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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Childhood Medulloblastoma; Childhood High-grade Cerebral Astrocytoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Childhood Oligodendroglioma
• Intervention / Treatment: Drug: tipifarnib

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.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; 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; Given orally

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Maryam Fouladi, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start: November 1, 2003
• Primary Completion (Actual): September 1, 2006

Study Registration Dates

• First Submitted: October 3, 2003
• First Submitted That Met QC Criteria: October 6, 2003
• First Posted (Estimate): October 7, 2003

Study Record Updates

• Last Update Posted (Estimate): October 8, 2013
• Last Update Submitted That Met QC Criteria: October 7, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence; Glioma; Medulloblastoma; Astrocytoma; Oligodendroglioma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Antineoplastic Agents; Tipifarnib
• Other Study ID Numbers: NCI-2012-01806 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA098543 (U.S. NIH Grant/Contract); CDR0000334862; COG-ACNS0226; ACNS0226 (Other Identifier: CTEP)