Protocol Number: 03-C-0018

Title:

A Phase II Trial of LY317615 In Patients with Recurrent High-Grade Gliomas

Number:

03-C-0018

Summary:

This study will determine the safety and effectiveness of an experimental drug called LY317615 for treating patients with gliomas (a type of brain tumor). Gliomas are nourished by blood delivered through blood vessels whose formation is stimulated by substances produced by the tumor itself. Stopping the growth of new vessels can slow or prevent tumor growth. LY317615 has shown activity against gliomas in pre-clinical testing.

Patients 18 years of age and older with a primary glioma that is growing and does not respond to standard treatment, such as surgery, chemotherapy or radiation therapy, may be eligible for this study. Candidates will be screened with a medical history, physical examination, blood and urine tests, electrocardiogram (ECG), and magnetic resonance imaging (MRI) or computed tomography (CT) of the head. They will also complete a health-related quality of life questionnaire called a Functional Assessment of Cancer Therapy for Brain (FACT-Br).

Participants will be divided into two groups: Group A consists of patients who are not taking anti-seizure medications, and Group B patients who are taking anti-seizure medications. Both groups will take LY317615 once a day in treatment cycles of 6 weeks each. The drug dose for Group B patients will be increased with each new group of 5 patients until the optimum effective dose is determined for patients taking anti-seizure drugs. Patients in both groups will continue treatment as long as they do not have serious side effects and show no signs of tumor growth. Patients whose tumor grows significantly or who develop unacceptable side effects will be taken of the study. Patients who are doing well on the drug after completing nine treatment cycles (after about 1 year) will be evaluated to decide if therapy should continue or stop.

While on the study, patients will undergo the following tests and procedures:

-Medical history, physical and neurologic examinations, and FACT-Br questionnaires every 3 weeks for the first 6-week cycle and every 6 weeks thereafter.

-MRI or CT brain scan every 6 weeks. MRI is a diagnostic test that uses a strong magnetic field and radio waves to show structural and chemical changes in tissues. During the scan, the patient lies on a table in a narrow cylinder containing a magnetic field. The patient can speak with a staff member through an intercom system at all times during the procedure. CT produces pictures of the brain in small sections. The procedure is similar to MRI, but radiation is used to produce he images, and the enclosure is not confining.

-Routine blood tests every 3 weeks.

-ECG on day 21 of each cycle just before taking LY317615 and 30 minutes and 4 hours after taking the drug.

-Additional blood tests to detect substances that stimulate new blood vessel growth or to determine blood levels of LY317615. Group A patients will have four additional samples drawn in the first treatment cycle (two on day 1 and two on day 15), and Group B will have blood drawn at 1, 2, 4, 6, 8, 12, and 24 hours after the first dose of LY317615.

Patients may also be asked to undergo magnetic resonance with spectroscopy (MRS) or positron emission tomography (PET) scanning to help distinguish live tumor from dying tumor. The experience of having MRS is identical to that of the standard MRI and will be done at the same time as the MRI. The procedure for PET is similar to CT and MRI. This test shows cellular activity in the brain and can be used to evaluate tumor status.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Patients with histologically proven intracranial malignant glioma will be eligible for this protocol. Malignant glioma include glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO) or malignant astrocytoma NOS (not otherwise specified).

Patients must have unequivocal evidence for tumor progression by MRI or CT scan. This scan should be performed within 14 days prior to registration and on a steroid dosage that has been stable for at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline MR/CT is required. The same type of scan, i.e., MRI or CT must be used throughout the period of protocol treatment for tumor measurement.

Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: a) They have recovered from the effects of surgery. b) Residual disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual disease post-operatively, a CR/MRI should be done:

no later than 96 hours in the immediate post-operatively period

Or

at least 4 weeks post-operatively, and

within 14 days of registration, and

on a steroid dosage that has been stable for at least 5 days.

If the 96 hour scan is more than 21 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days.

Patients must have failed prior radiation therapy and must have an interval of greater than or equal to 4 weeks from the completion of radiation therapy to study entry.

All patients must sign an informed consent indicating that they are aware of the investigational nature of this study.

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 recovered from the toxic effects of prior therapy: 2 weeks from any investigational agent, 4 weeks from prior cytotoxic therapy, two weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.

Patients must have adequate bone marrow function (WBC greater than or equal to 3,000/microliter, ANC greater than or equal to 1,500/mm(3), platelet count of 100,000/mm(3), and hemoglobin greater than or equal to 10 gm/dl), adequate liver function (SGOT and bilirubin less than 2 times ULN), and adequate renal function (creatinine less than 1.5 mg/dL and/or creatinine clearance greater than or equal to 60 cc/min) before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.

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 patients' ability to tolerate this therapy

This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will based on race. Minorities will actively be recruited to participate.

Patients must practice adequate contraception.

EXCLUSION CRITERIA:

Patients, who in the view of the treating physician, have significant active cardiac, hepatic, renal, or psychiatric diseases are ineligible.

No concurrent use of other standard chemotherapeutics or investigative agents.

Patients known to have an active malignancy (except non-melanoma skin cancer or carcinoma in-situ of the cervix).

Patients who have an active infection requiring IV antibiotics.

Patients who are pregnant or breast feeding.

Patients who have any disease that will obscure toxicity or dangerously alter drug metabolism.

Special Instructions: Currently Not Provided

Keywords:

Experimental

Oral Drug

Brain Tumor

Pharmacokinetics

Electrocardiograms

Recruitment Keywords:

Brain Tumor

Glioma

Conditions:

Glioma

Investigational Drug(s):

LY317615

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:

Dinapoli RP, Brown LD, Arusell RM, Earle JD, O'Fallon JR, Buckner JC, Scheithauer BW, Krook JE, Tschetter LK, Maier JA, et al. Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma. J Clin Oncol. 1993 Jul;11(7):1316-21.

Takahashi JA, Mori H, Fukumoto M, Igarashi K, Jaye M, Oda Y, Kikuchi H, Hatanaka M. Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and

peptide in tumor tissues. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5710-4.

Takahashi JA, Fukumoto M, Igarashi K, Oda Y, Kikuchi H, Hatanaka M. Correlation of basic fibroblast growth factor expression levels with the degree of malignancy and vascularity in human gliomas. J Neurosurg. 1992 May;76(5):792-8.

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