Tipifarnib in Treating Young Patients With Recurrent or Progressive High-Grade Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, or Brain Stem Glioma

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying how well tipifarnib works in treating young patients with recurrent or progressive high-grade glioma, medulloblastoma, primitive neuroectodermal tumor, or brain stem glioma. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth.

Detailed Description
-----------------
OBJECTIVES: I. Determine the response rate in pediatric patients with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor (PNET), or brain stem glioma treated with tipifarnib. II. Determine the distribution of time to progression, time to treatment failure, and time to death in patients treated with this drug. OUTLINE: This is an open-label, multicenter study. Patients are stratified according to disease (high-grade glioma vs recurrent or progressive medulloblastoma/primitive neuroectodermal tumor [PNET] vs progressive diffuse, intrinsic brain stem glioma). Patients receive oral tipifarnib twice daily on days 1-21. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Official Title
-----------------
A Phase II Study of R115777 (Zarnestra) (NSC # 702818, IND# 58,359) in Children With Recurrent or Progressive: High Grade Glioma, Medulloblastoma/PNET or Brainstem Glioma

Conditions
-----------------
Childhood High-grade Cerebral Astrocytoma, Childhood Oligodendroglioma, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Medulloblastoma, Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor, Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Intervention / Treatment
-----------------
* Drug: tipifarnib


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral tipifarnib twice daily on days 1-21. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. | Drug: tipifarnib<br>* Given orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best objective tumor response rates (complete and partial response), based on MRIs | Estimated ultimately as a simple binomial proportion. Estimated actuarially, using the product-limit (PL) estimate. | Up to 2 years | 
| Time to tumor progression (TTP) | The distribution of TTP will be analyzed using PL estimate. | Time from study enrollment to radiographically determined tumor progression or recurrence, assessed up to 2 years | 
| Time to treatment failure (TTF) | The distribution of TTF will be analyzed using PL estimate. | Time from study enrollment to tumor progression, tumor recurrence, death from any cause, or occurrence of a second malignant neoplasm, assessed up to 2 years | 
| Time to death (TTD) | The distribution of TTD will be analyzed using PL estimate. | Time from study enrollment to death from any cause, assessed up to 2 years | 
| Incidence of adverse events graded according to NCI CTCAE version 3.0 |  | Up to 2 years |