CCI-779 in Treating Patients With Malignant Glioma

OBJECTIVES:

• Determine the maximum tolerated dose of CCI-779 in patients with malignant glioma.
• Determine the safety profile of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Determine the efficacy of this drug, in terms of survival and objective response, in these patients.

OUTLINE: This is a dose-escalation study. Patients in phase II are stratified according to use of enzyme-inducing antiepileptic drugs (EIAEDs) (yes vs no) and disease type (glioblastoma multiforme with stable neuro-imaging after radiotherapy vs recurrent malignant glioma). Patients in phase I must be currently receiving EIAEDs.

• Phase I: Patients receive CCI-779 IV over 30 minutes once weekly. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of CCI-779 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: Patients receive CCI-779 as in Phase I. Patients who are candidates for surgical resection of recurrent disease receive CCI-779 IV over 30 minutes 2 hours prior to surgery and then once weekly, as above, once recovered from surgery.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for phase I of this study within 12 months. A total of 87 patients will be accrued for phase II of this study within 12 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed intracranial malignant glioma

• Glioblastoma multiforme
• Anaplastic astrocytoma
• Anaplastic oligodendroglioma
• Anaplastic mixed oligoastrocytoma
• Malignant astrocytoma not otherwise specified
• Initial diagnosis of low-grade allowed, if subsequently progressed
• Recurrent disease must have documented progression by MRI or CT scan
• Progressive disease must have failed prior radiotherapy
• Recent resection of recurrent or progressive tumor allowed provided all of the following are met:

• Recovered from surgery
• CT scan or MRI performed no more than 96 hours postoperatively OR at 4-6 weeks postoperatively
• Concurrent steroid dosage must be stable
• Confirmation of true progressive disease (by PET, thallium scan, MR spectroscopy, or surgical documentation) required after prior interstitial brachytherapy or stereotactic radiosurgery

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• More than 8 weeks

Hematopoietic:

• WBC at least 3,000/mm3
• Absolute neutrophil count at least 2,000/mm3
• Platelet count at least 120,000/mm3
• 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
• Cholesterol less than 350 mg/dL
• Triglycerides less than 400 mg/dL

Renal:

• Creatinine less than 1.5 mg/dL
• Creatinine clearance at least 60 mL/min

Other:

• No active infection
• No other malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the cervix
• No significant medical illness that would preclude study
• No disease that would obscure toxicity or dangerously alter drug metabolism
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to CCI-779 or allergy to or inability to receive antihistamines
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 weeks after study

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
• Phase I:

• 2 prior chemotherapy regimens allowed
• 1 prior adjuvant regimen and 1 prior regimen for recurrent or progressive disease OR
• 2 prior regimens for progressive tumor
• Phase II:

• No more than 1 prior chemotherapy regimen for recurrent malignant glioma
• No prior chemotherapy allowed for stable glioblastoma multiforme

Endocrine therapy:

• See Disease Characteristics
• At least 1 week since prior tamoxifen

Radiotherapy:

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy for progressive disease
• No more than 1 month since prior radiotherapy for nonprogressive glioblastoma multiforme

Surgery:

• See Disease Characteristics

Other:

• Recovered from prior therapy
• At least 1 week since prior noncytotoxic agents