Inclusion Criteria:
1. Patients with histologically proven supratentorial WHO grade IV glioma (glioblastoma
or gliosarcoma) will be eligible for the study.
2. Patients must have shown unequivocal evidence for tumor recurrence or progression by
MRI scan and should have failed radiation therapy. The scan done prior to study
entry documenting progression will be reviewed by the treating physician to document
changes in tumor dimension to confirm recurrence. Patients with prior therapy that
included interstitial brachytherapy or stereotactic radiosurgery must have
confirmation of true progressive disease rather than radiation necrosis.
3. (2. continued) Patients with prior therapy that included interstitial brachytherapy,
Gliadel wafers or stereotactic radiosurgical procedures must have confirmation of
true progressive disease rather than radiation necrosis. Such confirmation may be
using advanced imaging studies (e.g. PET scans, diffusion-perfusion MRI, SPECT etc)
or if available, surgical sampling and histological confirmation (surgery is not
required).
4. Patients may have had up to 2 prior relapses.
5. All patients must sign an IRB approved informed consent indicating their awareness
of the investigational nature of this study. Patients must have signed an
authorization for the release of their protected health information.
6. The baseline on-study MRI should be performed within 14 days (+ 3 working days)
prior to registration and on a steroid dosage that has been stable or decreasing for
at least 5 days. If the steroid dose is increased between the date of imaging and
the initiation of therapy (or at that time), a new baseline MRI is required. The
same type of scan, i.e., MRI, must be used throughout the period of protocol
treatment for tumor measurement.
7. Patients who have undergone recent resection of recurrent or progressive tumor will
be eligible as long as they have recovered from the effects of surgery. Evaluable or
measurable disease following resection of recurrent tumor is not mandated for
eligibility into the study. To best assess the extent of residual measurable disease
post-operatively, a MRI should be done no later than 96 hours in the immediate
post-operative period or 4-6 weeks post-operatively.
8. Patients must be 18 years old or older.
9. Patients must have a Karnofsky performance status equal or greater than 60.
10. Patients must have recovered from the toxic effects of prior therapy to < grade 2
non hematological or grade 2 or lesser hematological toxicity per CTC ver 4 (except
deep vein thrombosis): 4 weeks from prior cytotoxic therapy and/or at least two
weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine
administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen,
cis-retinoic acid, etc. (radiosensitizer does not count). Patients who receive
anticancer agents for non-therapeutic purposes unrelated to this study. 11. (10. continued) (such as presurgically for obtaining pharmacology data for the
agent) will be eligible to enter the study provided they have recovered from the
toxic effects of the agent if any. Any questions related to the definition of
non-cytotoxic agents should be directed to the Study Chair.
12. Patients must have adequate bone marrow function (ANC = or > 1,500/mm^3 and platelet
count of = or > 100,000/mm^3), adequate liver function (SGPT = or < 3 times upper
limit of normal and alkaline phosphatase = or < 2 times upper limit of normal,
bilirubin = or <1.5 mg/dl), adequate renal function (BUN and creatinine = or <1.5
times upper limit of normal) and normal serum amylase and lipase prior to starting
therapy. Elevated cholesterol and triglycerides are not a contraindication to study
enrollment, but should be managed as clinically appropriate by the treating
physician.
13. Patients must be willing and able to comply with the FDA mandated iPLEDGE program
for treatment with isotretinoin (cRA). Patients must sign specific informed consents
for treatment with cRA, as mandated by iPLEDGE guidelines. Women of childbearing
potential must not be pregnant, must not be breast-feeding and must practice
adequate contraception during and one month after participation in the study. Male
and Female patients on treatment with vorinostat must agree to use an adequate
method of contraception for the duration of the study, and for 30 days after the
last dose of study medication.
14. Prior treatment with dose dense regimens of temozolomide is not allowed (e.g, 7 days
on/7 days off, 21 day/28 day and daily low dose continuous dosing). However, prior
treatment with standard day 1-5 dosing in the adjuvant setting and low dose daily
dosing as part of chemoradiation therapy are allowed. 15. Prior treatment with isotretinoin is allowed because the trial is based on the
hypothesis that HDAC inhibition will potentially overcome resistance to retinoids.
Exclusion Criteria:
1. Patients with a history of any other cancer (except non-melanoma skin cancer or
carcinoma in-situ of the cervix or bladder), unless in complete remission and off of
all therapy for that disease for a minimum of 3 years.
2. Patients must not have: a) active infection; b) disease that will obscure toxicity
or dangerously alter drug metabolism, especially liver disease; c) serious
intercurrent medical illness; d) prior treatment with HDAC inhibitors. However,
patients who have received anticancer agents for non-therapeutic purposes (for eg.,
as part of a pharmacology study without therapeutic intent) will remain eligible for
enrollment into the study.
3. Prior treatment with bevacizumab is not allowed.
4. Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor
properties, will be excluded, unless they are switched to an alternative agent prior
to treatment initiation. No wash out period is required.
5. Patients on previous treatment with carboplatin.
6. Patients with a known allergy to any component of vorinostat, or a known allergy to
temozolomide and/or isotretinoin.
7. Patient must be able to tolerate the procedures required in this study including
periodic blood sampling, study related assessments, and management at the treating
institution for the duration of the study. Inability to comply with protocol or
study procedures (for example, an inability to swallow tablets) will be an exclusion
criterion.
8. Patients receiving treatment with other antiepileptic medications will not be
excluded. Vorinostat is not metabolized by cytochrome P450 3A4 (CYP 3A4). However,
vorinostat may potentially suppress CYP 3A4 activity. Therefore, patients should
preferably be treated with non-enzyme inducing anti-epileptic medications to avoid
any potential interactions with vorinostat.
9. (8. continued) However, the use of non-enzyme inducing anti-epileptic medications is
not mandatory. If enzyme-inducing antiepileptic drugs are used, monitoring of drug
levels should be considered, as considered clinically appropriate by the treating
physician.
