A Phase I/II Study of Venetoclax in Combination with ASTX727 (cedazuridine/decitabine) in Treatment-Naïve High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)
Authors: Venugopal Sangeetha , Kantarjian Hagop , Maiti Abhishek , Short Nicholas J. , Montalban-Bravo Guillermo , Alvarado Yesid , Chien Kelly S. , Kanagal-Shamanna Rashmi , Pemmaraju Naveen , Daver Naval , Kadia Tapan M. , Borthakur Gautam , Jabbour Elias J. , Garcia-Manero Guillermo 
Published: November 2021

Abstract
Background: In MDS, hypomethylating agents (HMA) remain the standard of care. ASTX727, an oral formulation of the fixed dose combination of the HMA decitabine and cytidine deaminase inhibitor cedazuridine, was recently approved for the treatment of MDS and CMML. Venetoclax (Ven), an orally bioavailable BCL-2 inhibitor in combination with azacitidine has shown clinical activity in treatment-naïve higher risk MDS. Based on this data, we designed a total oral therapy with Ven+ASTX727 combination to improve the clinical outcomes and quality of life in pts with higher risk MDS or CMML.
Methods: This single arm Phase I/II study of orally administered ASTX727 in combination with Ven (NCT04655755) is enrolling pts aged ≥18 years with treatment-naïve higher risk MDS (intermediate-2 or high) per IPSS or CMML with excess blasts ≥5%. Prior bcl2 inhibitor therapy is not allowed. To mitigate tumor lysis syndrome, pretreatment white blood cell count should be less than 10 × 10 9/L. Cytoreduction is allowed. The phase I 3+3 design of venetoclax with ASTX727 has an intended sample size of 12 pts. ASTX727 (cedazuridine/decitabine at 100 mg/35 mg) is administered orally daily on days 1-5 of each treatment cycle and Ven on days 1-14 of the first cycle and thereafter. Three dose levels of venetoclax in combination with ASTX727 will be tested (Table 1)
The safety population includes all patients who received any dose of Ven+ ASTX727, and the efficacy population includes patients who have a valid baseline and post-baseline disease assessment and had received at least one dose of the study drug. The primary objective is to determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase 2) of Ven+ASTX727 combination.
Results: In phase I portion, seven pts have been enrolled to date (Table 2). The median age is 72 years (range, 54-84) with five pts aged ≥65 yrs. These pts had a median bone marrow blast count of 13% (range,6-15), and harbored a median number of 4 (range,1-7) mutations. Greater than 50% of the cohort harbored adverse risk mutations such as ASXL1(71%), RUNX1 (57%). Three pts were enrolled in dose level 0 and four pts in dose level +1.
No DLTs were observed in the initial 6 pt safety lead-in. The 30-day and 60-day mortality rates were 0% each. No tumor lysis syndrome was observed. All seven pts achieved a response (100%) with three pts achieving CR (43%) and four pts achieving marrow CR (57%). Among the responders, two pts achieved MRD negativity (29%). All pts achieved a response within 1 cycle. One pt with TP53mut proceeded to hematopoietic stem cell transplant at the end of 2 cycles and the remaining six pts continue on study. At a median follow up of 3.8 months, the median duration of response was not reached (range,1.8-5.1+ months), and the median overall survival was not reached (range,2.7-6.2+ months).
Conclusion: Ven+ASTX727 combination appears safe and demonstrates preliminary efficacy in pts with higher risk MDS or CMML with excess blasts. Total oral therapy of Ven+ASTX727 combination appears to be a promising strategy for HR MDS or CMML pts who often require long term treatment.
Figure 1 Figure 1.

Disclosures
Kantarjian: Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Ascentage: Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Precision Biosciences: Honoraria; Amgen: Honoraria, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding. Short: Novartis: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: CytomX Therapeutics: Consultancy; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Jazz Pharmaceuticals: Research Funding. Pemmaraju: ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; MustangBio: Consultancy, Other; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Dan's House of Hope: 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; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Celgene Corporation: Consultancy; Aptitude Health: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Affymetrix: Consultancy, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Incyte: Consultancy; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Glycomimetics: Research Funding; FATE Therapeutics: Research Funding; Abbvie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Hanmi: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kadia: Sanofi-Aventis: Consultancy; AstraZeneca: Other; Ascentage: Other; Genfleet: Other; Amgen: Other: Grant/research support; BMS: Other: Grant/research support; Cure: Speakers Bureau; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Astellas: Other; Cellonkos: Other; Pulmotech: Other. Borthakur: Astex: Research Funding; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding.