Protocol Number: 04-C-0035

Title:

A Phase I Trial of CC8490 for the Treatment of Patients with Recurrent/Refractory High-Grade Gliomas

Number:

04-C-0035

Summary:

This study examines the use of CC-8490, which has been demonstrated as having significant preclinical activity, in patients who have gliomas that recur or that are resistant to treatment, or both. Malignant gliomas-tumors arising from tissue that is mingled with essential parts of nervous tissue-are a major cause of cancer-related illness and death in the United States. These tumors are the second leading cause of cancer in people under the age of 35 and the fourth leading cause in those under age 54. Although the cause of the disease is unknown, there is speculation about a genetic tendency, chemical causes, or viral causes. Recent research suggests a significant increase in the incidence of malignant gliomas, particularly in elderly people.

Despite recent advances in techniques of neuroimaging, neuroanesthesia, and neurosurgery, the prognosis for patients with malignant gliomas treated by surgical removal alone remains low. These gliomas show unique ability to infiltrate and grow, making a total removal impossible without causing unacceptable neurological damage to the patient. Most important, however, is that gliomas tend to have essential resistance to most standard anticancer agents. Thus, new such agents are needed, and a Phase I trial that escalates the dose of CC-8490 is proposed. Researchers have noted that high doses of tamoxifen had effects against the proliferation activity of cultured gliomas cells. Consequently, there is interest in finding more powerful agents called selective estrogen receptor modulators, or SERMS. CC-8490 has a specific way of acting on the ERa receptor and inhibits the rapid increase of MCF-7 human breast carcinoma cells. CC-8490 also acts against the proliferation of glioblastoma cells, independent of estrogen receptor binding.

Patients 18 years of age and older with malignant gliomas who have shown recurrence or progression of a tumor and who failed previous radiation therapy may be eligible for this study.

Participants will take CC-8490 once daily on an every-4-week cycle, with no breaks in between, and will be given increasingly higher doses until a maximum tolerated dose is established. Dose levels begin at 500 mg and escalate by levels of 500 mg, to a total of 2500 mg. In addition, participants will undergo the following procedures and tests:

- History, physical, and neurological examination every 2 weeks for the first cycle and every 4 weeks after that.

- Blood tests, including complete blood count, and differential and platelet count obtained every 2 weeks.

- Tests for various chemistries every 2 weeks for the first 2 cycles and then every 4 weeks; tests for calcium, phosphorous, magnesium, and uric acid performed before each cycle.

- Magnetic resonance imaging or computed tomography performed every 4 weeks.

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 supratentorial malignant gliomas or patients with a clinical and radiographic diagnosis of progressive low-grade gliomas will be eligible for this protocol. These include glioblastoma multiforme (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), malignant glioma/astrocytoma NOS (not otherwise specified). Also included will be radiographically diagnosed infiltrating brain stem gliomas not amenable to biopsy. Other CNS tumor histologies will not be eligible for this trial.

Patients must have shown either evidence for tumor recurrence or progression by CT or (preferably) MRI scan performed within 21 days prior to registration or had biopsy proven recurrent glioma within the last 12 weeks prior to enrollment (in order to allow the enrollment of patients with recurrent gliomas who have undergone a complete radiographic resection and now have no radiographic evaluable disease).

Patients having undergone recent resection of a recurrent or progressive tumor, as stated above, will be eligible two weeks after surgery.

Patient must have failed prior radiation therapy and must have an interval of greater than or equal to 2 weeks from the completion of radiation therapy to study entry.

All patients must sign an informed consent, or if cognitively impaired, their assigned DPA, indicating that they are aware of the investigational nature of this study.

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

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

Additionally, patients must be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide or carboplatin, 3 weeks from procarbazine, and 2 weeks from last vincristine administration. Patients must be at least 4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen).

Patients must have adequate bone marrow function (granulocyte count greater than or equal to 1500/mm(3), platelet count of greater than or equal to 100,000/mm(3), and hemoglobin greater than or equal to 8 gm%), adequate liver function (total bilirubin less than or equal to 1.5 mg/dL, AST/ALT less than or equal to 2 x ULN), and adequate renal function (creatinine less than or equal to 1.5 mg/dL 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. Eligibility level for platelets may not be reached by transfusion.

Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.

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

Patients must not be pregnant or nursing, and all patients (both men and women) must be willing to practice birth control during and for 2 months after treatment with CC-8490. Women of childbearing potential (WCBP) who are sexually active must agree to use adequate contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner).

Patients must be able to swallow capsules whole.

EXCLUSION CRITERIA:

Patients who, in the view of the treatment physician, have significant active cardiac, hepatic, renal, or psychiatric diseases that would significantly increase the risk of using CC-8490 are ineligible.

Concurrent use of other standard chemotherapeutics or investigative agents.

Pregnant or lactating females.

Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study, obscures the evaluation of toxicity or alters drug metabolism.

Use of other experimental study drug within 28 days of registration.

Patients who are pregnant or breastfeeding.

Special Instructions: Currently Not Provided

Keywords:

Brain Tumors

Brain Cancer

Clinical Trial

Selective Estrogen Receptor Modulator

Progressive Disease

Brain Tumor

Malignant Glioma

Recruitment Keywords:

None

Conditions:

Glioma

Investigational Drug(s):

CC8490

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:

Barker D, et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science. 1987 May 29;236(4805):1100-2.

Bigner SH, Bjerkvig R, Laerum OD. DNA content and chromosomal composition of malignant human gliomas. Neurol Clin. 1985 Nov;3(4):769-84. Review.

Moss AR. Occupational exposure and brain tumors. J Toxicol Environ Health. 1985;16(5):703-11.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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