Protocol Number: 03-C-0189

Title:

Phase I Trial of R115777 with Radiation Therapy in Patients with Newly Diagnosed Glioblastoma Multiforme

Number:

03-C-0189

Summary:

The purposes of this study are the following:

- To find a safe dose of Tipifarnib (also known as R115777 or ZARNESTRA) to be given with radiation therapy in patients who are, and who are not, taking the following anti-seizure medications: Dilantin, Tegretol, Carbatrol, Trileptal, and Mysoline;

- To determine the safety and side effects of Tipifarnib and radiation therapy when given to patients with glioma (a type of brain tumor); and,

- To determine if gliomas shrink when Tipifarnib is given with radiation therapy.

Current post-surgical treatment of malignant (cancerous) gliomas with chemotherapy is disappointing. This study will test whether the findings of a recent pilot study suggesting a possible beneficial effect of Tipifarnib in patients with recurrent malignant gliomas can be confirmed.

Patients 18 years of age and older with glioblastoma multiforme who have not received prior radiation therapy to the brain or cytotoxic or non-cytotoxic experimental drug therapy against the brain tumor may be eligible for this study. Patients may have received corticosteroids, antiepileptics, pain killers, and other drugs to treat symptoms or prevent complications. Candidates will be screened with a physical examination, magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain, and routine laboratory tests.

Participants will receive Tipifarnib twice a day by mouth for 21 days, followed by 7 days without drug. This regimen constitutes one treatment cycle. These 4-week cycles will be repeated as long as the patient's disease does not worsen and the side effects of treatment are acceptable. After beginning treatment with Tipifarnib, patients will receive standard radiation therapy for glioblastoma. Radiation therapy lasts approximately 6 weeks.

During treatment with R115777 and radiation therapy, participants will be seen in the clinic once a week. After radiation is completed, they will be seen every 4 weeks. Blood will be drawn once a week during radiation therapy and once every 2 weeks after completing radiation therapy. Patients will also have periodic physical and neurologic examinations. Brain MRI or CT scans will be done at diagnosis, after surgery, 4 weeks after completion of radiation therapy, and then at 8-week intervals.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Patients will have histologically proven intracranial Glioblastoma Multiforme (GBM) or gliosarcoma (GS).

Diagnosis will have been established by biopsy or resection within 4 weeks prior to registration.

Cranial MRI or contrast CT must have been performed within 21 days of study entry. The use of MRI rather than CT is preferred. The same type of scan, i.e., MRI or CT must be used throughout the period of protocol treatment for tumor measurement. If the surgical procedure was a resection, cranial MRI or contrast CT performed with 96 hours of resection is preferred but not required. Patients without measurable or assessable disease are eligible.

Patients must have a plan to begin partial brain radiotherapy within 5-9 days after beginning R115777, and within 35 days (5 weeks) of the surgical procedure that established the diagnosis.

Patients must be willing to forego cytotoxic and non-cytotoxic drug therapy against the tumor while being treated with R115777.

All patients must sign an informed consent indicating that they are aware of the investigational nature of this study. Patients must be registered in the North American Brain Tumor Consortium Data Management Center (NABTC DMC) database prior to treatment with study drug.

Patients must be greater than or equal to 18 years old, and with a life expectancy greater than 8 weeks.

Patients must have a Karnofsky performance status of greater than or equal to 60.

Patients must have adequate bone marrow function (WBC greater than or equal to 3,000/ul, ANA greater than or equal to 1,500/mm (3), platelet count of greater than or equal to 100,000/mm(3), and hemoglobin greater than or equal to 10 gm/dl) and the test must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.

Patients must have adequate liver function (SGOT and bilirubin less than 2 times ULN) and the test must be performed within 14 days prior to registration.

Patient must have adequate renal function (creatinine less than 1.5 mg/dL) before starting therapy and the test must be performed within 14 days prior to registration.

EXCLUSION CRITERIA:

Patients must not have received previous radiotherapy to the brain.

Patients must not have received cytotoxic drug therapy, non-cytotoxic drug, or experimental drug therapy directed against the brain tumor. Patients who received Gliadel wafers will be excluded

Patients may have received or be receiving corticosteroids, antiepileptics, analgesics, and other drugs to treat symptoms or prevent complications.

Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy. Patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism.

Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.

Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race.

Patients must not have active infection.

Women must not be pregnant or Breast-feeding, and women with reproductive potential must practice adequate contraception

Patients must not be on chronic coumadin therapy for prior medical problems (e.g. cardiac valve prophylaxis). Patients who develop or have recently developed a deep venous thrombosis or pulmonary embolism who are on or will take coumadin will be allowed to participate.

Special Instructions: Currently Not Provided

Keywords:

Experimental

Glioma

Drugs

Toxicity

Radiotherapy

Recruitment Keywords:

Glioma

Glioblastoma Multiforme

GBM

Glioblastoma

GS

Conditions:

Glioblastoma Multiforme

Investigational Drug(s):

R115777 (Zarnestra)

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson JS, Tsukada Y. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer. 1983 Sep 15;52(6):997-1007. PMID: 6349785

Fetell MR, Grossman SA, Fisher JD, Erlanger B, Rowinsky E, Stockel J, Piantadosi S. Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New

Approaches to Brain Tumor Therapy Central Nervous System Consortium. J Clin Oncol. 1997 Sep;15(9):3121-8.

PMID: 9294475

Guha A. Ras activation in astrocytomas and neurofibromas. Can J Neurol Sci. 1998 Nov;25(4):267-81. Review.

PMID: 9827227

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