A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Advanced Acute Leukemia

Rationale: BET-bromodomain (BRD) proteins play a major role in the epigenetic regulation of gene transcription, notably of genes with superenhancer promoter regions including many oncogenes, such as MYC. OTX015 is a specific BRD 2, 3 and 4 inhibitor that blocks oncogene transcription, and triggers growth inhibition and apoptosis in acute leukemia cell lines and patient cells in vitro (Braun et al. ASH Annual Meeting 2013). Based on these findings, a Phase 1 study of OTX015 was designed for patients with advanced acute leukemia.

Patients & Methods: Patients with various unselected relapsed/refractory leukemia subtypes for which no standard therapy options were available were enrolled in this ongoing Phase 1 study. Patients aged < 60 years had to have failed at least two lines of therapy and those aged >60 years at least one line. At least 5% bone marrow leukemic blasts were required at study entry. OTX015 was given orally, daily for 14 days of 21-day cycles (cy). The dose was escalated from 10 to 160 mg daily (QD) according to a standard 3+3 dose-escalation design, to determine the maximum tolerated dose (MTD) or biologically optimal dose. A BID schedule was tested at dose level (DL) 4 (40 mg x 2) and a continuous schedule at 120 mg. Pharmacokinetics was studied on day 1 and residual concentrations were measured on days 2, 8 and 15. Responses were assessed on blood and bone marrow aspirations at baseline, days 8, 22 and 43. Blasts at baseline and day 8 were stored for pharmacodynamic biomarker evaluation. Cytogenetic and molecular markers were collected based on center practice.

Results: From January 2013 to June 2014, 36 patients were treated over 6 dose levels: 33 with acute myeloid leukemia (AML), 2 with acute lymphoblastic leukemia and 1 with refractory anemia with excess blasts. Median age was 70 years (range 19-85), 20 patients were male, 29 patients had ECOG 0-1, and 16 AML patients had normal karyotype. Patients had a median of 2 prior therapy lines (range 1-4). The median number of OTX015 cycles administered was 2 (range 1-14+), including 9 patients with >3 cycles. Among the 28 patients evaluable for dose limiting toxicity (DLT), no DLTs were observed through DL5 (120 mg QD). The MTD was exceeded at DL6 (160 mg QD) with one patient experiencing grade 3 diarrhea and another grade 3 fatigue and anorexia. The main toxicities were non-cumulative grade 1-2 gastrointestinal events (6 patients diarrhea, 3 dysgueusia, 3 abdominal pain, 3 nausea, 1 anorexia), hyperglycemia (3 patients), coagulation factor VII decrease (6 patients) and direct bilirubin increase (3 patients) (two latter AEs asymptomatic). These toxicities were mainly observed at QD doses above 80 mg and with 40 mg BID. Dose proportional plasma concentrations were observed and trough concentrations > 500 nM (in vitro active concentrations) were regularly observed from 80 mg/day. Clinically relevant activity was reported in 5 AML patients treated at 10, 40 and 80 mg, including one sustained CR from cy 4 to cy 12 (40 mg QD) and one CR with incomplete platelet recovery (CRp) from cy 2 to cy 5 (80 mg QD). Two patients (10 mg QD, 40 mg QD) had partial blast clearance (disappearance of peripheral blasts and decrease >50% in bone marrow blast percentage) and the remaining patient (40 mg BID) had gum hypertrophy resolution. Four of these 5 patients had secondary or therapy-related AML, 4 had normal karyotype and 2 had an NPM1 gene mutation.

Conclusions: OTX015 single agent exhibits antileukemic activity over a wide range of DLs and plasma concentrations in patients with advanced AML. MTD is exceeded at 160 mg QD. The safe recommended dose and schedule is close to being identified. Central extensive molecular marker analysis is being performed and will be prospectively implemented in an expansion cohort. Updated data will be presented and will include correlations between regimen, pharmacokinetics, clinical activity and molecular profile.