Vorinostat, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
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Purpose
This phase I/II trial is studying 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
| Condition | Intervention | Phase |
|---|---|---|
|
Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Cognitive/Functional Effects |
Radiation: 3-dimensional conformal radiation therapy Drug: temozolomide Drug: vorinostat Procedure: cognitive assessment |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma |
- Maximum tolerated dose of vorinostat, defined as the dose at which fewer than one-third of patients experience DLTs, graded according to NCI CTCAE version 3.0 (Phase I) [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
- Overall survival (Phase II) [ Time Frame: Time from study registration to the date of death from any cause, assessed at 15 months ] [ Designated as safety issue: No ]Survival will be estimated using a Kaplan-Meier curve.
- Incidence of adverse events, based on CTC severity grade (Phase I) [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]Safety variables will be summarized by descriptive statistics. AEs that occur will be reported for each 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.
- Time to tumor progression (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
- Incidence of adverse events, as per NCI CTCAE version 3.0 (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]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.
| Estimated Enrollment: | 132 |
| Study Start Date: | July 2009 |
| Estimated Primary Completion Date: | September 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (radiotherapy, vorinostat, temozolomide)
Patients undergo radiotherapy and receive oral vorinostat once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive oral temozolomide once daily on days 1-42. Beginning 4-6 weeks later, patients receive oral vorinostat once daily on days 1-7 and 15-21 and oral temozolomide once daily 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
Undergo radiotherapy
Other Names:
Drug: temozolomide
Given orally
Other Names:
Drug: vorinostat
Given orally
Other Names:
Procedure: cognitive assessment
Ancillary studies
|
Detailed Description:
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose of vorinostat when administered with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma multiforme. (Phase I) II. To determine the efficacy of this regimen, in terms of overall survival, in these patients. (Phase II)
SECONDARY OBJECTIVES:
I. To determine the toxicity of this regimen in these patients. (Phase I) II. To determine progression-free survival of patients treated with this regimen. (Phase II) III. To further evaluate the safety profile of this regimen in these patients. (Phase II) IV. To determine the neurocognitive effects in these patients and correlate the results with outcome endpoints. (Phase II)
TERTIARY OBJECTIVES:
I. To correlate tumor molecular characteristics and expression profile with outcome.
II. To evaluate potential mechanisms of therapy resistance in tumor samples obtained at the time of tumor progression.
OUTLINE: This is a multicenter, phase I, dose-escalation study of vorinostat followed by a phase II study.
Patients undergo radiotherapy and receive oral vorinostat once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive oral temozolomide once daily on days 1-42. Beginning 4-6 weeks later, patients receive oral vorinostat once daily on days 1-7 and 15-21 and oral temozolomide once daily 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.
Patients enrolled in phase II and those who are treated at the maximum tolerated dose in phase I submit tumor tissue samples for correlative laboratory studies. Studies include assessment of histone acetylation status by immunohistochemistry; gene expression profiling; and assessment of MGMT methylation status by polymerase chain reaction. Patients enrolled in phase II and those who are treated at the maximum tolerated dose in phase I complete a neurocognitive assessment prior to, during, and after completion of study therapy. The assessment includes the Hopkins Verbal Learning Test (HVLT-R) (Revised), the Controlled Oral Word Association test from the Multilingual Aphasia Examination (COWA), the Trail Making Test A: Visual scanning speed, and the Trail Making Test B: Divided attention.
