Sirolimus in Treating Patients With Glioblastoma Multiforme

Sponsor

Jonsson Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00047073

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: Rapamycin Procedure: Surgery Procedure: Supportive Care	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 2002

Actual Primary Completion Date :

Jun 1, 2005

Actual Study Completion Date :

Oct 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 See intervention description.	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. Other Names: Sirolimus 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.
Experimental: Phase 2 See intervention description.	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. Other Names: Sirolimus 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.

Arm

Intervention/Treatment

Experimental: Phase 1

See intervention description.

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.

Other Names:

Sirolimus

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.

Experimental: Phase 2

See intervention description.

Drug: Rapamycin

Other Names:

Sirolimus

Procedure: Surgery

Surgical resection.

Procedure: Supportive Care

Outcome Measures

Primary Outcome Measures

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

Safety Profile (phase I) [end of phase I]
Further evaluate safety profile [end of phase II]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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