NCCTG Status Report for Study N May 2010

Transcription

1 Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic cid SH), Temozolomide, and Radiation Therapy in Patients with Newly Diagnosed Glioblastoma Purpose of - Phase I Study: 1) 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). 2) To define the safety of vorinostat with RT and TMZ in this population. - Phase II - Primary 1) 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 gliosarcoma as measured by overall survival. - Secondary 1) To determine progression-free survival in newly diagnosed GBM and gliosarcoma patients treated with the study regimen. 2) To further evaluate the safety profile of vorinostat in combination with RT and TMZ in this patient population. 3) Determine the neurocognitive effects in patients treated on this protocol and correlate these results with outcome endpoints. - Exploratory 1) To explore the extent to which the tumors' molecular charateristics and expression profile correlate with outcome. Study Chairs: Evanthia Galanis M.D. QC Specialist: Butch K. Kvittem CCRP Statistician: Wenting Wu Ph.D. Nurse Resource: Beverly L Kowbel RN, BSN Status: 07/10/2009 ctivated Projected Number of Patients: 132 Excluded: None Final ccrual: N Stratification None Schema: Pre-registration Registration RT + SH + TMZ --> SH + TMZ Treating Schedule: rm gent Dose Route Days Freq Phase I NCCTG Committee N Page 1 of 5

2 rm gent Dose Route Days Freq - RT 60Gy Start day 1 (5 days out of 7) - SH ssigned by NCCTG Registration Office Weekly (5 days out of 7) x 6 (total of 30 treatments) Oral 1 through 5 Weekly x 6* - TMZ 75 mg/m2 Oral 1 through 42 Daily (including weekends and holidays)** 4-6 WEEK REST PERIOD - SH 500 mg Oral 1 through 7; 15 Every 28 days x 6 cycles*** through 21 - TMZ 150 mg/m2 Oral 1 through 5 Every 28 days x 6 cycles*** Phase II - RT 60Gy Start day 1 (5 days Weekly x 6 out of 7) - SH MTD determined Oral 1 through 5 Weekly X 6* from Phase I - TMZ 75 mg/m2 Oral 1 through 42 Daily (inlcuding weekends and holidays)** 4-6 WEEK REST PERIOD - SH 500 mg Oral 1 through 7; 15 Every 28 days x 6 cycles*** through 21 - TMZ 150 mg/m2 Oral 1 through 5 Every 28 days x 6 cycles*** *If the course of RT extends beyond 42 days because of delays, the course of vorinostat may be extended to a maximum of 47 days (i.e., 5 additional doses of vorinostat). If RT is still not completed, additional vorinostat beyond 47 days is not permitted. **If the course of RT extends beyond 42 days because of delays, the course of temozolomide may be extended to a maximum of 49 days. If RT is still not completed, additional temozolomide beyond 49 days is not permitted. ***May extend to 12 cycles if acceptable tolerance and no evidence of progression. NCCTG Committee N Page 2 of 5

3 Study Design: This clinical trial will enroll patients with newly diagnosed glioblastoma and gliosarcoma. It is comprised of 2 component studies: PHSE I is a phase I study designed to determine the maximum tolerated dose (MTD) of vorinostat (SH) in combination with concomitant radiation therapy (RT) and temozolomide (TMZ) followed by adjuvant SH and TMZ. PHSE II is a phase II trial evaluating the efficacy of SH in combination with RT and TMZ followed by SH in combination with TMZ in patients with newly diagnosed GBM and gliosarcomas as measured by overall survival. The Phase I portion of the trial will use a cohortof-3 Phase I design. Three patients will be treated at each dose level, and can be enrolled simultaneously. If one DLT is encountered, an additional 3 patients will be added to that dose level. If at any point two DLTs are encountered within a given dose level, then the MTD has been exceeded and three more patients are treated at the next lower dose (if only three patients were previously treated at that prior dose). Once the MTD has been established, an additional 6 patients will be treated at this dose (for a total of up to 12 patients). The Phase II portion of the trial will use a single-arm phase II design with the primary efficacy endpoint as survival status at 15 months (OS15). ccrual: This study was activated on 8/04/2009. s of 3/23/2010, 6 patients have been enrolled at Mayo (3 at MCR and 3 at MCF). Patient Characteristics: vailable baseline information is summarized in the Baseline Characteristics Table below. The 6 patients are 3 (50%) male and 3 (50%) female ranging in age from 44 to 73 (median age=58.5). No one is classified as a minority. vailable Information: s of 3/23/2010, 6 patients are alive with 4 still on-study. No patients have been declared ineligible. No patients have been replaced. ll 6 patients have response data. dverse Events: With adverse event information available for all 6 patients, five grade 4 events have been seen in 3 patients (1 hyperglycemia, 1 neutrophil count decreased, 1 thrombocytopenia, 1 leukopenia, 1 thrombosis), of which 3 of the 5 were considered to be treatment related. No grade 5 events were seen. No DLTs have been seen at dose level 0. Three DLTs have been seen (one grade 4 thrombocytopenia, anemia, neutrophil count decreased and grade 3 fatigue, one grade 3 wound dehiscence, and one grade 3 fatigue) at dose level 1. Study Status: s of 3/23/2010, the study is open to accrual for an additional 3 patients at dose level 0. ccrual Table: NCCTG Committee N Page 3 of 5

4 Randomizing Membership Total Entered Past 6 Months Past 12 Months Florida Mayo Total Membership ccrual Baseline Characteristics Table: Corticosteroid Therapy Characteristics Missing 3 Yes 3 Gender Female 3 Male 3 Group PhI (dose escalation) 6 History Brain Missing 3 No 3 Race White 6 rm Grade 4/5 and Most Frequent dverse Event Table: Evaluable Patients: 6 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Hematology LEUKOPENI LYMPHOPENI THROMBOCYTOPENI NEMI NEUTROPHIL COUNT DECRESED llergy/immunology LLERGIC RHINITIS Cardiovascular THROMBOSIS Constitutional Symptoms FTIGUE Dermatology/Skin WOUND DEHISCENCE Gastrointestinal NOREXI NUSE DEHYDRTION CONSTIPTION NCCTG Committee N Page 4 of 5

5 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % DIRRHE TSTE VOMITING Hepatic SGOT (ST) SGPT (LT) HYPOLBUMINEMI Metabolic/Laboratory HYPOCLCEMI HYPONTREMI HYPERKLEMI HYPOKLEMI HYPOPHOSPHTEMI HYPERGLYCEMI METBOLIC/LB Renal /Genitourinary CRETININE INCRESED Maximum Grade dverse Event NCCTG Committee N Page 5 of 5