Abstract CT231: BET-bromodomain inhibitor OTX015 shows clinically meaningful activity at nontoxic doses: interim results of an ongoing phase I trial in hematologic malignancies
Authors: Patrice E. Herait, Celine Berthon, Catherine Thieblemont, Emmanuel Raffoux, Valeria Magarotto, Anastasios Stathis, Xavier Thomas, Xavier Leleu, Carlos Gomez-Roca, Elodie Odore, Christophe Roumier, Fabrice Bourdel, Bruno Quesnel, Emanuele Zucca, Mauricette Michallet, Christian Recher, Esteban Cvitkovic, Keyvan Rezai, Claude Preudhomme, Thierry Facon, Antonio Palumbo, Herve Dombret
Journal: Cancer Research (2014)

Abstract Aim: The bromodomain and extraterminal (BET) subfamily of human bromodomain (BRD) proteins associates with acetylated chromatin and plays a key role in the epigenetic control of transcriptional activation, notably of genes with super-enhancers, such as the MYC oncogene. OTX015, a potent small molecule inhibitor of BRD2/3/4 (Noel et al, EORTC-NCI-AACR 2013), inhibits proliferation of a wide range of hematologic malignancies (HMs) in vitro (Bonetti et al, EORTC-NCI-AACR 2012; Boi et al, EORTC-NCI-AACR 2013; Braun et al, ASH 2013). This phase I study, designed to determine the recommended dose and pharmacokinetics of oral OTX015 as a single agent, is the first reported clinical study evaluating the effects of BRD inhibition in patients (pts) with HMs. Methods: Two independent cohorts of pts having failed all standard therapies were given ascending oral doses of OTX015 in a conventional 3+3 design, with acute leukemias (AL) treated 14 days on/7 days off and other HMs (OHM) treated continuously in 21-day cycles. OTX015 was given once daily (QD), then twice daily (BID). Results: From Jan to Dec 2013, 16 pts with AL (14 AML, 2 ALL) and 17 with OHM (6 DLBCL, 5 other lymphomas, 6 multiple myelomas) were enrolled over 4 dose levels, 10, 20, 40 and 80 mg QD. Exposure increased dose-proportionally. Plasma trough concentrations at 80 mg QD and 12h concentrations at 40 mg QD were ≥ IC50 values in vitro (250 nM), justifying the shift to a BID schedule. The 40 mg BID cohort is ongoing. Pts have a median age of 70 years (range 32-83) and median of 2 (1-8) prior therapies; 10 of 16 AL pts had AML secondary to pre-existing conditions or chemotherapy. No dose limiting toxicity was observed up to 80 mg QD/40 mg BID. Adverse events (AEs) were mainly grade (G) 1-2 hematologic and gastrointestinal events and diabetes aggravation. G 3-4 AEs were reversible thrombocytopenia in 3 pts with OHM (40 and 80 mg), and neutropenia, diarrhea, and elevated transaminases in 1 pt each. No cumulative toxicity was observed. Nine pts received &amp;gt;3 (range 4-7) cycles without or with minor interruptions. Among 28 pts evaluable for response, 6 had clinically meaningful activity, with 4 of 6 treated at 80 mg. Four pts with refractory/relapsed secondary or post-treatment AML achieved significant peripheral and bone marrow blast decrease or clearance, including 1 complete remission (CR) and 1 CR with incomplete recovery. Among OHM, 1 DLBCL had a partial response (PR) and 1 lymphoplasmacytic lymphoma had metabolic PR on cycle 2 PET-scan. Treatment of 5 of 6 responding pts is ongoing. Responses occurred in pts with various clinical, cytogenetic and molecular profiles. Conclusion: OTX015 is the first BRD inhibitor demonstrating clinical activity. Maximum tolerated dose was not reached at 80 mg QD or 40 mg BID; dose escalation is ongoing with the BID schedule and further schedule optimization. Updated results will be presented. Citation Format: Patrice E. Herait, Celine Berthon, Catherine Thieblemont, Emmanuel Raffoux, Valeria Magarotto, Anastasios Stathis, Xavier Thomas, Xavier Leleu, Carlos Gomez-Roca, Elodie Odore, Christophe Roumier, Fabrice Bourdel, Bruno Quesnel, Emanuele Zucca, Mauricette Michallet, Christian Recher, Esteban Cvitkovic, Keyvan Rezai, Claude Preudhomme, Thierry Facon, Antonio Palumbo, Herve Dombret. BET-bromodomain inhibitor OTX015 shows clinically meaningful activity at nontoxic doses: interim results of an ongoing phase I trial in hematologic malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT231. doi:10.1158/1538-7445.AM2014-CT231