A Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]) in Combination With Temozolomide in Patients With Malignant Gliomas
Overview
- Phase
- Phase 1
- Intervention
- Temozolomide
- Conditions
- Adult Anaplastic Astrocytoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 83
- Locations
- 17
- Primary Endpoint
- MTD of vorinostat with temozolomide defined as the dose at which less than one-third of patients experience dose-limiting toxicity based on the CTC severity grading (Part I)
- Status
- Active, not recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
This phase I trial is studying the side effects and best dose of vorinostat when given together with temozolomide in treating patients with malignant gliomas. Drugs used in chemotherapy, such as vorinostat and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vorinostat may help temozolomide work better by making tumor cells more sensitive to the drug. Giving vorinostat together with temozolomide may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of vorinostat (suberoylanilide hydroxamic acid \[SAHA\]) in combination with temozolomide in patients with malignant gliomas. II. To characterize the safety profile of vorinostat (SAHA) in combination with temozolomide. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetics of vorinostat (SAHA) in combination with temozolomide. II. To determine efficacy of vorinostat (SAHA) in combination with temozolomide as measured by objective response. TERTIARY OBJECTIVES: I. To explore the association of response to treatment to the molecular phenotype of the tumor. II. To assess the effects of vorinostat (SAHA) on histone acetylation status in peripheral mononuclear cells. OUTLINE: This is a 2-part, dose-escalation study of vorinostat. PART I: Patients receive vorinostat orally (PO) once (QD) or twice daily (BID) on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Beginning in course 2, some patients may receive a higher dose of temozolomide. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part 1\*. \[Note: \*Beginning in course 2, all patients receive a higher dose of temozolomide.\] After completion of study treatment, patients are followed up periodically.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with histologically proven intracranial malignant glioma will be eligible for this protocol; malignant gliomas include glioblastoma multiforme (GBM), gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma 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
- •All patients must sign an informed consent indicating that they are aware of the investigational nature of this study; patients must have signed an authorization for the release of their protected health information; patients must be registered with the Adult Brain Tumor Consortium (ABTC) Central Office database prior to treatment with study drug
- •Life expectancy \> 8 weeks
- •Karnofsky performance status of \>= 60
- •White blood cell (WBC) \>= 3,000/mm\^3
- •Absolute neutrophil count (ANC) \>= 1,500/mm\^3
- •Platelet count \>= 100,000/mm\^3
- •Hemoglobin \>= 10 g/dL; eligibility level for hemoglobin may be reached by transfusion
- •Serum glutamic oxaloacetic transaminase (SGOT) \< 2 times upper limit of normal (ULN)
- •Bilirubin \< 2 times ULN
Exclusion Criteria
- •Patients who have progressed on temozolomide are ineligible
- •Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy; patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible
- •Patients must not have active infection or serious intercurrent medical illness
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with vorinostat (SAHA); potential risks may also apply to temozolomide
- •Patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism
- •Patients who are known to be human immunodeficiency virus (HIV) positive and are receiving combination antiretroviral therapy are ineligible
- •Patients may not be receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other agents used in study
- •Patients should not have taken valproic acid (another histone deacetylase inhibitor) for at least 2 weeks prior to enrollment
Arms & Interventions
Treatment (vorinostat, temozolomide)
PART I: Patients receive vorinostat PO QD or BID on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part I\*. \[Note: Beginning in course 2, some patients may receive a higher dose of temozolomide.\]
Intervention: Temozolomide
Treatment (vorinostat, temozolomide)
PART I: Patients receive vorinostat PO QD or BID on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part I\*. \[Note: Beginning in course 2, some patients may receive a higher dose of temozolomide.\]
Intervention: Laboratory Biomarker Analysis
Treatment (vorinostat, temozolomide)
PART I: Patients receive vorinostat PO QD or BID on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part I\*. \[Note: Beginning in course 2, some patients may receive a higher dose of temozolomide.\]
Intervention: Pharmacological Study
Treatment (vorinostat, temozolomide)
PART I: Patients receive vorinostat PO QD or BID on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part I\*. \[Note: Beginning in course 2, some patients may receive a higher dose of temozolomide.\]
Intervention: Vorinostat
Outcomes
Primary Outcomes
MTD of vorinostat with temozolomide defined as the dose at which less than one-third of patients experience dose-limiting toxicity based on the CTC severity grading (Part I)
Time Frame: 28 days
For both parts of the study, treatment administration will be described for all cycles. Doses administered, dose modifications/delays, and duration of therapy will be evaluated. Safety variables summarized by descriptive statistics. Adverse events that occur will be reported for each dose level and described in terms of incidence and severity. Laboratory data will be presented by dose level at each observation time. Values outside of normal limits will be identified and their frequency calculated. Distribution by CTC severity grade (when applicable) and clinical relevance will be given.
Secondary Outcomes
- Efficacy in terms of anti-tumor activity based on clinical, radiographic, and biologic assessments (Part II)(Up to 4 years)
- Plasma pharmacokinetic parameters of vorinostat(Baseline, 1, 2, 3, 4, 6, 8, and 24 hours post-dose day 1 of course 1)