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