Final Results of a Phase 1b Study of BET Inhibitor PLX2853 in Patients with Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.3420-3420
• Main Authors: Mims, Alice S., Solh, Melhem, Saultz, Jennifer N., Borate, Uma, Pemmaraju, Naveen, Borthakur, Gautam, Roboz, Gail J., Powell, Ben, Matusow, Bernice, Halladay, Jason, Vali, Shireen, Hope, Chelsea L., Kundu, Madan G., Hsu, Ching, Watkins, Paul, Zhang, Chao, Walling, Jackie M., Tsiatis, Athanasios C., DeZern, Amy E.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-152040

Background: Relapsed and refractory myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a clinical challenge due to high mortality, morbidity, and lack of effective therapeutic agents. PLX2853 is an orally available, non-benzodiazepine bromodomain and extraterminal domain (BET) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second of the double bromodomains of the BET proteins. By regulating genes (e.g., BCL2 and MYC) central to leukemic cell proliferation and survival, PLX2853 has demonstrated broad anti-leukemic activity both as a single agent and in combination with other agents in preclinical models. The pharmacokinetic (PK) profiles in patients with solid tumors revealed high peak plasma concentrations, a short terminal half-life (T 1/2 < 3 hour), and nearly complete elimination from the plasma by 9 hours post dose. This PK profile is hypothesized to improve tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: This is an open-label, Phase 1b dose-escalation study of PLX2853 as a single agent, administered with oral daily dosing for 21-day cycles in adult patients with relapsed or refractory (R/R) AML or high risk MDS. A modified continuous reassessment model with overdose control was used to guide dose escalation decisions and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamic biomarker assessments. Results: Fourteen patients with R/R AML and 8 patients with high risk MDS (median age 69 years, range 47 - 79 years; median number of prior therapies 2, range 1-7) received PLX2853 in escalating doses from 20 to 180 mg QD. Through the data cut-off of 30 Jun 2021 (n=22), the most common treatment emergent adverse events (AEs) regardless of causality occurring in ≥20% of patients (n≥5) are: fatigue (n=14), nausea (n=13), decreased appetite (n=13), anemia (n=10), diarrhea (n=10), vomiting (n=9), hypokalemia (n=9), international normalized ratio increased (n=8), hyperglycemia (n=8), hypophosphatemia (n=8), peripheral edema (n=7), blood bilirubin increased (n=7), dyspnea (n=7), febrile neutropenia (n=6), constipation (n=6), sepsis (n=6), hypoalbuminemia (n=6), hyponatremia (n=6), insomnia (n=6), proteinuria (n=6), and hypertension