Dose Optimization Of Mk-8628 (Otx015), A Small Molecule Inhibitor Of Bromodomain And Extra-Terminal (Bet) Proteins, In Patients (Pts) With Recurrent Glioblastoma (Gb)

e14123Background: Bromodomains (BRD) bind to acetylated lysine residues on histone tails and are directly involved in remodeling chromatin and regulating transcription, thus representing a potentially important anticancer target. MK-8628 is a synthetic small molecule targeting BRD2, 3 and 4 of the tandem-BRD-containing family of transcriptional regulators, the BET proteins. It has shown cytotoxic activity in in vitro GB models. We conducted a phase IIa trial with dose optimization to determine the MTD, safety and clinical activity of MK-8628 in pts with a first GB recurrence. Methods: In the first step, a traditional 3+3 dose escalation schema was used. At first recurrence of GB, pts were treated with MK-8628 administered orally at 3 dose levels (DL1: 80 mg QD, DL2: 120 mg QD, DL3: 160 mg QD) with 4-week cycles. PK analyses were performed on day 1 of cycle 1 and residual samples were drawn on day 28. MRI assessment was performed every 2 cycles (RANO). Results: Twelve pts were included between December 201...