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Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Cognitive/Functional Effects

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Trial Information

Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of vorinostat when administered with temozolomide
and radiotherapy in patients with newly diagnosed glioblastoma multiforme. (Phase I) II. To
determine the efficacy of this regimen, in terms of overall survival, in these patients.
(Phase II)

SECONDARY OBJECTIVES:

I. To determine the toxicity of this regimen in these patients. (Phase I) II. To determine
progression-free survival of patients treated with this regimen. (Phase II) III. To further
evaluate the safety profile of this regimen in these patients. (Phase II) IV. To determine
the neurocognitive effects in these patients and correlate the results with outcome
endpoints. (Phase II)

TERTIARY OBJECTIVES:

I. To correlate tumor molecular characteristics and expression profile with outcome.

II. To evaluate potential mechanisms of therapy resistance in tumor samples obtained at the
time of tumor progression.

OUTLINE: This is a multicenter, phase I, dose-escalation study of vorinostat followed by a
phase II study.

Patients undergo radiotherapy and receive oral vorinostat once daily on days 1-5, 8-12,
15-19, 22-26, 29-33, and 36-40. Patients also receive oral temozolomide once daily on days
1-42. Beginning 4-6 weeks later, patients receive oral vorinostat once daily on days 1-7
and 15-21 and oral temozolomide once daily on days 1-5. Treatment with vorinostat and
temozolomide repeats every 28 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.

Patients enrolled in phase II and those who are treated at the maximum tolerated dose in
phase I submit tumor tissue samples for correlative laboratory studies. Studies include
assessment of histone acetylation status by immunohistochemistry; gene expression profiling;
and assessment of MGMT methylation status by polymerase chain reaction. Patients enrolled in
phase II and those who are treated at the maximum tolerated dose in phase I complete a
neurocognitive assessment prior to, during, and after completion of study therapy. The
assessment includes the Hopkins Verbal Learning Test (HVLT-R) (Revised), the Controlled Oral
Word Association test from the Multilingual Aphasia Examination (COWA), the Trail Making
Test A: Visual scanning speed, and the Trail Making Test B: Divided attention.

After completion of study treatment, patients are followed every 3 months for 2 years and
then every 6 months for 1 year.


Inclusion Criteria:



- Histologically confirmed glioblastoma multiforme, including gliosarcoma or other
grade 4 astrocytoma variant (e.g., giant cell glioblastoma)

- Bidimensionally measurable or evaluable disease by gadolinium MRI or
contrast-enhanced CT scan

- Has undergone surgery for the brain tumor within the past 2-5 weeks

- Karnofsky performance status (PS) 60-100% or ECOG PS 0-2

- Life expectancy ≥ 12 weeks

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- WBC ≥ 3,000/mm^3

- Hemoglobin ≥ 10.0 g/dL (transfusion allowed)

- Total bilirubin ≤ 2.0 times upper normal limit (ULN)

- AST ≤ 2.0 times ULN

- Creatinine ≤ 1.5 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 12 weeks after
completion of study treatment

- No known hypersensitivity to any of the components of vorinostat or other drugs used
in the study

- No other active malignancy within the past 3 years, except nonmelanotic skin cancer
or carcinoma in situ of the cervix

- No uncontrolled infection

- Known HIV positivity allowed provided there is no clinical evidence of an
immunocompromised state

- No co-morbid systemic illness or other concurrent severe illness that, in the opinion
of the investigator, would preclude study participation

- No concurrent uncontrolled illness (e.g., ongoing or active infection or psychiatric
illness/social situation) that would preclude study compliance

- No myocardial infarction or unstable angina within the past 6 months

- No congestive heart failure requiring ongoing maintenance therapy

- No life-threatening ventricular arrhythmias

- No congenital long QT syndrome

- No prolonged QTc interval (i.e., QTc > 450 msec)

- Able to take oral medications

- Willing to provide mandatory tissue samples for research studies (for patients
treated at the maximum tolerated dose)

- Willing and able to complete neurocognitive assessments (patients enrolled in phase
II and those who are treated at the maximum tolerated dose in phase I)

- No concurrent treatment for another malignancy other than hormonal therapy

- No prior cytotoxic, non-cytotoxic, or experimental drug therapy for the brain tumor

- No prior cranial radiotherapy

- No prior Gliadel wafers

- More than 7 days since prior and no concurrent Category I drugs that have a risk of
causing torsades de pointes (e.g., quinidine, procainamide, disopyramide, amiodarone,
sotalol, ibutilide, dofetilide, erythromycin, clarithromycin, chlorpromazine,
haloperidol, mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol,
methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl,
pentamidine, sparfloxacin, or lidoflazine)

- More than 2 weeks since prior and no concurrent valproic acid or other histone
deacetylase inhibitors

- Concurrent corticosteroids allowed provided patient is on a fixed or decreasing dose
for ≥ 5 days prior to study enrollment

- No other concurrent investigational agents for the brain tumor

- No other concurrent cytotoxic or non-cytotoxic drug therapy for the brain tumor

- No concurrent stereotactic radiosurgery or brachytherapy

- No concurrent antiretroviral therapy for HIV-positive patients

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of vorinostat, defined as the dose at which fewer than one-third of patients experience DLTs, graded according to NCI CTCAE version 3.0 (Phase I)

Outcome Time Frame:

10 weeks

Safety Issue:

Yes

Principal Investigator

Evanthia Galanis

Investigator Role:

Principal Investigator

Investigator Affiliation:

North Central Cancer Treatment Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00672

NCT ID:

NCT00731731

Start Date:

July 2009

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Cognitive/Functional Effects
  • Glioblastoma
  • Gliosarcoma

Name

Location

Henry Ford HospitalDetroit, Michigan  48202
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Munson Medical CenterTraverse City, Michigan  49684
MeritCare Medical GroupFargo, North Dakota  58122
Rice Memorial HospitalWillmar, Minnesota  56201
Queen's Medical CenterHonolulu, Hawaii  96813
University of PittsburghPittsburgh, Pennsylvania  15261
Kapiolani Medical Center at Pali MomiAiea, Hawaii  96701
Kapiolani Medical Center for Women and ChildrenHonolulu, Hawaii  96826
Straub Clinic and HospitalHonolulu, Hawaii  96813
Hawaii Medical Center EastHonolulu, Hawaii  96817
Castle Medical CenterKailua, Hawaii  96734
Oncare Hawaii Inc-POB IIHonolulu, Hawaii  96813
Oncare Hawaii Inc-KuakiniHonolulu, Hawaii  96817
Resurrection HealthcareChicago, Illinois  60631
Merit Care Clinic BemidjiBemidji, Minnesota  56601
Meritcare HospitalFargo, North Dakota  58122
Sanford University of South Dakota Medical CenterSioux Falls, South Dakota  57117-5134
Kuakini Medical CenterHonolulu, Hawaii  96817
Wilcox Memorial Hospital and Kauai Medical ClinicLihue, Hawaii  96766-1099
Oncare Hawaii Inc - Kapiolani Medical Center at Pali MomiAiea, Hawaii  96701