Vorinostat and Temozolomide in Treating Patients With Malignant Gliomas

Condition(s) targeted: Brain and Central Nervous System Tumors

Intervention: temozolomide (Drug); vorinostat (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: North American Brain Tumor Consortium

Official(s) and/or principal investigator(s):
Patrick Y. Wen, MD, Principal Investigator, Affiliation: Dana-Farber Cancer Institute

RATIONALE: Drugs used in chemotherapy, such as vorinostat and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vorinostat may help temozolomide work better by making tumor cells more sensitive to the drug. Giving vorinostat together with temozolomide may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat when given together with temozolomide in treating patients with malignant gliomas.

Official title: Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]) in Combination With Temozolomide in Patients With Malignant Gliomas

Study design: Treatment

Detailed description: OBJECTIVES:

Primary

- Determine the maximum tolerated dose (MTD) of vorinostat in combination with

temozolomide in patients with malignant gliomas.

- Characterize the safety profile of vorinostat in combination with temozolomide in these

patients.

Secondary

- Characterize the pharmacokinetics of vorinostat (SAHA) in combination with temozolomide

in these patients.

- Determine efficacy of vorinostat (SAHA) in combination with temozolomide as measured by

objective response in these patients.

Exploratory

- Correlate response to treatment with the molecular phenotype of the tumor in these

patients.

OUTLINE: This is a 2-part, multicenter, dose-escalation study of vorinostat.

- Part 1: Patients receive oral vorinostat once or twice daily on days 1-7 and 15-21 OR

once or twice daily on days 1-7. Patients also receive oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Beginning in course 2, some patients may receive a higher dose of temozolomide. Treatment may continue beyond 13 courses at the discretion of the investigator.

Cohorts of 3-6 patients receive escalating doses of vorinostat during course 1 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. At least 6 patients are treated at the MTD.

- Part 2: Patients receive vorinostat and temozolomide as in part 1*. NOTE: *Beginning in

course 2, all patients receive a higher dose of temozolomide.

Cohorts of 3-6 patients receive de-escalating doses of vorinostat (beginning at the MTD determined in part 1) during courses 1 and 2 until the MTD for part 2 is determined. The MTD is defined as in part 1. An additional 6 patients are treated at the MTD.

After completion of study treatment, patients are followed periodically for survival.

PROJECTED ACCRUAL: A total of 77 patients will be accrued for this study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically proven intracranial malignant glioma, including the following

subtypes:

- Glioblastoma multiforme

- Gliosarcoma

- Anaplastic astrocytoma

- Anaplastic oligodendroglioma

- Anaplastic mixed oligoastrocytoma

- Malignant astrocytoma NOS (not otherwise specified)

- Original histology of a low-grade glioma and a subsequent histological diagnosis

of a malignant glioma

- Patients who have progressed on temozolomide are ineligible

- Patients in part 1 of this study must meet the following requirements:

- Stable disease or progression after radiation therapy (except if they have

progressed on temozolomide therapy) OR recurrent disease after treatment for any number of prior relapses

- Must have recovered from the toxic effects of prior therapy

- 28 days since prior investigational agent

- 28 days since prior cytotoxic therapy

- 23 days since prior temozolomide for patients on a standard regimen (i. e., 5

days every 28 days)

- 14 days since prior vincristine

- 42 days since prior nitrosoureas

- 21 days since prior procarbazine administration

- 7 days since prior non-cytotoxic agents (e. g., interferon, tamoxifen,

thalidomide, cis-retinoic acid, etc.) except as a radiosensitizer

- Patients who have recently undergone resection of recurrent or progressive

disease must meet the following conditions:

- Recovered from the effects of surgery

- Residual disease following resection is not mandated for eligibility into

the study

- Patients with prior therapy that included interstitial brachytherapy or

stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis by positron emission tomography or thallium scanning, MR spectroscopy or surgical documentation of disease

- Patients in part 2 of this study must meet the following requirements:

- Stable disease after radiation therapy

- Concurrent temozolomide with radiation therapy or radiation therapy alone,

is the only prior therapy permitted

- No recurrent disease

- Must be willing to participate in the pharmacokinetic studies

PATIENT CHARACTERISTICS:

- Life expectancy > 8 weeks

- Karnofsky performance status ≥ 60

- WBC > 3,000/mm^3

- Absolute neutrophil count > 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin > 10 g/dL (transfusion allowed)

- SGOT < 2 times upper limit of normal (ULN)

- Bilirubin < 2 times ULN

- Creatinine < 1. 5 mg/dL

- Pregnant women are excluded

- Women of childbearing potential must have a negative pregnancy test

- Women of childbearing potential and men must agree to use adequate contraception

(hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of the study

- Breastfeeding should be discontinued

- 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

- No 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

- Must not have active infection or serious intercurrent medical illness

- Must not have any disease that will obscure toxicity or dangerously alter drug

metabolism

- No history of allergic reactions attributed to compounds of similar chemical or

biologic composition to vorinostat or other agents used in study

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 2 weeks since prior valproic acid

- At least 3 weeks since radiation therapy

- No patients who are known to be HIV positive and are receiving combination

antiretroviral therapy

- No other investigational agents

- No other anticancer therapy (including chemotherapy, radiation, hormonal treatment or

immunotherapy) of any kind is permitted during the study period

- No concurrent routine prophylactic use of filgrastim (G-CSF)

Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California 90095-1781, United States; Recruiting
Clinical Trials Office - Jonsson Comprehensive Cancer Center a, Phone: 888-798-0719

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94115, United States; Recruiting
Clinical Trials Office - UCSF Helen Diller Family Comprehensi, Phone: 877-827-3222

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States; Recruiting
Clinical Trials Office - Dana-Farber/Harvard Cancer Center, Phone: 617-582-8480

Memorial Sloan-Kettering Cancer Center, New York, New York 10021, United States; Recruiting
Lisa M. DeAngelis, MD, Phone: 212-639-7997

Duke Comprehensive Cancer Center, Durham, North Carolina 27710, United States; Recruiting
David A. Reardon, MD, Phone: 919-668-1409, Email: reard003@mc.duke.edu

UPMC Cancer Centers, Pittsburgh, Pennsylvania 15232, United States; Recruiting
Clinical Trials Office - UPMC Cancer Centers, Phone: 412-647-8073

M. D. Anderson Cancer Center at University of Texas, Houston, Texas 77030-4009, United States; Recruiting
Clinical Trials Office - M. D. Anderson Cancer Center at the U, Phone: 713-792-3245

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin 53792-6164, United States; Recruiting
Clinical Trials Office - University of Wisconsin Paul P. Carbo, Phone: 608-262-5223

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: December 2005
Last updated: July 23, 2008