Abstract A093: Phase 1/2 study of INCB054329, a bromodomain and extraterminal (BET) protein inhibitor, in patients (pts) with advanced malignancies
Authors: Falchook Gerald , Talpaz Moshe , Mita Monica , Szmulewitz Russ , Piha-Paul Sarina , Harb Wael , Morgensztern Daniel , Kaplan Jason , Munster Pamela , Cornell Robert F. , Zheng Fred , Yeleswaram Swamy , Zhou Gongfu , Cassaday Ryan 
Published: August 2018

Abstract
Introduction: BET proteins are key epigenetic regulators of transcription whose inhibition may suppress expression of genes that promote oncogenic pathways. INCB054329, a potent small-molecule inhibitor of BET proteins, inhibited growth of model cell lines derived from solid and hematologic tumors in vitro and in vivo. We report safety, pharmacokinetics (PK), pharmacodynamics (Pd), and efficacy from a phase 1/2 study of INCB054329 in pts with advanced malignancies (NCT02431260). Methods: Eligible adults with relapsed and/or refractory advanced malignancies, ≥1 prior therapy, and ECOG performance status ≤1 received oral INCB054329 in 21-d cycles until withdrawal criteria were met. Dose escalation followed a 3+3 design; PK and Pd were assessed after single and multiple doses. Primary endpoints were safety and tolerability. Results: As of the data cut-off, 54 pts (solid tumors, n=50; lymphoma, n=4) were enrolled at doses ranging from 15-30 mg QD to 15-25 mg BID, including intermittent regimens (5 d on/2 d off, 4 d on/3 d off, 7 d on/7 d off). One dose-limiting toxicity (DLT) occurred at 30 mg QD (grade [G] 3 thrombocytopenia). Although a maximum tolerated dose was not identified, doses &gt;20 mg BID were not tolerated beyond cycle 1. At the nontolerated dose of 22.5 mg BID, G3/4 thrombocytopenia was observed in 2 out of 3 pts in cycle 2. Therefore, 20 mg BID was selected as the starting dose for further exploration in a planned intrapatient dose titration cohort. 41 pts (76%) had treatment-related treatment-emergent adverse events (TEAEs), most frequently nausea (n=17 [31%]), fatigue (n=15 [28%]), thrombocytopenia (n=14 [26%]), and decreased appetite (n=13 [24%]). Treatment-related G ≥3 TEAEs were thrombocytopenia (n=5 [9%]); neutropenia (n=2 [4%]); anemia, elevated aspartate aminotransferase, hyponatremia, and hypophosphatemia (n=1 [2%] each). Three pts (6%) had 4 treatment-related serious TEAEs (thrombocytopenia, n=3; anemia, n=1). Treatment-related TEAEs led to dose interruption in 13 pts (primarily due to thrombocytopenia [8/13]) and dose reduction in 1 pt (neutropenia). Two fatal TEAEs occurred (septic shock, n=1; respiratory failure; n=1), neither treatment-related. Median INCB054329 exposure was 8.5 wk (range, 1.1-69.7). Mean terminal elimination half-life of INCB054329 was short (~2-3 h), and PK was characterized by high interpatient variability. Exposure correlated with thrombocytopenia on an individual basis; PK associated closely with activity in a Pd assay of c-Myc expression. Among pts with solid tumors, 1 pt (2%) with NSCLC had a partial response (61% decrease in target lesion per RECIST v1.1; the pt soon came off study treatment due to a diagnosis of a new malignancy [CRC]), 3 pts (6%) had stable disease (SD) ≥6 mo (12, 9, and 6 mo), 14 pts (28%) had SD &lt;6 mo, and 25 pts (50%) had radiographic progressive disease as best response; 5 pts (10%) had clinical progression, 1 pt (2%) withdrew consent, and 1 pt (2%) was lost to follow-up. Conclusion: Initial data show that INCB054329 has preliminary activity and is reasonably well tolerated. Thrombocytopenia, an on-target effect of BET inhibition, was the only DLT and was associated with exposure. Updated data in all enrolled cohorts including the intrapatient dose titration cohort will be presented.
Citation Format: Gerald Falchook, Moshe Talpaz, Monica Mita, Russ Szmulewitz, Sarina Piha-Paul, Wael Harb, Daniel Morgensztern, Jason Kaplan, Pamela Munster, Robert F. Cornell, Fred Zheng, Swamy Yeleswaram, Gongfu Zhou, Ryan Cassaday. Phase 1/2 study of INCB054329, a bromodomain and extraterminal (BET) protein inhibitor, in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A093.