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: Phase I/II trial to study the effectiveness of combining everolimus with gefitinib in treating patients who have progressive glioblastoma multiforme or progressive metastatic prostate cancer.

Condition	Treatment or Intervention	Phase
adult glioblastoma recurrent prostate cancer recurrent adult brain tumor stage IV prostate cancer adult giant cell glioblastoma adult gliosarcoma	Drug: everolimus  Drug: everolimus/gefitinib  Drug: gefitinib  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: combination therapy  Procedure: enzyme inhibitor therapy  Procedure: growth factor antagonist therapy  Procedure: protein tyrosine kinase inhibitor therapy	Phase I Phase II

Further Study Details: 

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. (Phase I)
• Determine the safety and efficacy of this regimen in patients with progressive castrate metastatic prostate cancer. (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.

• 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): 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.

PROJECTED ACCRUAL: A total of 3-18 patients will be accrued for the phase I portion of this study within 6 months. A total of 27-40 patients will be accrued for the phase II portion of this study within 8 months.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

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 (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

New York
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States; Recruiting

Study chairs or principal investigators

Howard I. Scher, MD,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   
Neal Rosen, MD,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   
Lauren E. Abrey, MD,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   

Study ID Numbers:  CDR0000370826; MSKCC-04010; NCT00085566
Record last reviewed:  May 2004
Last Updated:  December 6, 2004
Record first received:  June 10, 2004
ClinicalTrials.gov Identifier:  NCT00085566
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08