Vorinostat, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studies the side effects and best dose of vorinostat when given together with temozolomide and radiation therapy and to see how well they work in treating patients with newly diagnosed glioblastoma multiforme. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with temozolomide and radiation therapy may kill more tumor cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of vorinostat in patients with newly diagnosed glioblastoma multiforme (GBM) and gliosarcomas, who are also receiving concomitant radiation therapy (RT) and temozolomide (TMZ). (Phase I) II. To define the safety of vorinostat with RT and TMZ in this population. (Phase II) III. To determine the efficacy of vorinostat in combination with RT and TMZ followed by vorinostat in combination with TMZ in patients with newly-diagnosed GBM and gliosarcomas as measured by overall survival at 15 months (OS15). (Phase II) SECONDARY OBJECTIVES: I. To determine progression-free survival in newly diagnosed GBM and gliosarcoma patients treated with the study regimen. (Phase II) II. To further evaluate the safety profile of vorinostat in combination with RT and TMZ in this patient population. (Phase II) III. Determine the neurocognitive effects in patients treated on this protocol and correlate these results with outcome endpoints. (Phase II) TERTIARY OBJECTIVES: I. To explore the extent to which the tumor's molecular characteristics and expression profile correlate with outcome. II. Evaluate potential mechanisms of therapy resistance in tumor samples obtained at the time of tumor progression. OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study. Patients undergo radiotherapy and receive vorinostat orally (PO) once daily (QD) on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive temozolomide PO QD on days 1-42. Beginning 4-6 weeks later, patients receive vorinostat PO QD on days 1-7 and 15-21 and temozolomide PO QD on days 1-5. Treatment with vorinostat and temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 2 months for 1 year, every 3 months for 1 year and then every 6 months for 3 years.

Official Title
-----------------
Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma

Conditions
-----------------
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Intervention / Treatment
-----------------
* Radiation: 3-Dimensional Conformal Radiation Therapy
* Procedure: Cognitive Assessment
* Other: Laboratory Biomarker Analysis
* Drug: Temozolomide
* Drug: Vorinostat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: PRE-REGISTRATION: Central pathology review submission; this review is mandatory prior to registration to confirm eligibility; it should be initiated as soon after surgery as possible Treatment should begin >= 2 weeks and =< 5 weeks following surgery REGISTRATION: Histologically confirmed glioblastoma multiforme as determined by pre-registration central pathology review; Note: gliosarcomas and other grade 4 astrocytoma variants (e.g., giant cell) are eligible Measurable or evaluable disease by gadolinium magnetic resonance imaging (MRI) or contrast computed tomography (CT) scan; Note: patients who have had a gross total resection (GTR) are eligible on the basis of evaluable disease Must begin partial brain radiotherapy on the same day that vorinostat and temozolomide begin Karnofsky performance status of >= 60 Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 White blood cell (WBC) >= 3,000/mm^3 Hemoglobin >= 10.0 g/dL; Note: this level may be reached by transfusion Total bilirubin =< 2.0 x institutional upper limit of normal (ULN) Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.0 x ULN Creatinine =< 1.5 mg/dL Life expectancy >= 12 weeks Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only For Phase I established MTD and Phase II patients only: Willing and able to complete neurocognitive testing Ability to provide informed written consent Willing to return to Alliance or Adult Brain Tumor Consortium (ABTC) enrolling institution for follow-up Phase I established MTD patients and Phase II patients: Willing to provide mandatory tissue samples (slides or blocks) for research purposes Willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while being treated with vorinostat and temozolomide Exclusion Criteria: Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception throughout the duration of the study and for 12 weeks after treatment has ended Prior cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy for brain tumors Prior cranial RT Prior Gliadel wafers Known hypersensitivity to any of the components of vorinostat or other agents used in study Valproic acid, another histone deacetylase inhibitor, =< 2 weeks prior to registration and during treatment Other active malignancy =< 3 years prior to registration; Exception: non-melanotic skin cancer or carcinoma in situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer Uncontrolled infection Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; Note: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial Co-morbid systemic illness or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with proper assessment of safety and adverse events of the prescribed regimens Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements History of myocardial infarction or unstable angina =< 6 months prior to registration or congestive heart failure (CHF) requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias New York Heart Association (NYHA) >= Class II Congestive Heart Failure Inability to take oral medications Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm Congenital long QT syndrome Prolonged corrected (QTc) interval (> 450 msec) Any of the following Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes =< 7 days prior to registration Quinidine, procainamide, disopyramide Amiodarone, sotalol, ibutilide, dofetilide Erythromycin, clarithromycin Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (radiation therapy, vorinostat, temozolomide)<br>Patients undergo radiotherapy and receive vorinostat PO QD on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive temozolomide PO QD on days 1-42. Beginning 4-6 weeks later, patients receive vorinostat PO QD on days 1-7 and 15-21 and temozolomide PO QD on days 1-5. Treatment with vorinostat and temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation, 3D Conformal;Procedure: Cognitive Assessment<br>* Ancillary studies<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;Drug: Vorinostat<br>* Given PO<br>* Other names: Zolinza;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Vorinostat, Defined as the Dose at Which Fewer Than One-third of Patients Experience DLTs, Graded According to NCI CTCAE (Common Toxicity Criteria for Adverse Effects) Version 3.0 (Phase I) | The Maximum Tolerated Dose (MTD) will be based on the assessment of Dose Limiting Toxicity (DLT) during the first 10 weeks of treatment only, and will be defined as the dose at which fewer than one-third of patients experience a DLT to vorinostat. The MTD is the dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. > > DLT will be defined as any of the following events occurring during treatment with vorinostat and temozolomide and attributable to one or both study drugs: Grade 3 or 4 thrombocytopenia, grade 4 anemia or grade 4 neutropenia lasting > 7 days Any non-hematologic grade 3 or greater adverse event, excluding alopecia and venous thromboembolism Grade 4 radiation-induced skin changes Failure to recover from toxicities to be eligible for re-treatment with vorinostat and temozolomide ≤ 14 days of the last dose of the two drugs | 10 weeks | 
| Overall Survival at 15 Months (Phase II) | The primary endpoint will be survival status at 15 months (OS15). In addition, survival will be estimated using a Kaplan-Meier curve. For this analysis, patients who are still alive at the time of analysis have survival time censored at the last contact date. | Time from study registration to the date of death from any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events, Based on CTC (Common Toxicity Criteria) Severity Grade | Safety variables will be summarized by descriptive statistics. Adverse Events (AEs) that occur will be reported for each phase and dose level and described in terms of incidence and severity. Parameters will be described based on the CTC severity grading. Distribution by CTC severity grade and clinical relevance will be given. | Up to 5 years | 
| Time to Tumor Progression (Phase II) | Progression free survival time will be defined from date of registration to date of progression or death. | Up to 5 years | 
| Incidence of Adverse Events, as Per NCI CTCAE Version 3.0 (Phase II) | The maximum grade for each type of treatment-related adverse event will be recorded for each patient, and frequency tables for each arm will be reviewed to determine patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. | Up to 5 years |