Bromodomain and extra-terminal (BET) inhibitor INCB057643 (LIMBER-103) in patients (pts) with relapsed or refractory myelofibrosis (R/R MF) and other advanced myeloid neoplasms: A phase 1 study.

Justin M. Watts Sylvester Cancer Center, University of Miami, Miami, FL info_outline Justin M. Watts, Anthony Hunter, Alessandra Iurlo, Blanca Xicoy, Francesca Palandri, Brandi Reeves, Alessandro M. Vannucchi, Prithviraj Bose, Rosa Ayala Diaz, Anna B. Halpern, Xuejun Chen, Francis Seguy, Feng Zhou, Fred Zheng, Pankit Vachhani

Authors Justin M. Watts Sylvester Cancer Center, University of Miami, Miami, FL info_outline Justin M. Watts, Anthony Hunter, Alessandra Iurlo, Blanca Xicoy, Francesca Palandri, Brandi Reeves, Alessandro M. Vannucchi, Prithviraj Bose, Rosa Ayala Diaz, Anna B. Halpern, Xuejun Chen, Francis Seguy, Feng Zhou, Fred Zheng, Pankit Vachhani Organizations Sylvester Cancer Center, University of Miami, Miami, FL, Emory University School of Medicine, Atlanta, GA, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy, Hospital Germans Trias i Pujol, Institut Català d'Oncologia, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy, University of North Carolina at Chapel Hill Division of Hematology/Oncology, Chapel Hill, NC, AOU Careggi, University of Florence, Florence, Italy, The University of Texas MD Anderson Cancer Center, Houston, TX, Hospital Universitario 12 de Octubre, Madrid, Spain, Hematology Division at University of Washington Medical Center, Fred Hutchinson Cancer Center, Seattle, WA, Incyte Corporation, Wilmington, DE, Incyte Biosciences International Sàrl, Morges, Switzerland, O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Incyte Corporation Background: BET proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of hematologic malignancies, including MF. INCB057643 is a small-molecule BET inhibitor evaluated as monotherapy and in combination with ruxolitinib (RUX) in pts with advanced malignancies in 2 previous phase 1/2 clinical trials. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) evaluates safety and tolerability of INCB057643 (4 mg once daily [qd]; escalation up to 12 mg qd) in pts aged ≥18 years as (1) monotherapy (part 1) in R/R MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to RUX (part 2) in pts with MF and suboptimal response to RUX. The primary endpoint is safety and tolerability, including identification of dose-limiting toxicities (DLTs). Results: 13 pts have been treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=1; 12 mg, n=2), and 3 pts received 4 mg + RUX in part 2 (overall age range, 50–79 years; men, n=9; study treatment duration range, 15–314 days). 12 pts had MF, and 4 had MDS/MPN. All 6 pts in the 4-mg cohort discontinued treatment (3 for progressive disease [PD]; MF, n=2; MDS/MPN, n=1); 1 pt with MF in the 12-mg cohort discontinued for thrombocytopenia. The other 9 pts remain on treatment. Thrombocytopenia was the most common treatment-emergent adverse event (TEAE; n=9; Table) and the only TEAE leading to discontinuation (n=3). Grade ≥3 TEAEs occurring in ≥1 pt were thrombocytopenia (n=4), anemia (n=3), and hypokalemia (n=2). There were 8 serious AEs across 4 pts, with only COVID-19 occurring in >1 pt (n=2); all but one (pneumonia) were considered unrelated to study treatment. There were 2 DLTs (thrombocytopenia [MDS/MPN pt] and hyperbilirubinemia [MF pt]; both 12-mg cohort) and 2 deaths (both 4-mg cohort due to PD [MF, n=1; MDS/MPN, n=1]). Conclusions: Treatment with INCB057643 monotherapy (4 and 8 mg qd) and in combination (4 mg qd) with RUX was generally well tolerated in this pt population. The 12-mg qd monotherapy dose was not tolerated and caused 2 DLTs. There were no treatment-related fatal events. Dose finding in part 1 is ongoing with 10 mg qd, after which a recommended phase 2 dose will be declared. Combination dose escalation is also ongoing. Preliminary efficacy including spleen size and symptoms will be available for presentation. Clinical trial information: NCT04279847. TEAEs occurring in ≥3 patients. TEAE, n (%) 4 mg (n=6) 8 mg (n=4) 10 mg (n=1) 12 mg (n=2) 4 mg + RUX (n=3) Total (N=16) Thrombocytopenia 3 (50) 2 (50) 1 (100) 1 (50) 2 (67) 9 (56) Dysgeusia 0 1 (25) 1 (100) 2 (100) 1 (33) 5 (31) Nausea 1 (17) 2 (50) 0 1 (50) 0 4 (25) Anemia 2 (33) 1 (25) 0 0 0 3 (19) Blood bilirubin increased 1 (17) 2 (50) 0 0 0 3 (19) Ejection fraction decreased 0 1 (25) 0 0 2 (67) 3 (19) COVID-19 0 2 (50) 0 0 1 (33) 3 (19)

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