Sirolimus in Treating Patients With Glioblastoma Multiforme

Study Overview
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Brief Summary
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RATIONALE: Chemotherapy drugs such as sirolimus use different ways to stop tumor cells from dividing so they stop growing or die. Giving a chemotherapy drug before surgery may shrink the tumor so that it can be removed during surgery. PURPOSE: Phase I/II trial to study the effectiveness of sirolimus in treating patients who have glioblastoma multiforme that did not respond to previous radiation therapy.

Detailed Description
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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.

Official Title
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A Modified Phase I/II Trial Of Rapamycin In Patients With Glioblastoma Multiforme

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: Rapamycin
* Procedure: Surgery
* Procedure: Supportive Care


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1<br>See intervention description. | Drug: Rapamycin<br>* 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.<br>* Other names: Sirolimus;Procedure: Surgery<br>* Surgical resection.<br>Procedure: Supportive Care<br>* 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.<br>|
| Experimental: Phase 2<br>See intervention description. | Drug: Rapamycin<br>* 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.<br>* Other names: Sirolimus;Procedure: Surgery<br>* Surgical resection.<br>Procedure: Supportive Care<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (for phase 1) |  | end of phase 1 | 
| Efficacy in terms of progression-free survival at 6 months and objective response (phase II) |  | 6 months after last subject finishes trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Profile (phase I) |  | end of phase I | 
| Further evaluate safety profile |  | end of phase II | 

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