Tipifarnib in Treating Patients With Recurrent or Progressive Malignant Glioma

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)

Overall Status

Completed

CT.gov ID

NCT00005859

Collaborator

National Cancer Institute (NCI) (NIH)

136

Enrollment

Locations

74.5

Actual Duration (Months)

12.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth.

PURPOSE: Phase II trial to study the effectiveness of tipifarnib in treating patients who have recurrent or progressive malignant glioma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: tipifarnib	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Determine the maximum tolerated dose of tipifarnib in patients with recurrent or progressive malignant glioma receiving enzyme-inducing antiepileptic drugs. (Stratum II in the phase I portion of this study closed to accrual effective 07/16/2001.) (Phase I completed effective 10/2/2001.) (Phase II open only to patients requiring resection and who provide surgical tissue samples [effective 3/13/2003].)
Define the safety and pharmacokinetic profile of this drug in this patient population.
Assess for evidence of antitumor activity of this drug in these patients.
Assess for evidence of inhibition of farnesyl protein transferase (FTase) on peripheral blood monocytes as a surrogate endpoint of effective biologic activity of this drug in these patients.
Determine the efficacy of this drug as measured by 6-month progression-free survival and objective tumor response in these patients.
Evaluate further the safety profile of this drug in these patients.
Correlate treatment response with inhibition of FTase in peripheral blood monocytes in patients treated with this drug.

OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to their pretreatment medications (not receiving enzyme-inducing antiepileptic drugs [EIAEDs] vs receiving EIAEDs with or without steroids).

Patients receive oral tipifarnib twice daily on days 1-21. Courses repeat every 4 weeks in the absence of unacceptable toxicity or disease progression.

Phase I (completed 10/2/2001): Cohorts of 3-6 patients from stratum II receive escalating doses of tipifarnib 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. (Stratum II in the phase I portion of this study closed to accrual effective 07/16/2001.)
Phase II (open only to patients requiring resection and who provide surgical tissue samples [effective 3/13/2003]): Once the MTD is determined, additional patients with glioblastoma multiforme from stratum II are accrued to receive treatment with tipifarnib at the recommended phase II dose.

Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 1 year, and then every 6 months until progression. Patients are then followed every 4 months thereafter.

PROJECTED ACCRUAL: Approximately 30 patients (15 per stratum) will be accrued for the phase I portion of this study within 10 months. (Stratum II in the phase I portion of this study closed to accrual effective 07/16/2001.) (Phase I completed effective 10/2/2001.) A total of 24 patients with glioblastoma multiforme from stratum II will be accrued for the phase II portion of this study. (Phase II open only to patients requiring resection and who provide surgical tissue samples [effective 3/13/2003].)

Study Design

Study Type:

Interventional

Actual Enrollment :

136 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II Trial of R115777 in Patients With Recurrent Malignant Glioma

Actual Study Start Date :

May 16, 2000

Actual Primary Completion Date :

Jul 1, 2005

Actual Study Completion Date :

Aug 1, 2006

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed intracranial primary malignant glioma
Glioblastoma multiforme
Anaplastic astrocytoma*
Anaplastic oligodendroglioma*
Anaplastic mixed oligodendroglioma*
Malignant astrocytoma (not otherwise specified)* NOTE: *Closed to accrual effective 5/28/2002
Progressive or recurrent disease confirmed by MRI or CT scan within the past 14 days
Stable steroid dose for at least 5-7 days
Confirmation of true progressive disease by PET scan, thallium scan, MR spectroscopy, or surgery if prior therapy included interstitial brachytherapy or stereotactic radiosurgery
Failed prior radiotherapy
Phase I (phase I completed effective 10/2/2001): No more than 2 prior chemotherapy or cytotoxic regimens, including 1 prior adjuvant therapy and 1 prior regimen for progressive or recurrent disease, or 2 prior regimens for progressive disease
Phase II (phase II open only to patients requiring resection and who provide surgical tissue samples [effective 3/13/2003]): No more than 2 prior chemotherapy or cytotoxic regimens for relapsed disease following initial therapy (radiotherapy with or without chemotherapy)
Prior surgical resection for relapsed disease with no anticancer therapy for up to 12 weeks followed by another surgical resection is considered 1 relapse
Patients who received prior therapy for a low-grade glioma with a surgical diagnosis of a high-grade glioma are considered to be in first relapse

PATIENT CHARACTERISTICS:

Age:

18 and over

Performance status:

Karnofsky 60-100%

Life expectancy:

More than 8 weeks

Hematopoietic:

WBC at least 3,000/mm^3
Absolute neutrophil count at least 2,000/mm^3
Platelet count at least 100,000/mm^3
Hemoglobin at least 10 g/dL (transfusion allowed)

Hepatic:

Bilirubin no greater than 2.5 times upper limit of normal (ULN)
SGOT no greater than 2.5 times ULN

Renal:

Creatinine less than 1.5 mg/dL

Cardiovascular:

No uncontrolled high blood pressure
No unstable angina
No symptomatic congestive heart failure
No myocardial infarction within the past 6 months
No serious uncontrolled cardiac arrhythmia

Other:

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No severe nonmalignant systemic diseases or active infections
No other severe concurrent disease that would preclude study therapy
No allergy to azoles (e.g., ketoconazole, itraconazole, or voriconazole)
HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy:

At least 1 week since prior interferon
No concurrent anticancer immunotherapy
No concurrent routine prophylactic filgrastim (G-CSF) during first course of study
No concurrent sargramostim (GM-CSF)

Chemotherapy:

See Disease Characteristics
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, suramin, or mitomycin)
At least 3 weeks since prior procarbazine
At least 2 weeks since prior vincristine
No other concurrent anticancer chemotherapy

Endocrine therapy:

See Disease Characteristics
At least 1 week since prior tamoxifen
Concurrent corticosteroids allowed
No concurrent anticancer hormonal therapy

Radiotherapy:

See Disease Characteristics
At least 4 weeks since prior radiotherapy and recovered
No concurrent anticancer radiotherapy

Surgery:

See Disease Characteristics
At least 3 weeks since prior resection and recovered
Prior recent resection of recurrent or progressive tumor allowed

Other:

Recovered from all prior therapy (excluding neurotoxicity or alopecia)
Prior radiosensitizers allowed
Concurrent H2 blockers and antacids allowed provided taken at least 2 hours before and after tipifarnib
No concurrent proton pump inhibitors (e.g., omeprazole or lansoprazole)
No other concurrent medication that would preclude study therapy (e.g., immunosuppressive agents)
No other concurrent anticancer therapy
No other concurrent investigational drugs
No concurrent participation in any other clinical study
No other concurrent medications except analgesics, chronic treatments for concurrent medical conditions, or agents for life-threatening medical problems

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jonsson Comprehensive Cancer Center, UCLA	Los Angeles	California	United States	90095
2	UCSF Comprehensive Cancer Center	San Francisco	California	United States	94115
3	Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support	Bethesda	Maryland	United States	20892-1182
4	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
5	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-0942
6	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
7	Hillman Cancer Center at University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15232
8	Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390-9154
9	University of Texas - MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
10	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78284-6220
11	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin	United States	53792