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


Phase 2
18 Years
N/A
Not Enrolling
Both
Brain and Central Nervous System Tumors

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Trial Information

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


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].)

Inclusion 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

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Timothy F. Cloughesy, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Jonsson Comprehensive Cancer Center

Authority:

United States: Federal Government

Study ID:

CDR0000067888

NCT ID:

NCT00005859

Start Date:

August 2000

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • recurrent adult brain tumor
  • adult glioblastoma
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms
  • Glioma

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
University of Texas - MD Anderson Cancer CenterHouston, Texas  77030-4009
University of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan  48109-0752
Jonsson Comprehensive Cancer Center, UCLALos Angeles, California  90095-1781
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
University of Wisconsin Comprehensive Cancer CenterMadison, Wisconsin  53792
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
UCSF Comprehensive Cancer CenterSan Francisco, California  94115
Hillman Cancer Center at University of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania  15236
Simmons Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390-9063
Warren Grant Magnuson Clinical Center - NCI Clinical Studies SupportBethesda, Maryland  20892-1182