Phase 1 first-in-human trial of MTB-9655, the first oral inhibitor of ACSS2, in patients with advanced solid tumors
Abstract
e20609 Background: ACSS2 catalyzes the ligation of acetate with Co-enzyme A to generate Acetyl-CoA. Selection to an acetate dependent state has been demonstrated and is associated with the induction of ACSS2 gene expression in certain human cancers. The ACSS2 gene is amplified in human breast cancers, and its expression is up-regulated in human colorectal, breast, ovarian and lung cancers. MTB-9655 is a potent (IC50 = 0.15nM in biochemical, and EC50 = 3nM in cellular assays) oral inhibitor of ACSS2 and induces anti-tumor effects in xenograft mouse models of human colorectal, breast and lung cancers that express high levels of ACSS2. Methods: Using a combined accelerated (single patient for the first two dose levels) and 3+3 dose escalation and dose expansion design, MTB-9655 was administered on a once daily (QD) schedule in 21-day cycles in a Phase 1 trial to assess safety, tolerability, PK and potential anti-tumor activity in patients with advanced solid tumors. Re-staging was performed every 2 cycles. Results: To-date, 10 subjects have received MTB-9655 at doses up to 225mg. MTB-9655 was absorbed rapidly post oral dosing with a half-life of 6-12 hours. Dose proportional exposure was observed on day 1 of the first dosing cycle, and steady-state exposure was noted between day 8 and day 1 of the second dosing cycle. Dose limiting toxicities or Grade 3 treatment-related adverse events (AEs) have not been observed up to the 225mg dose level. The most common AE was nausea (29%).…
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