Phase I / II Adaptive Randomized Trial of Vorinostat, Isotretinoin and Temozolomide in Adults with Recurrent Glioblastoma Multiforme
The goal of this clinical research study is to find the highest safe dose of vorinostat (SAHA) when given with Accutane (isotretinoin) and temozolomide to patients with malignant gliomas. The safety and effectiveness of this drug combination will also be studied.
Disease Group: Brain
Treatment Agent: Isotretinoin
Treatment Location: Only at MD Anderson
Estimatated Length of Stay in Houston: None
Return Visit: Every 4 weeks for the first 2 cycles, then every 8 weeks.
Home Care: Vorinostat, temozolomide and isotretinoin are oral drugs that may be taken at ;home.
Phase I 1. To determine the maximum tolerated dose (MTD) of vorinostat/isotretinoin (cRA), temozolomide (TMZ)/cRA and vorinostat/cRA/TMZ combinations in adult patients with recurrent glioblastoma multiforme (GBM) and anaplastic gliomas. Phase II Primary objective 1. To determine the efficacy of vorinostat/cRA versus TMZ/cRA versus vorinostat/cRA/TMZ in patients with recurrent GBM as determined by Progression Free Survival (PFS) using an adaptive randomization phase II trial design. Secondary objectives 2. To determine the radiological response, progression free survival at 6 months, overall survival and unexpected toxicity in the three treatment arms. 3. To obtain exploratory data regarding histone 3 and 4 acetylation and p21 levels in tumor tissue and peripheral monocytes in a subset of surgical patients and in non-surgical patients with available tissue from previous surgical procedures. 4. To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool.
IRB Review and Approval Date: 01/05/2007
Recruitment Status: Not Accepting
Projected Accrual: N/A
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 .
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.