Actr-40. Phase 2 Safety and Efficacy of Ar-67 (7-T-Butyldimethylsiltyl-10-Hydroxycamptothecin) in Patients With Recurrent Glioblastoma Multiforme (Gbm) or Gliosarcoma

Abstract

BACKGROUND AR-67 (formerly DB-67) is a novel 3rd generation camptothecin with improved safety and lipophilicity than current drugs in this class. Safety and efficacy of AR-67 were evaluated in a Phase 2 study in recurrent GBM/gliosarcoma in adult patients. METHODS AR-67 (7.5 mg/m2) was administered once daily by IV infusion for 5 consecutive days on a 21-day cycle. Cohort 1 patients (N=31/46 enrolled) had not received (or had not recently failed) bevacizumab. Cohort 2 patients (N=13/46 enrolled) had failed bevacizumab within 90 days before screening. Cohort assignments for 2/46 patients were undetermined. Tumor response was assessed ≥14d after every second cycle and before every third cycle using MRI. Primary endpoints were 6-month PFS (Cohort 1), and 2-month PFS (Cohort 2). RESULTS 45/46 patients received ≥ one dose of AR-67; one patient (Cohort 1) died prior to dosing. Efficacy: 6/30 (Cohort 1) and 2/13 (Cohort 2) treated patients achieved the primary endpoints of 6- and 2-month PFS, respectively. Across the study, PR was the best overall response in 3/45 treated patients, all in Cohort 1. SD was the best overall disease response in 7/45 treated patients (5 in Cohort 1 and 2 in Cohort2). Safety: AR-67 was well tolerated; 17 patients (38%) exhibited serious adverse events (SAEs) including headache and Grade 4/5 muscular weakness (2.2%). Most TEAEs were mild/moderate in intensity and Grade 1–3 intoxicity. Notably absent was Grade 4 diarrhea, a hallmark of other approved camptothecin chemotherapies. CONCLUSIONS AR-67 was well tolerated and exhibited a safety profile consistent with or better than currently approved camptothecins. 6/30 treated patients in Cohort 1 and 2/13 patients in Cohort 2 achieved the primary endpoints of 6- and 2-month PFS, respectively. PR was the best overall response in 3/45 treated patients and SD was the best overall response in 7/45 patients.

Looking for the Holy Grail—Drug Candidates for Glioblastoma Multiforme Chemotherapy

“…In 2010, a phase 2 clinical trial of AR-67 in adults patients with recurrent GBM or gliosarcoma (NCT1124539) was registered. Kumthekar et al [85] reported that among AR-67-treated recurrent GBM patients, the drug appeared to be tolerated well and exhibited a safety profile consistent with or better than currently approved camptothecins. In patients not treated with Bevacizumab, 6/30 patients achieved the primary endpoint of 6-PFS.…”

“…On the other hand, in patients who failed Bevacizumab treatment, 2/13 of patients achieved a 2-month PFS endpoint. A partial response (PR) was the best overall response in 3/45 treated patients, and stable disease (SD) was the best overall response in 7/45 patients [85].…”