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High-Dose Vorinostat With Radiation Therapy in the Treatment of Recurrent Glioma

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

High-Dose Vorinostat With Radiation Therapy in the Treatment of Recurrent Glioma


I. To determine the phase II dose when intermittent short-course vorinostat is combined with
fractionated radiation therapy in recurrent high-grade glioma.


I. Define the pharmacokinetics of vorinostat entry into the cerebrospinal fluid (CSF) and
demonstrate that vorinostat influences glioma biology.

OUTLINE: This is a dose-escalation study of vorinostat.

Patients receive high-dose vorinostat orally (PO) at 48, 27, and 3 hours prior to surgery.
Beginning 2-6 weeks later, patients receive vorinostat PO once daily (QD) on days 1-3 in
weeks 1-2and undergo fractionated stereotactic body radiation therapy on days 1-5 in weeks
1-2. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3
months for 2 years.

Inclusion Criteria:

- Patients must have a previously histologically or cytologically confirmed glioma
(astrocytic or oligodendroglial supratentorial tumors grades 3 or 4 according to the
World Health Organization [WHO] 2007 classification) that has been previously treated
with fractionated radiation therapy and now shows evidence of recurrence

- Patients must have recovered from the toxic effects of prior therapy

- Patients must have recovered from the effects of any prior surgery to any part of the
body; there must be a minimum of 28 days from the day of surgery to the day of
registration; for core or needle biopsy, a minimum of 7 days must have elapsed prior
to registration

- Patients may have previously undergone more than one craniotomy

- Prior treatment with cytotoxic and biological agents is permissible; there should be
at least a 2 week break between prior treatment and enrollment; (in the case of
bevacizumab, since this trial involves surgery, at least 4 weeks should elapse
between last dose of drug and enrollment, in the case of nitrosoureas or mitomycin C,
at least 6 weeks)

- Prior treatment with fractionated radiation therapy (up to 60 Gray [Gy]) is an
eligibility criterion, however this should have been completed >= 4 weeks prior to
enrollment and there should not have been a second course of fractionated
radiotherapy to the supratentorial area

- One prior single fraction radiosurgical procedure within the treatment field is
acceptable if V12 < 5 cc (V12 is the volume of brain receiving 12 or more Gy);
additional radiosurgical procedures outside of the treatment area are acceptable

- Patients should not have received prior histone deacetylase therapy (HDAC) therapy,
an exception being the anti-seizure medicine valproic acid; however even valproic
acid should not be given concurrently with vorinostat

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 2 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on

- Women of childbearing potential must have a negative beta-human chorionic
gonadotropin (HCG) pregnancy test documented within 7 days prior to registration

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; the effects of vorinostat on the developing
human fetus are unknown; HDAC inhibitor agents as well as the ionizing radiation used
in this trial are known to be teratogenic; should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had:

- Radiotherapy within 4 weeks

- Chemotherapy/biological agents (excluding bevacizumab, nitrosoureas and
mitomycin C) within 2 weeks

- Bevacizumab within 4 weeks

- Nitrosoureas and mitomycin C within 6 weeks prior to entering the study

- Those who have not recovered from acute adverse events due to any prior
therapeutic agents

- Patients may not be receiving any other investigational agents

- Evidence of recent myocardial infarction or ischemia by the findings of S-T
elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed
within 14 days of registration

- A history of long QT syndrome, or corrected QTc (QTc) prolongations > 470 ms at

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat or other HDAC inhibitor or other agents used in study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because vorinostat is an antineoplastic
agent with the potential for teratogenic or abortifacient effects, class D; because
there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with vorinostat, breastfeeding should be
discontinued if the mother is treated with vorinostat; these potential risks may also
apply to other agents used in this study

Type of Study:


Study Design:

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

Outcome Measure:

Maximal tolerated dose (MTD), defined as one level below at which 2 of 6 patients experience a dose-limiting toxicity (DLT)

Outcome Description:

Analysis of study data will be descriptive, including summary tables of toxicity. An exploratory retrospective trend analysis will be performed assessing for a correlation between plasma drug level and toxicity, using exact logistic regression models.

Outcome Time Frame:

48 hours

Safety Issue:


Principal Investigator

Wenyin Shi

Investigator Role:

Principal Investigator

Investigator Affiliation:

Thomas Jefferson University


United States: Food and Drug Administration

Study ID:




Start Date:

June 2012

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



Thomas Jefferson University HospitalPhiladelphia, Pennsylvania  19131