Phase I / II Adaptive Randomized Trial of Vorinostat, Erlotinib and Temozolomide in Adults with Recurrent Glioblastoma Multiforme
The goal of this clinical research study is to find the highest tolerable dose of the combination vorinostat and erlotinib, with or without temozolomide, that can be given to patients with malignant gliomas. The safety of these drug combinations will also be studied.
Disease Group: Brain,CNS
Treatment Agent: Erlotinib,Temozolomide,Vorinostat
Treatment Location: Only at MD Anderson
Estimatated Length of Stay in Houston: N/A
Sponsor: Merck and Co., Inc
Return Visit: every 4 weeks
Home Care: Patients will take vorinostst, temozolomide and erlotinib at home
1. Phase I To determine the maximum tolerated dose (MTD) of vorinostat + erlotinib versus vorinostat + erlotinib + temozolomide in adult patients with recurrent glioblastoma multiforme (GBM) and anaplastic gliomas. 2. Phase II Primary To determine the efficacy of vorinostat + erlotinib versus vorinostat + erlotinib + temozolomide in patients with recurrent glioblastoma multiforme as progession free survival using a two arm adaptive randomization phase II trial design. Secondary To determine the radiological response, progression free survival (PFS) at 6 months , overall survival and unexpected toxicity in the two treatment arms. To obtain exploratory data regarding histone 3 and 4 acetylation, treatment related changes in the epidermal growth factor receptor (EGFR) pathway proteins, and changes in e-cadherin and vimentin expression (mRNA /protein) levels in tumor tissue and peripheral monocytes in a subset of surgical patients.
IRB Review and Approval Date: 06/21/2011
Recruitment Status: Not Accepting
Projected Accrual: N/A
1) Patients with histologically proven glioblastoma multiforme,
gliosarcoma or anaplastic glioma will be eligible for the Phase I
component. Anaplastic gliomas include anaplastic astrocytoma (AA),
anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), or
malignant glioma 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. 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. Patients should have completed radiation therapy at least 3 months prior to entry into the study. 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.
3) (2. continued) Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have reasonable confirmation of true progressive disease rather than radiation necrosis as determined by the treating physician and neuro-radiologist; for example, through MRI, MR spectroscopy, or PET scan of the brain.
4) For the Phase I component, any number of prior relapses is allowed, provided the patient fulfills all other eligibility criteria particularly that of the functional status. For the phase II component, patients may have had up to 2 prior relapses
5) All patients must sign an informed consent indicating their awareness of the investigational nature of this study in keeping with the policies of this hospital.
6) The baseline on-study MRI should be performed within 14 days (+/- 3 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 having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: a) They have recovered from the effects of surgery. b) Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study. c) 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 (KPS) equal or greater than 60
10) Patients must have recovered from the toxic effects of prior therapy to grade 1 non hematological or </= grade 2 hematological toxicity (except deep vein thrombosis): 4 weeks from prior cytotoxic therapy or bevacizumab 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).
11) (10. continued) Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study (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>/= 1,500/mm^3 and platelet count of >/= 100,000/mm^3), adequate liver function (SGPT </= 3 times normal and alkaline phosphatase </= 2 times normal, bilirubin </= 1.5 mg/dl), adequate renal function (BUN and creatinine </= 1.5 times institutional normal) prior to registration.
13) Women of childbearing potential on treatment must not be pregnant, must not be breast-feeding and must practice adequate contraception. 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.
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 are ineligible.
2) Patients must not have: a) active infection b) disease that will obscure toxicity or dangerously alter drug metabolism, especially liver disease including cirrhosis or hepatic dysfunction c) serious intercurrent medical illness
3) Patients who are currently on active treatment for AIDS or hepatitis will be excluded due to the potential for adverse interaction with ongoing treatment agents and for unknown toxicity.
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. A 5 day wash out period is required.
5) Prior treatment with EGFR inhibitors or temozolomide on a standard day 1-5 dosing and low dose daily dosing as part of chemoradiation therapy is allowed 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 EGFR inhibitors and temozolomide. However, prior treatment with dose dense regimens of temozolomide (7 days on/ 7 days off, 21 days/28 days or continuous low dose daily dosing not with chemoradiation) and HDAC inhibitors other than valproic acid (such as depsipeptide, LBH-589 or vorinostat) are not permitted.
6) Patients with a known allergy to any component of vorinostat, or a known allergy to Temozolomide or erlotinib will be excluded.
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.
8) This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender.
9) No exclusion to this study will be based on race. The malignant glioma patient population treated at MDACC over the past year is as follows: American Indian or Alaskan Native - 0; Asian or Pacific Islander - <2%; Black, not of Hispanic Origin - 3%; Hispanic - 6%; White, not of Hispanic Origin - 88%; Other or Unknown - 2%; Total-100%
Information and next steps
Phase I/Phase II
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