Clinical Trial Finder

DISEASE CHARACTERISTICS:

• - Histologically confirmed intracranial glioblastoma multiforme.

• - Disease progression by MRI or CT scan.

• - Confirmation of true progressive disease (not radiation necrosis) by positron-emission tomography, thallium scanning, MRI, or surgical documentation required if patient received prior interstitial brachytherapy or stereotactic radiosurgery.

• - Failed prior radiotherapy.

• - Phase I patients: - Eligible for salvage surgery.

• - No limits on prior therapy.

• - Phase II patients: - Tumor progression by MRI or CT scan required within the past 14 days if recurrent disease is present.

• - No prior therapy for more than 3 relapses.

• - Recent resection of recurrent or progressive tumor allowed as long as all of the following conditions apply: - Recovered from surgery.

• - MRI or CT scan performed no more than 96 hours since prior surgery OR within 4-6 weeks after surgery.

• - Baseline MRI or CT scan performed within 14 days of study entry.

PATIENT CHARACTERISTICS: Age.

• - 18 and over.

Performance status.

• - Karnofsky 60-100% Life expectancy.

• - More than 8 weeks.

Hematopoietic.

• - WBC at least 3,000/mm^3.

• - Absolute neutrophil count at least 2,000/mm^3.

• - Platelet count at least 100,000/mm^3.

• - Hemoglobin at least 10 g/dL (transfusion allowed) Hepatic.

• - Bilirubin less than 1.5 times upper limit of normal (ULN) - SGOT less than 1.5 times ULN.

Renal.

• - Creatinine less than 1.5 mg/dL.

Other.

• - Cholesterol less than 350 mg/dL.

• - Triglycerides less than 400 mg/dL.

• - No concurrent disease that would obscure toxicity or dangerously alter drug metabolism.

• - No other significant uncontrolled serious medical illness that would preclude study participation.

• - No other cancer except non-melanoma skin cancer or carcinoma in situ of the cervix unless patient is in complete remission and off all therapy for that disease for at least 3 years.

• - No active infection.

• - No prior allergic reactions to compounds of similar chemical or biological composition to sirolimus.

• - No psychiatric illness that would preclude study participation.

• - Not pregnant or nursing.

• - Negative pregnancy test.

• - Fertile patients must use effective barrier contraception.

PRIOR CONCURRENT THERAPY: Biologic therapy.

• - At least 1 week since prior interferon.

Chemotherapy.

• - At least 2 weeks since prior vincristine.

• - At least 3 weeks since prior procarbazine.

• - At least 6 weeks since prior nitrosoureas.

Endocrine therapy.

• - At least 1 week since prior tamoxifen.

Radiotherapy.

• - See Disease Characteristics.

• - At least 4 weeks since prior radiotherapy.

Surgery.

• - See Disease Characteristics.

Other.

• - Recovered from prior therapy.

- At least 1 week since prior noncytotoxic agents (except radiosensitizers)

OBJECTIVES:

• - Determine the maximum tolerated dose of sirolimus in patients with glioblastoma multiforme.

• - Determine the safety profile of this drug in these patients.

• - Determine the efficacy of this drug, in terms of 6-month progression-free survival and objective response, in these patients.

OUTLINE: This is a dose-escalation study.

• - Phase I: Patients receive oral sirolimus for 5-7 days before surgery.

Patients then undergo surgical resection. Patients resume oral sirolimus once daily after full recovery from surgery. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. 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 at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• - Phase II: Patients receive oral sirolimus as in phase I at the dose determined in that phase.

Patients are followed for survival. PROJECTED ACCRUAL: A total of 3-12 patients will be accrued for phase I of the study within 3-12 months. A total of 32 patients will be accrued for phase II of the study.

Arms

Experimental: Phase 1

See intervention description.

Experimental: Phase 2

See intervention description.

Interventions

Drug: - Rapamycin

Phase 1: Initial dose 6mg on day 1 and then 2mg each day for 5-7 days before surgery. No dosing during surgery recovery. After recorvery 6mg loading dose on day 1 then 2mg each day. Cycle is every 4 weeks. Dose escalation: Level 2: 15mg load/5mg/day, Level 3: 30mg load/10mg/day, Level 4: 45mg load/15mg/day. Phase 2: Will utilize dose established in phase I. Dosing schedule will remain the same.

Procedure: - Surgery

Surgical resection.

Procedure: - Supportive Care

Corticosteroids should be used in smallest dose to control symptoms of cerebral edema and mass effect. Anti-seizure medications should be used as indicated. Febrile neutropenia may be managed according to local institution's infectious disease guidelines. If neurosurgical management is required for reasons not due to tumor progression, these procedures must be documented.