Vorinostat, Isotretinoin and Temozolomide in Adults With Recurrent Glioblastoma Multiforme (GBM)

• Register: ClinicalTrials.gov
• Last refreshed on: 17 October 2012
• Main ID: NCT00555399
• Date of registration: 06/11/2007
• Primary sponsor: M.D. Anderson Cancer Center
• Public title: Vorinostat, Isotretinoin and Temozolomide in Adults With Recurrent Glioblastoma Multiforme (GBM)
• Scientific title: Phase I / II Adaptive Randomized Trial of Vorinostat, Isotretinoin and Temozolomide in Adults With Recurrent Glioblastoma Multiforme
• Date of first enrolment: November 2007
• Target sample size: 189
• Recruitment status: Recruiting
• URL: http://clinicaltrials.gov/show/NCT00555399
• Study type: Interventional
• Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Countries of recruitment

United States

Contacts

• Name: Vinay K. Puduvalli, MD

• Name: Vinay K. Puduvalli, MD
• Affiliation: M.D. Anderson Cancer Center

Key inclusion & exclusion criteria

Inclusion Criteria:

1. Patients with histologically proven supratentorial glioblastoma multiforme,
gliosarcoma or anaplastic glioma will be eligible for the Phase I component of this
protocol. Anaplastic gliomas include anaplastic astrocytoma, anaplastic
oligodendroglioma, anaplastic mixed oligoastrocytoma, or malignant glioma NOS.
Patients will be eligible if the original histology was low-grade glioma and a
subsequent histological diagnosis of a malignant glioma is made. Only patients with
histologically proven supratentorial glioblastoma multiforme or gliosarcoma will be
eligible for the Phase II component.

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. Patients may have had up to 2 prior relapses provided the functional status and other
eligibility criteria for enrollment are met.

4. All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study in keeping with the policies of this hospital.

5. 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.

6. Patients having 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.

7. Patients must be 18 years old or older.

8. Patients must have a Karnofsky performance status equal or greater than 60.

9. 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 3 (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

10. ( 9. 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. Because the trial is based on the hypothesis that the
combination of agents used will be synergistic in their effects, and that HDAC
inhibition will potentially overcome resistance to retinoids, prior treatment with
cRA is allowed. Any questions related to the definition of non-cytotoxic agents
should be directed to the Study Chair.

11. 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 normal
and alkaline phosphatase = or < 2 times normal, bilirubin = or <1.5 mg/dl), adequate
renal function (BUN and creatinine = or <1.5 times institutional 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.

12. 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 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.

13. 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, standard
day 1-5 dosing and low dose daily dosing as part of chemoradiation therapy are
allowed .

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 recurrence with other 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.

3. Pregnant and breast feeding women.

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
criteria.



Age minimum: 18 Years
Age maximum: N/A
Gender: Both

Health Condition(s) or Problem(s) studied

Anaplastic Glioma

Glioblastoma Multiforme

Intervention(s)

Drug: Isotretinoin

Drug: Temozolomide

Drug: Vorinostat

Procedure: Surgical Resection

Primary Outcome(s)

Maximum tolerated dose (MTD) [Time Frame: Each 4 week period to accomodate 28 day cycles]

Secondary ID(s)

2006-0709

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Merck