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2861 Phase 1b Study of BET Inhibitor PLX2853 in Patients with Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III
Hematology Disease Topics & Pathways:
AML, Diseases, Therapies, MDS, Biological Processes, epigenetics, Myeloid Malignancies
Monday, December 7, 2020, 7:00 AM-3:30 PM

Alice S. Mims, MD1, Melhem Solh, MD2, Uma Borate3, Naveen Pemmaraju, MD4, Gautam Borthakur, MD5, Gail J. Roboz, MD6, Ben Powell, PhD7*, Paul Severson, PhD7*, Bernice Matusow7*, Jason Halladay, PhD7*, Ching Hsu, PhD8*, Paul Watkins7*, Chao Zhang, PhD7*, Jackie M. Walling, PhD, MD7, Athanasios C. Tsiatis, MD7 and Amy E. DeZern, MD9

1Arthur G. James Cancer Center Hospital, The Ohio State University Comprehensive Cancer Center, Columbus, OH
2Northside Hospital Cancer Institute, Atlanta, GA
3Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
4University of Texas, MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
6Weill Medical College of Cornell University New York-Presbyterian Hospital, New York, NY
7Plexxikon Inc., Berkeley, CA
8Daiichi Sankyo Inc., Basking Ridge, NJ
9Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD

Background: Relapsed and refractory myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a clinical challenge due to high morbidity and mortality as well as a paucity 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 bromodomain (BD2) of the BET proteins. By regulating genes (e.g., MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 has demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profiles in patients with AML or MDS revealed high peak plasma concentrations, a short terminal half-life (T1/2 < 3 hour), and nearly complete elimination from the plasma by 9 hour post dose. This PK profile is hypothesized to enable improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing.

Methods: This is an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily for 21 day cycles in adult patients with relapsed or refractory AML or high risk MDS. A modified continuous reassessment model with escalation with overdose control is employed to determine the recommended phase 2 dose (RP2D). Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments. Enrollment through Cohort 5 (140 mg QD) is ongoing as of July 2020.

Results: 9 subjects with relapsed or refractory AML and 7 subjects with high risk MDS (median age 65.7 years, range 47-77 years old; median number of prior therapies 2.3, range 1-5 prior therapies) have received PLX2853 in escalating doses from 20 to 140 mg QD. Through the data cut-off of 19 Jul 2020 (n=16), the most common treatment emergent adverse events (AEs) regardless of causality occurring in ≥20% of patients (n≥4) are: decreased appetite (n=9), (n=8), fatigue (N=8), hyperbilirubinemia (N=8), nausea (n=7), constipation (n=6), hypokalemia (n=6), leukopenia (n=6), vomiting (n=5), international normalised ratio increased (n=5), proteinuria (n=5), and dyspnea (n=5). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patients are: anemia (n=7), leukopenia (n=5) hyperbilirubinemia (n=4), febrile neutropenia (n=4), sepsis (n=3), thrombocytopenia (n=3), hypertension (n=2), lymphocyte count decreased (n=3), and neutrophil count decreased (n=3). No dose limiting toxicity (DLT) has been observed. Following a daily dose of PLX2853 the median time to reach maximal plasma concentration (Tmax) is 1 hour, and no accumulation observed at steady state, which is consistent with the short T1/2 (< 3 hours). Dose-dependent increases in exposures were observed across the dose range tested (20-80 mg daily). Fifteen of 16 subjects have completed at least 1 cycle of treatment. The following best overall responses have been observed: 1 subject with a confirmed marrow complete remission, 1 subject with a partial remission (myeloid sarcoma), 10 subjects with stable disease, 1 subject with progressive disease, and 3 subjects not evaluable.

Conclusions: In an ongoing Ph1b study of PLX2853, four cohorts have been completed with continuous, once daily dosing in patients with relapsed or refractory AML or high risk MDS, and no DLTs have been observed yet. As dose escalation continues, PK, PD, preliminary safety, and efficacy data will be reviewed further to determine the clinical significance of this BET inhibitor and identify the RP2D. This clinical trial is registered at clinicaltrials.gov: NCT03787498.

Disclosures: Mims: Agios: Consultancy; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Novartis: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board. Borate: 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; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Pemmaraju: Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Blueprint Medicines: Honoraria; MustangBio: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria. Borthakur: BioTherix: Consultancy; BioLine Rx: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; BMS: Research Funding; Jannsen: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Consultancy; AstraZeneca: Research Funding. Roboz: GlaxoSmithKline: Consultancy; Bristol Myers Squibb: Consultancy; Mesoblast: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Amgen: Consultancy; Agios: Consultancy; Amphivena: Consultancy; Astex: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Epizyme: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Trovagene: Consultancy; Takeda: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; AstraZeneca: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Argenx: Consultancy; Actinium: Consultancy. Powell: Plexxikon Inc.: Current Employment. Severson: Plexxikon Inc.: Current Employment. Matusow: Plexxikon Inc.: Current Employment. Halladay: Plexxikon Inc.: Current Employment. Hsu: Daiichi Sankyo Inc.: Current Employment. Watkins: Plexxikon Inc.: Current Employment. Zhang: Plexxikon Inc.: Current Employment. Walling: Plexxikon Inc.: Consultancy; Aduro Biotech: Consultancy; Arch Oncology: Consultancy; CytomX Therapeutics: Consultancy; Harpoon Therapeutics: Consultancy; ImmuNext: Consultancy; Myovant Sciences: Consultancy; Nurix Therapeutics: Consultancy; Que Oncology: Consultancy; Sesen Bio: Consultancy; Amgen: Consultancy; Aminex: Consultancy; Crown Bio: Consultancy; Leap Therapeutics: Consultancy; Prothena Corporation: Consultancy; Puma Biotechnology: Consultancy; Rhizen Pharmaceuticals: Consultancy; Shanghai Pharmaceuticals: Consultancy; Stealth Biotherapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Upsher-Smith Laboratories: Consultancy; Flag Therapeutics: Consultancy; January Therapeutics: Consultancy. Tsiatis: Plexxikon Inc.: Current Employment. DeZern: Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy; MEI: Consultancy.

*signifies non-member of ASH