Vorinostat and Temozolomide in Treating Patients With Malignant Gliomas

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of vorinostat (suberoylanilide hydroxamic
acid [SAHA]) in combination with temozolomide in patients with malignant gliomas.

II. To characterize the safety profile of vorinostat (SAHA) in combination with temozolomide.

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetics of vorinostat (SAHA) in combination with
temozolomide.

II. To determine efficacy of vorinostat (SAHA) in combination with temozolomide as measured
by objective response.

TERTIARY OBJECTIVES:

I. To explore the association of response to treatment to the molecular phenotype of the
tumor.

II. To assess the effects of vorinostat (SAHA) on histone acetylation status in peripheral
mononuclear cells.

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

PART I: Patients receive vorinostat orally (PO) once (QD) or twice daily (BID) on days 1-7
and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD 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.

PART II: Patients receive vorinostat and temozolomide as in part 1*.

[Note: *Beginning in course 2, all patients receive a higher dose of temozolomide.]

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients with histologically proven intracranial malignant glioma will be eligible for
this protocol; malignant gliomas include glioblastoma multiforme (GBM), gliosarcoma
(GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed
oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified);
patients will be eligible if the original histology was low-grade glioma and a
subsequent histological diagnosis of a malignant glioma is made

- All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study; patients must have signed an authorization for
the release of their protected health information; patients must be registered with
the Adult Brain Tumor Consortium (ABTC) Central Office database prior to treatment
with study drug

- Life expectancy > 8 weeks

- Karnofsky performance status of >= 60

- White blood cell (WBC) >= 3,000/mm^3

- Absolute neutrophil count (ANC) >= 1,500/mm^3

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

- Hemoglobin >= 10 g/dL; eligibility level for hemoglobin may be reached by transfusion

- Serum glutamic oxaloacetic transaminase (SGOT) < 2 times upper limit of normal (ULN)

- Bilirubin < 2 times ULN

- If liver function tests are above the institutional upper limit of normal but < 2
times institutional upper limit of normal, the decision to initiate temozolomide
treatment should carefully consider the benefits and risks for the individual patient

- Creatinine < 1.5 mg/dL

- A scan should be performed within 14 days prior to registration and on a steroid dose
that has been stable for at least 5 days; if the steroid dose is increased between the
date of imaging and registration a new baseline magnetic resonance (MR)/computed
tomography (CT) is required; the same type of scan, i.e., magnetic resonance imaging
(MRI) or CT must be used throughout the period of protocol treatment for tumor
measurement

- Patients must have an interval of greater than or equal to 3 weeks (21) days from the
completion of radiation therapy to study entry

- Women of childbearing potential must have a negative beta-human chorionic gonadotropin
(HCG) pregnancy test documented within 7 days prior to registration; should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately

- 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 participation in the study

- Patients must be willing to participate in the pharmacokinetic studies

- ELIGIBILITY CRITERIA SPECIFIC FOR PATIENTS IN PART I OF THE STUDY

- Patients with either stable disease after radiation therapy or with progression are
eligible (except if they have progressed on temozolomide; patients who have received
prior treatment with temozolomide and have stable disease are eligible

- Patients with recurrent disease may have had treatment for any number of prior
relapses; relapse is defined as progression following initial therapy (i.e. radiation
+/- chemo if that was used as initial therapy)

- Patients must have recovered from the toxic effects of prior therapy: 28 days from any
investigational agent, 28 days from prior cytotoxic therapy except 23 days from last
dose of temozolomide for patients taking the standard 5 days every 28 day regimen of
temozolomide, 14 days from vincristine, 42 days from nitrosoureas, 21 days from
procarbazine administration, and 7 days for non-cytotoxic agents, e.g., interferon,
tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count); any
questions related to the definition of non-cytotoxic agents should be directed to the
study chair

- Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:

- They have recovered from the effects of surgery

- Residual disease following resection is not mandated for eligibility into the
study; to best assess the extent of residual disease post-operatively, a CT/MRI
should be done no later than 96 hours in the immediate post-operative period or
at least 4 weeks post-operatively, within 14 days prior to registration; if the
96-hour scan is more than 14 days before registration, the scan needs to be
repeated; if the steroid dose is increased between the date of imaging and
registration, a new baseline MRI/CT is required on a stable steroid dosage for at
least 5 days

- Patients with prior therapy that included interstitial brachytherapy or stereotactic
radiosurgery must have confirmation of true progressive disease rather than radiation
necrosis based upon either positron emission tomography (PET) or thallium scanning, MR
spectroscopy or surgical documentation of disease

- ELIGIBILITY CRITERIA SPECIFIC FOR PATIENTS IN PART II OF THE STUDY

- Only patients with stable disease after radiation therapy are eligible for part 2 of
the study; patients with recurrent disease are ineligible

- The only prior therapy permitted for patients in part 2 of the study is concomitant
temozolomide with radiation therapy or radiation therapy alone; patients that are
stable on adjuvant temozolomide may also participate

- Patients with recurrent disease and prior chemotherapies (except concurrent or
adjuvant temozolomide) will not be included in this part of the study

Exclusion Criteria:

- Patients who have progressed on temozolomide are ineligible

- Patients 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; patients with a 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
are ineligible

- Patients must not have active infection or serious intercurrent medical illness

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with vorinostat (SAHA); potential risks may also apply to
temozolomide

- Patients must not have any disease that will obscure toxicity or dangerously alter
drug metabolism

- Patients who are known to be human immunodeficiency virus (HIV) positive and are
receiving combination antiretroviral therapy are ineligible

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat (SAHA) or other agents used in study

- Patients should not have taken valproic acid (another histone deacetylase inhibitor)
for at least 2 weeks prior to enrollment