Phase 1 Study of AXL/MER/CSF1R Inhibitor Q702 with Azacitidine and Venetoclax for Relapsed or Refractory Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is the most common leukemia among the adult population and accounts for about 80% of all cases. Patients with relapsed or refractory (R/R) AML have dismal outcomes. Complete remission (CR) rates with the best salvage therapy regimens range from 3 to 14% with median overall survival (OS) of 3 to 6 months. Despite the advent of venetoclax, more than 40% responders experience relapse, leading to 4-year OS of less than 15%. Axl, Mer and CSF1R expression are associated with inferior prognosis in AML and have been recognized as cell intrinsic and tumor microenvironmental therapeutic targets. AXL/MER inhibition has been shown to be active as single agent as well as in combination with venetoclax in AML cell lines and patient derived xenografts, including highly aggressive AML bearing FLT3-ITD, as well as primary AML samples resistant to venetoclax. Inhibiting CSF1R has also been shown to target AML by depleting supportive microenvironmental signals. Furthermore, AXL inhibition in macrophages can stimulate myeloid-centered anti-leukemia immune response. Q702 is an orally administrated novel Axl/Mer/CSF1R tyrosine kinase inhibitor that inhibits cell growth of human eosinophilic leukemia cells (EOL-1) and human AML cells (MOLM-13, MV4-11) with IC50 of 20, 110 and 200 nM, respectively. We hypothesize that combining Axl/Mer/CSF1R inhibition with venetoclax and azacitidine will work synergistically and improve outcomes in patients with AML. Consequently, we propose a phase 1 dose escalation and expansion trial to evaluate the safety and preliminary efficacy of Q702 in combination with venetoclax and azacitidine in patients with R/R AML.

Methods: This is an investigator-initiated, open-label, phase 1b dose escalation and expansion study (NCT06445907) to evaluate Q702 in combination with venetoclax and azacitidine in patients with R/R AML. In dose escalation phase, up to 2 dose levels of Q702 will be evaluated using a Bayesian optimal interval (BOIN) design starting with 90 mg. Additional or intermediate dose levels of Q702 may be evaluated based on emergent safety, efficacy and pharmacokinetic (PK)/pharmacodynamic (PD) data from this study. After completion of the dose escalation phase, the totality of safety, tolerability, preliminary activity from each dose level, PK/PD and preclinical data will be taken into consideration to determine the minimal safe and biologically effective dose of Q702 in combination with venetoclax and azacitidine to bring forward into dose expansion phase. A maximum of 20 patients with R/R AML will receive treatment at RP2D of Q702 in combination with venetoclax and azacitidine. During 28-day cycle, Q702 will be dosed followed by week on/week off regimen. Azacitidine will be administered at 75 mg/m² subcutaneously or intravenously for the first 7 days of dosing cycle. Venetoclax will be dose escalated daily over 3 days to the goal dose of 400 mg daily or equivalent with concomitant azole antifungal agent. Key eligibility criteria include 18 years or older patients with R/R or R/R myelodysplastic syndrome (MDS)/AML with 10 to 19% blasts per the International Consensus Classification 2022 or the WHO 2022 classification. Patients with t(15;17) karyotypic abnormality, known symptomatic or uncontrolled CNS leukemia will be excluded. Primary objective is to study the safety and tolerability of Q702 in combination with venetoclax and azacitidine. Secondary objectives are to study preliminary efficacy of the combination regimen in terms of response rates and survival outcomes. Exploratory objectives include to further study response, survival endpoints and correlative studies to understand mechanisms of response and resistance. Funding: Supported in part by the MDACC CCSG P30CA016672 and Qurient Co., Ltd.

Maiti:CytoMed Therapeutics: Research Funding; Chimeric Therapeutics: Research Funding; Indapta Therapeutics: Research Funding; Inspirna: Research Funding; Lin Biosciences: Research Funding; Hibercell Inc.: Research Funding. DiNardo:Genetech: Honoraria; ImmuneOnc: Research Funding; AstraZeneca: Honoraria; Stemline: Consultancy; GenMab: Consultancy, Honoraria, Other: data safety board; Gilead: Consultancy; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy; Astellas: Consultancy, Honoraria; Notable Labs: Honoraria; Loxo: Research Funding; GSK: Consultancy, Honoraria; Riegel: Honoraria; Jazz: Consultancy, Honoraria; Immunogen: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Rigel: Research Funding; Cleave: Research Funding; Foghorn: Research Funding; Schrodinger: Consultancy, Honoraria. Daver:FATE Therapeutics: Other: Consulting Fees, Research Funding; Agios: Consultancy; Astellas: Consultancy, Research Funding; Trovagene: Research Funding; Novartis: Consultancy; Arog: Consultancy; Jazz: Consultancy; Pfizer: Consultancy, Research Funding; Hanmi: Research Funding; Servier: Consultancy, Research Funding; KITE: Research Funding; Novimmune: Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Menarini Group: Consultancy; Gilead: Consultancy, Research Funding; Syndax: Consultancy; Trillium: Consultancy, Research Funding; Shattuck Labs: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Glycomimetics: Research Funding. Kadia:Cellenkos: Research Funding; ASTEX: Research Funding; Ascentage: Research Funding; Rigel: Honoraria; JAZZ: Research Funding; Novartis: Honoraria; Servier: Consultancy; Amgen: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Sellas: Consultancy, Research Funding; BMS: Consultancy, Research Funding; DrenBio: Consultancy, Research Funding; Regeneron: Research Funding; Abbvie: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding. Andreeff:Syndax: Honoraria, Research Funding; Kintor Pharmaceutical: Research Funding; Paraza: Honoraria; Glycomimetics: Honoraria; Aptose: Honoraria; Sellas: Honoraria, Research Funding; Chimerix: Current holder of stock options in a privately-held company; SentiBio: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Oncolyze: Current holder of stock options in a privately-held company; Daiichi-Sankyo: Research Funding; Ona: Honoraria; Oxford Biomedical: Research Funding; Boehringer-Ingelheim: Honoraria; Ellipses: Research Funding; Roivant: Honoraria; Eterna: Current holder of stock options in a privately-held company, Honoraria, Research Funding. Ravandi:BMS: Consultancy, Honoraria; Astyex/Taiho: Research Funding; Xencor: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria. Borthakur:Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding.