Clinical trial NCT00047073: Sirolimus in Treating Patients With Glioblastoma Multiforme
Official title: A Modified Phase I/II Trial Of Rapamycin In Patients With Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Brain and Central Nervous System Tumors
Keywords: recurrent adult brain tumor
adult glioblastoma
adult giant cell glioblastoma
adult gliosarcoma
Lead sponsor: Jonsson Comprehensive Cancer Center
Sponsor class: OTHER
First posted: 2003-01-27
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Maximum tolerated dose (for phase 1)
timeFrame: end of phase 1
measure: Efficacy in terms of progression-free survival at 6 months and objective response (phase II)
timeFrame: 6 months after last subject finishes trial
Secondary outcomes:
measure: Safety Profile (phase I)
timeFrame: end of phase I
measure: Further evaluate safety profile
timeFrame: end of phase II
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center at UCLA
state: California
Study officials:
affiliation: Jonsson Comprehensive Cancer Center
name: Timothy F. Cloughesy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008 Jan 22;5(1):e8. doi: 10.1371/journal.pmed.0050008.