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

Phase 1
18 Years
Open (Enrolling)
Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Recurrent Adult Brain Tumor

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Trial Information

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


I. Determine the maximum tolerated dose (MTD) of vorinostat in combination with temozolomide
in patients with malignant gliomas.

II. Characterize the safety profile of vorinostat in combination with temozolomide in these


I. Characterize the pharmacokinetics of vorinostat (SAHA) in combination with temozolomide
in these patients.

II. Determine efficacy of vorinostat (SAHA) in combination with temozolomide as measured by
objective response in these patients.


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

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

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.

Inclusion Criteria:

- 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

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

- Histologically proven intracranial malignant glioma, including the following

- 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 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

- 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

- Life expectancy > 8 weeks

- Karnofsky performance status >= 60

- WBC > 3,000/mm^3

- Absolute neutrophil count > 1,500/mm^3

- Platelet count >= 100,000/mm^3

- 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

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to vorinostat or other agents used in study

- At least 2 weeks since prior valproic acid

- At least 3 weeks since radiation 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)

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of SAHA with Temozolomide defined as the dose at which less than one-third of patients experience DLT based on the CTC severity grading (Phase I)

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Patrick Wen

Investigator Role:

Principal Investigator

Investigator Affiliation:

North American Brain Tumor Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

December 2005

Completion Date:

Related Keywords:

  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Oligodendroglioma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Recurrent Adult Brain Tumor
  • Astrocytoma
  • Brain Neoplasms
  • Glioblastoma
  • Glioma
  • Oligodendroglioma
  • Gliosarcoma



Dana-Farber Cancer Institute Boston, Massachusetts  02115
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
University of Pittsburgh Pittsburgh, Pennsylvania  15261
M D Anderson Cancer Center Houston, Texas  77030
University of California San Francisco Medical Center-Mount Zion San Francisco, California  94115
University of California at Los Angeles (UCLA ) Los Angeles, California  90095
North American Brain Tumor Consortium Watertown, Massachusetts  02472