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

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.

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