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
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. 
Published: November 2021

Abstract
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 &lt; 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 (n=6). Two dose limiting toxicities (DLTs) were observed at the two highest doses: G3 and G4 hyperbilirubinemia at 180 mg QD and 140 mg QD respectively. The MTD is 140 mg QD and the RP2D, determined on the totality of data in this study and the companion phase 1 study in solid tumors (NCT03297424), is 80 mg QD. The median time to reach maximal PLX2853 plasma concentration (T max) is 1 hour, with no accumulation observed at steady state, consistent with the short T 1/2 (&lt; 3 hours). Dose-dependent increases in exposures were observed across the dose range tested (20-180 mg daily). Fifteen of 22 patients completed at least 1 cycle of treatment. Median duration of treatment was 49 days (range 8 - 232 days). Best Overall Response: 1 patient with a confirmed marrow CR (MDS), 2 x partial remission (1 AML and 1 myeloid sarcoma), 12 x stable disease (7 AML and 5 MDS), 2 x progressive disease (1 AML and 1 MDS), and 5 x not evaluable (4 AML and 1 MDS).
Conclusions: Daily dosing of PLX2853 was well tolerated as a monotherapy and showed early signs of clinical activity in some patients with relapsed or refractory AML or high risk MDS, with potential for combination with other agents. The RP2D is 80 mg QD continuous dosing. This clinical trial is registered at clinicaltrials.gov: NCT03787498.

Disclosures
Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Solh: Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Partner Therapeutics: Research Funding; BMS: Consultancy. Saultz: IKENA: Research Funding. Borate: Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Jazz Pharma: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Pemmaraju: CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Affymetrix: Consultancy, Research Funding; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sager Strong Foundation: Other; DAVA Oncology: Consultancy; Springer Science + Business Media: Other; Aptitude Health: Consultancy; MustangBio: Consultancy, Other; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Celgene Corporation: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Borthakur: Protagonist: Consultancy; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Roboz: Actinium: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Blueprint Medicines: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Jazz: Consultancy; Bayer: Consultancy; Agios: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Astex: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Janssen: Research Funding; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Powell: Plexxikon Inc.: Current Employment. Matusow: Plexxikon Inc.: Current Employment. Halladay: Plexxikon Inc.: Current Employment. Vali: Plexxikon Inc.: Current Employment. Hope: Plexxikon Inc.: Current Employment. Kundu: Daiichi Sankyo: Current Employment. Hsu: Daiichi Sankyo: Current Employment. Watkins: Plexxikon Inc.: Current Employment. Zhang: Plexxikon Inc.: Current Employment. Walling: Plexxikon Inc.: Consultancy; Aduro Biotech: Consultancy; Ambagon Therapeutics: Consultancy; Arch Oncology: Consultancy; CytomX: Consultancy; Flag Therapeutics: Consultancy; Harpoon Therapeutics: Consultancy; January Therapeutics: Consultancy; Myovant Sciences: Consultancy; Nurix Therapeutics: Consultancy; Propella Therapeutics: Consultancy; Prothena: Consultancy; Que Oncology: Consultancy; Shape Therapeutics: Consultancy; Aminex Therapeutics: Consultancy; Proximagen Neurosciences: Consultancy; Sesen Bio: Consultancy; Sunesis Pharmaceuticals: Consultancy; TRex BioSciences: Consultancy; Upsher-Smith: Consultancy; Nuvation Bio: Consultancy; Oryzon: Consultancy. Tsiatis: Plexxikon Inc.: Current Employment. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.