Tipifarnib in Treating Patients With Recurrent or Progressive Malignant Glioma

Johns Hopkins Medicine

Status and phase

Completed

Phase 2

Phase 1

Conditions

Brain and Central Nervous System Tumors

Treatments

Drug: tipifarnib

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00005859

U01CA062455 (U.S. NIH Grant/Contract)

CDR0000067888 (Registry Identifier)

NABTC-9901

Details and patient eligibility

About

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.

Full 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].)

Enrollment

136 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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