After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 1 year.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Histologically confirmed glioblastoma multiforme, including gliosarcoma or other grade 4 astrocytoma variant (e.g., giant cell glioblastoma)
- Bidimensionally measurable or evaluable disease by gadolinium MRI or contrast-enhanced CT scan
- Has undergone surgery for the brain tumor within the past 2-5 weeks
- Karnofsky performance status (PS) 60-100% or ECOG PS 0-2
- Life expectancy ≥ 12 weeks
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- WBC ≥ 3,000/mm^3
- Hemoglobin ≥ 10.0 g/dL (transfusion allowed)
- Total bilirubin ≤ 2.0 times upper normal limit (ULN)
- AST ≤ 2.0 times ULN
- Creatinine ≤ 1.5 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 12 weeks after completion of study treatment
- No known hypersensitivity to any of the components of vorinostat or other drugs used in the study
- No other active malignancy within the past 3 years, except nonmelanotic skin cancer or carcinoma in situ of the cervix
- No uncontrolled infection
- Known HIV positivity allowed provided there is no clinical evidence of an immunocompromised state
- No co-morbid systemic illness or other concurrent severe illness that, in the opinion of the investigator, would preclude study participation
- No concurrent uncontrolled illness (e.g., ongoing or active infection or psychiatric illness/social situation) that would preclude study compliance
- No myocardial infarction or unstable angina within the past 6 months
- No congestive heart failure requiring ongoing maintenance therapy
- No life-threatening ventricular arrhythmias
- No congenital long QT syndrome
- No prolonged QTc interval (i.e., QTc > 450 msec)
- Able to take oral medications
- Willing to provide mandatory tissue samples for research studies (for patients treated at the maximum tolerated dose)
- Willing and able to complete neurocognitive assessments (patients enrolled in phase II and those who are treated at the maximum tolerated dose in phase I)
- No concurrent treatment for another malignancy other than hormonal therapy
- No prior cytotoxic, non-cytotoxic, or experimental drug therapy for the brain tumor
- No prior cranial radiotherapy
- No prior Gliadel wafers
- More than 7 days since prior and no concurrent Category I drugs that have a risk of causing torsades de pointes (e.g., 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, or lidoflazine)
- More than 2 weeks since prior and no concurrent valproic acid or other histone deacetylase inhibitors
- Concurrent corticosteroids allowed provided patient is on a fixed or decreasing dose for ≥ 5 days prior to study enrollment
- No other concurrent investigational agents for the brain tumor
- No other concurrent cytotoxic or non-cytotoxic drug therapy for the brain tumor
- No concurrent stereotactic radiosurgery or brachytherapy
- No concurrent antiretroviral therapy for HIV-positive patients
Contacts and Locations| United States, Hawaii | |
| Oncare Hawaii Inc - Kapiolani Medical Center at Pali Momi | |
| Aiea, Hawaii, United States, 96701 | |
| Kapiolani Medical Center at Pali Momi | |
| Aiea, Hawaii, United States, 96701 | |
| Kuakini Medical Center | |
| Honolulu, Hawaii, United States, 96817 | |
| Kapiolani Medical Center for Women and Children | |
| Honolulu, Hawaii, United States, 96826 | |
| Queen's Medical Center | |
| Honolulu, Hawaii, United States, 96813 | |
| Straub Clinic and Hospital | |
| Honolulu, Hawaii, United States, 96813 | |
| Oncare Hawaii Inc-POB II | |
| Honolulu, Hawaii, United States, 96813 | |
| Oncare Hawaii Inc-Kuakini | |
| Honolulu, Hawaii, United States, 96817 | |
| Hawaii Medical Center East | |
| Honolulu, Hawaii, United States, 96817 | |
| Castle Medical Center | |
| Kailua, Hawaii, United States, 96734 | |
| Wilcox Memorial Hospital and Kauai Medical Clinic | |
| Lihue, Hawaii, United States, 96766-1099 | |
| United States, Illinois | |
| Resurrection Healthcare | |
| Chicago, Illinois, United States, 60631 | |
| United States, Massachusetts | |
| Dana-Farber Cancer Institute | |
| Boston, Massachusetts, United States, 02115 | |
| United States, Michigan | |
| Henry Ford Hospital | |
| Detroit, Michigan, United States, 48202 | |
| Munson Medical Center | |
| Traverse City, Michigan, United States, 49684 | |
| United States, Minnesota | |
| Merit Care Clinic Bemidji | |
| Bemidji, Minnesota, United States, 56601 | |
| Rice Memorial Hospital | |
| Willmar, Minnesota, United States, 56201 | |
| United States, North Dakota | |
| Meritcare Hospital | |
| Fargo, North Dakota, United States, 58122 | |
| MeritCare Medical Group | |
| Fargo, North Dakota, United States, 58122 | |
| United States, Pennsylvania | |
| University of Pittsburgh | |
| Pittsburgh, Pennsylvania, United States, 15213 | |
| United States, South Dakota | |
| Sanford University of South Dakota Medical Center | |
| Sioux Falls, South Dakota, United States, 57117-5134 | |
| Principal Investigator: | Evanthia Galanis | North Central Cancer Treatment Group |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00731731 History of Changes |
| Other Study ID Numbers: | NCI-2009-00672, N0874, U10CA025224, CDR0000609743 |
| Study First Received: | August 8, 2008 |
| Last Updated: | January 14, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Glioblastoma Gliosarcoma Astrocytoma Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue |
Temozolomide Dacarbazine Vorinostat Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antineoplastic Agents Therapeutic Uses Histone Deacetylase Inhibitors Enzyme Inhibitors |
ClinicalTrials.gov processed this record on May 19, 2013