A Phase II Study of R115777 (ZARNESTRA) (NSC# 702818, IND# 58359) in Children With Recurrent or Progressive: High Grade Glioma, Medulloblastoma/PNET or Brainstem Glioma

Inclusion Criteria:

- Histologically confirmed brain tumor, including the following:

- Anaplastic astrocytoma

- Glioblastoma multiforme

- Gliosarcoma

- Anaplastic oligodendroglioma

- Medulloblastoma/primitive neuroectodermal tumor (PNET)

- Diffuse intrinsic brain stem glioma*

- Progressive or relapsed disease after prior conventional therapy

- Radiographic evidence of measurable disease

- Performance status - Karnofsky 60-100% (over 16 years of age)

- Performance status - Lansky 60-100% (16 years of age and under)

- Performance status - ECOG 0-2

- At least 8 weeks

- Absolute neutrophil count at least 1,000/mm^3

- Platelet count at least 100,000/mm^3 (transfusion independent)

- Hemoglobin at least 8.0 g/dL (red blood cell transfusions allowed)

- Bilirubin no greater than 1.5 times upper limit of normal (ULN)

- SGPT and SGOT less than 2.5 times ULN

- Creatinine clearance OR radioisotope glomerular filtration rate at least 70 mL/min

- Maximum creatinine based on age as follows:

- 0.8 mg/dL (5 years and under)

- 1.0 mg/dL (6 to 10 years)

- 1.2 mg/dL (11 to 15 years)

- 1.5 mg/dL (over 15 years)

- Shortening fraction at least 27% by echocardiogram

- Ejection fraction at least 50% by MUGA

- No dyspnea at rest

- No exercise intolerance

- Pulse oximetry greater than 94%*

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Seizure disorder is allowed provided it is well-controlled on non-enzyme-inducing
anticonvulsants

- No active graft-versus-host disease

- No uncontrolled infection

- No allergy to azoles (e.g., ketoconazole, itraconazole, or fluconazole)

- Recovered from prior immunotherapy

- At least 7 days since prior antineoplastic biologic agents

- At least 1 month since prior autologous stem cell transplantation (SCT)

- At least 6 months since prior allogeneic SCT

- More than 1 week since prior growth factors

- No concurrent immunomodulating agents

- More than 2 weeks since prior myelosuppressive chemotherapy (4-6 weeks for
nitrosoureas or temozolomide) and recovered

- No concurrent anticancer chemotherapy

- Concurrent dexamethasone allowed provided patient is on a stable or decreasing dose
for at least 1 week prior to study entry

- Concurrent corticosteroids allowed only for treatment of increased intracranial
pressure

- Recovered from prior radiotherapy

- At least 2 weeks since prior local palliative radiotherapy (small port)

- At least 3 months since prior craniospinal radiotherapy

- At least 6 weeks since other prior substantial bone marrow radiotherapy

- No concurrent palliative radiotherapy

- No prior initiation of therapy on another phase II study

- No concurrent participation in another therapeutic COG study

- No concurrent enzyme-inducing anticonvulsants

- No other concurrent anticancer or experimental drugs

- No concurrent foods or medications that interfere with CYP3A4, including any of the
following:

- Carbamazepine

- Phenytoin

- Phenobarbital

- Grapefruit juice

- Erythromycin

- Azithromycin

- Clarithromycin

- Rifampin and its analogues

- Fluconazole

- Ketoconazole

- Itraconazole

- Cimetidine

- Cannabinoids (i.e., marijuana or dronabinol)

- Omeprazole

- Hypericum perforatum (St. John's wort)

- Ethosuximide

- Glucocorticoids

- Griseofulvin

- Nafcillin

- Nelfinavir

- Norfloxacin

- Norfluoxetine

- Nevirapine

- Oxcarbazepine

- Phenylbutazone

- Primidone

- Progesterone (all progestins)

- Rifabutin

- Rofecoxib

- Sulfadimidine

- Sulfinpyrazone

- Troglitazone

- Rifapentine

- Modafinil

- Amiodarone

- Anastrozole

- Clotrimazole

- Cyclosporine

- Danazol

- Delavirdine

- Diethyldithiocarbamate

- Diltiazem

- Dirithromycin

- Disulfiram

- Entacapone (high dose)

- Ethinyl estradiol

- Fluoxetine

- Fluvoxamine

- Gestodene

- Indinavir

- Isoniazid

- Metronidazole

- Mibefradil

- Miconazole

- Nefazodone

- Oxiconazole

- Paroxetine

- Propoxyphene

- Roxithromycin

- Quinidine

- Quinine

- Quinupristin and dalfopristin

- Ranitidine

- Ritonavir

- Saquinavir

- Sertindole

- Sertraline

- Troleandomycin

- Valproic acid

- Verapamil

- Voriconazole

- Zafirlukast

- Zileuton