Everolimus and Gefitinib in Treating Patients With Progressive Glioblastoma Multiforme or Progressive Metastatic Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Everolimus may stop the growth of tumor cells by stopping blood flow to the tumor. Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining everolimus with gefitinib may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with gefitinib and to see how well they work in treating patients with progressive glioblastoma multiforme or (progressive metastatic prostate cancer closed to accrual 10/19/06).

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of everolimus when given in combination with gefitinib in patients with progressive glioblastoma multiforme or (progressive castrate metastatic prostate cancer -closed to accrual as of 10/19/2006). (Phase I) Determine the safety and efficacy of this regimen in patients with progressive glioblastoma multiforme or (progressive castrate metastatic prostate cancer - closed to accrual as of 10/19/2006). (Phase II) Secondary Determine whether a pharmacokinetic interaction exists between everolimus and gefitinib in patients treated with this regimen. Determine the association between clinical outcomes and markers that may predict sensitivity of a tumor in patients treated with this regimen. Determine the pharmacodynamic effects of this regimen on post-therapy tumor specimens and peripheral blood mononuclear cells from these patients. OUTLINE: This is a phase I, open-label, non-randomized, dose-escalation study of everolimus followed by a phase II study. Phase I: Patients receive oral everolimus on day 1 and oral gefitinib once daily on days 8-21. Beginning on day 22, patients receive oral everolimus once weekly and oral gefitinib once daily. Treatment with the combination continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of everolimus 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 (prostate cancer patients only) (closed to accrual as of 10/19/2006): Patients receive oral everolimus (at the MTD determined in phase I) once weekly and oral gefitinib once daily. Treatment continues in the absence of disease progression or unacceptable toxicity.

Official Title
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A Phase I/II Trial to Assess the Tolerability of RAD 001 With Gefitinib in Patients With Glioblastoma Multiforme and Prostate Cancer and Efficacy in Patients With Castrate Metastatic Prostate Cancer

Conditions
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Brain and Central Nervous System Tumors, Prostate Cancer

Intervention / Treatment
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* Drug: everolimus
* Drug: gefitinib


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of 1 of the following: Glioblastoma multiforme (GBM) (phase I only) Progressive disease despite standard therapy Progressive disease based on 1 of the following: New or progressive (25% bidimensional increase) soft tissue masses on CT scan or MRI New or prior lesions that have increased in size by physical examination Patients who had prior interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true disease progression (rather than radiation necrosis) by positron-emission tomography scan, thallium scanning, magnetic resonance spectroscopy, or surgical documentation Castrate metastatic prostate cancer (closed to accrual as of 10/19/2006) (phase I and II) Progressive disease despite standard therapy AND castrate levels < 50 ng/dL of testosterone Progressive disease based on 1 or more of the following: A minimum of 3 rising levels of prostate-specific antigen (PSA) that are obtained 1 or more weeks apart OR 2 rising PSA values obtained more than 1 month apart with at least a 25% increase over the range of values New or progressive (25% bidimensional increase) soft tissue masses on CT scan or MRI New metastatic lesions Patients on an antiandrogen as part of initial therapy must show disease progression after discontinuation of the antiandrogen Patients who have not undergone surgical orchiectomy must continue with medical therapy (e.g., gonadotropin-releasing hormone analogs) to maintain castrate levels of serum testosterone No brain metastases PATIENT CHARACTERISTICS: Age Over 18 Performance status Karnofsky 70-100% Life expectancy More than 3 months Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 WBC ≥ 3,000/mm^3 Hepatic ALT and AST ≤ 2.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 mg/dL Renal Creatinine within 1.5 times ULN (< 1.95 mg/dL at MSKCC) Cardiovascular No significant cardiovascular disease No congestive heart failure No New York Heart Association class III or IV cardiac disease No active angina pectoris No myocardial infarction within the past 6 months Other Not pregnant Negative pregnancy test Fertile patients must use effective contraception No serious medical illness No severe infection No severe malnutrition No other active malignancy except non-melanoma skin cancer Patients are not considered to have an active malignancy if they have completed prior therapy and currently have a < 30% risk for relapse PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent biological therapy No concurrent immunotherapy Chemotherapy No concurrent chemotherapy Endocrine therapy See Disease Characteristics Radiotherapy See Disease Characteristics More than 4 weeks since prior radiotherapy No concurrent radiotherapy Surgery See Disease Characteristics Prior recent resection of recurrent or progressive GBM allowed provided patient has recovered More than 4 weeks since prior major surgery Other Recovered from all prior therapy More than 4 weeks since prior investigational anticancer drugs No concurrent anticonvulsant that interacts with CYP3A4 (e.g., phenytoin, carbamazepine, or phenobarbital) No other concurrent cytotoxic therapy No other concurrent investigational or commercial agents or therapies for the malignancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Male

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: Everolimus (RAD-001) and Gefitinib<br>•Phase I: Patients receive oral everolimus on day 1 and oral gefitinib once daily on days 8-21. Beginning on day 22, patients receive oral everolimus once weekly and oral gefitinib once daily. Treatment with the combination continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of everolimus 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 (prostate cancer patients only) (closed to accrual as of 10/19/2006): Patients receive oral everolimus (at the MTD determined in phase I) once weekly and oral gefitinib once daily. Treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: everolimus<br> <br> Drug: gefitinib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Objective Response | Response will be evaluated in this study using the new international criteria Response Evaluation Criteria in Solid Tumors (RECIST) | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult glioblastoma, recurrent prostate cancer, recurrent adult brain tumor, stage IV prostate cancer, adult giant cell glioblastoma, adult gliosarcoma