensive stage small cell lung cancer