Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

e14048 Background: ACT001 is an orally-available parthenolide derivative which inhibits NF-κB signaling, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). We performed a first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were ≥ 18 yrs and ECOG PS 0-1, with satisfactory hematologic, renal and hepatic function. GBM patients additionally had progressive disease (PD) despite initial radiation and temozolomide, measurable tumor, no radiation in the prior 3 months and no previous treatment with anti-VEGF drugs. ACT001 was given orally BID until intolerance or PD, and dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 13 patients were enrolled: 10 with GBM, 2 with anaplastic glioma and 1 with pleural mesothelioma. Median age was 53 yrs (range, 34-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID and 600 mg BID. Study treatment was well tolerated and no dose-limiting toxicities have occurred. Of 12 evaluable patients, best responses were a partial response in 1 GBM patient (ongoing after 10+ months of treatment), stable disease in 3 patients and PD in 8 patients. ACT001 plasma half life was 3-4 hours and no accumulation was observed after multiple dosing. At ≥ 400 mg BID, drug concentrations expected to have biological activity were reached. Conclusions: At well-tolerated doses, ACT001 showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in a subset of patients. Clinical trial information: ACTRN12616000228482.