Gefitinib and Sirolimus in Treating Patients With Recurrent or Refractory Stage IIIB or Stage IV Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as sirolimus, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sometimes when chemotherapy is given, it does not stop the growth of tumor cells. The tumor is said to be resistant to chemotherapy. Giving gefitinib together with sirolimus may reduce drug resistance and allow the tumor cells to be killed. PURPOSE: This phase I/II trial is studying the side effects and best dose of sirolimus when given with gefitinib and to see how well they work in treating patients with recurrent or refractory stage IIIB or stage IV non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of sirolimus when combined with gefitinib in patients with recurrent or refractory stage IIIB or IV non-small cell lung cancer. Secondary Determine the overall response rate (complete response [CR] and partial response [PR]) in patients treated with this regimen. Determine the disease control rate (CR, PR, and stable disease) in patients treated with this regimen. Determine the time to progression and overall survival of patients treated with this regimen. Determine the quality of life of patients treated with this regimen. OUTLINE: This is an open-label, phase I, dose-escalation study of sirolimus followed by a phase II study. Phase I: Patients receive oral gefitinib once daily and oral sirolimus once daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Cohorts of 3-6 patients receive escalating doses of sirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive gefitinib and sirolimus as in phase I at the MTD. Quality of life is assessed at baseline, day 1 of each course, and then at 1 month post-progression. Patients are followed every 9 weeks. Patients withdrawn from study treatment without evidence of disease progression are followed every 6 weeks until disease progression. PROJECTED ACCRUAL: A total of 25 patients (11 for phase I and 14 for phase II) will be accrued for this study within 8.3 months.

Official Title
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A Phase I/II Trial of ZD1839 (Iressa®) and Rapamycin (Rapamune) in Patients With Advanced Non Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: gefitinib
* Drug: sirolimus


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed non-small cell lung cancer Stage IIIB or IV disease Recurrent or refractory disease Received ≥ 1 prior platinum-containing chemotherapy regimen Unidimensionally measurable disease that has not been irradiated No newly diagnosed untreated brain metastases or spinal cord compression Paraffin-embedded tumor tissue or slides available PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-2 Life expectancy Not specified Hematopoietic Adequate bone marrow function Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic Adequate hepatic function No severe or uncontrolled hepatic disease Renal Adequate renal function Creatinine ≤ 3.0 times upper limit of normal No severe or uncontrolled renal disease Cardiovascular Adequate cardiac function No severe or uncontrolled cardiac disease No uncontrolled hyperlipidemia Pulmonary No unstable or uncompensated respiratory disease No clinically active interstitial lung disease Patients with chronic stable radiographic changes who are asymptomatic are eligible Gastrointestinal Able to take oral medication No gastrointestinal condition (e.g., peptic ulcer disease) that would affect absorption Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No serious infection No known severe hypersensitivity to gefitinib or any of its excipients No other malignancy within the past 5 years except treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No other severe or uncontrolled systemic disease No significant clinical disorder or laboratory finding that would preclude study participation PRIOR CONCURRENT THERAPY: Biologic therapy More than 14 days since prior biologic therapy No prior cetuximab, panitumumab, or bevacizumab Chemotherapy See Disease Characteristics More than 4 weeks since prior cytotoxic chemotherapy Endocrine therapy Not specified Radiotherapy See Disease Characteristics More than 3 weeks since prior radiotherapy No concurrent radiotherapy Surgery Recovered from prior oncologic or other major surgery No prior gastrointestinal surgery affecting absorption No concurrent surgery, including ophthalmic surgery, during and for 1 week after study treatment Other Recovered from all prior therapy More than 30 days since prior investigational agents No other prior HER1/epidermal growth factor receptor axis agents, including the following: Gefitinib Erlotinib CI-1033 Lapatinib No other prior vascular endothelial growth factor axis agents, including the following: ZD6474 Vatalanib No concurrent CYP3A4 inducers, including the following: Phenytoin Carbamazepine Rifampin Phenobarbital Barbiturates Hypericum perforatum (St. John's wort) No other concurrent systemic treatment for the malignancy No concurrent bisphosphonates for symptomatic bone metastases No concurrent systemic retinoids

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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: gefitinib|nan|
|Drug: sirolimus|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (Phase I) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response (complete response [CR] and partial response [PR]) as measured by RECIST criteria |  |  | 
| Disease control rate (CR, PR, and stable disease) correlated with smoking history |  |  | 
| Time to tumor progression and overall survival |  |  | 
| Quality of life as assessed by the Functional Assessment of Cancer Therapy-Lung (FACT-L) |  |  | 
| Lung cancer subscale from FACT-L |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer