Results from a Phase 1 Open-Label Dose Escalation and Expansion Trial of Oral Azacitidine + Cedazuridine (ASTX030) in Patients with Myelodysplastic Syndromes (MDS) and MDS/Myeloproliferative Neoplasms (MPN)

Background:

Azacitidine (AZA) and decitabine (DEC) are parenteral DNA methyltransferase inhibitors (DNMTis) approved for the treatment of patients with MDS and acute myeloid leukemia. Oral DNMTi options have been limited due to their rapid clearance by cytidine deaminase (CDA). Combining DNMTis with the CDA inhibitor cedazuridine (CED) has demonstrated oral availability and led to the approval of oral DEC-C based on pharmacokinetic (PK) area under the curve (AUC) exposure equivalence versus intravenous DEC. ASTX030-01 (NCT04256317) is a phase 1-3 trial of ASTX030 (oral AZA + CED) versus subcutaneous (SC) AZA in patients with MDS and MDS/MPN (including chronic myelomonocytic leukemia; CMML). The aim of the phase 1 trial was to determine the optimal dose and formulation to achieve oral AZA PK AUC comparable to SC AZA.

Methods:

This open-label phase 1 trial enrolled adult patients with confirmed MDS and MDS/MPN overlap syndromes who may benefit from single-agent AZA. Both immediate-release (IR) and delayed-release (DR) AZA formulations at several dose combinations were explored. There were six or more patients per dose cohort. The primary objective was to determine the ASTX030 recommended phase 2 dose (RP2D). Secondary objectives were safety, tolerability, PK, DNA methylation, and preliminary efficacy.

Results:

Overall, 88 patients received a median of 6.0 (range, 1-32) ASTX030 treatment cycles (data cutoff: May 24, 2024). Median age was 72 years (range, 26-87), 35% (n=31) of patients were female, prior treatments included DNMTis (9% [n=8]), luspatercept (3% [n=3])_, lenalidomide (3% [n=3]), and erythropoiesis-stimulating agents (3% [n=2]). Of the enrolled patients, 72% (n=63) had MDS, 22% (n=19) had CMML, and 7% (n=6) had non-CMML MDS/MPN overlap syndromes. In the dose-escalation part, sensitivity of AZA to CDA inhibition was confirmed with the IR formulation. To optimize the ASTX030 dose, six dose combinations of DR AZA (60-144 mg) and CED (20-100 mg) were evaluated. Two ASTX030 doses (136/20 mg and 144/20 mg AZA/CED) were investigated in the dose-expansion part.

Adverse events (AEs) were reported in 100% (n=88) of patients; 84% (n=74) of patients experienced a Grade ≥3 AE; 5% (n=4) of patients discontinued ASTX030 due to an AE. The most common Grade ≥3 AEs (any cause) were related to myelosuppression: leukopenia, 27%; neutropenia, 26%; thrombocytopenia, 23%. Gastrointestinal toxicities were similar for ASTX030 and SC AZA (VIDAZA USPI). One patient receiving 136/20 mg AZA/CED had a dose-limiting toxicity (DLT) of prolonged Grade 4 neutropenia, possibly related to study drug; no other DLTs were observed. Safety and tolerability up to 144 mg DR AZA was confirmed.

PK data indicated that 20 mg CED resulted in sufficient inhibition of CDA to increase absolute bioavailability of oral AZA to ~100% versus SC AZA. In the dose-expansion part, 144/20 mg AZA/CED slightly exceeded the 90-110% range of oral/SC ratio based on calculated total cycle AUC exposures and 136/20 mg AZA/CED achieved PK AUC in the lower end of the 90-110% range. Based on these data, 140/20 mg AZA/CED was selected as the RP2D.

LINE-1 demethylation data were comparable to those reported for SC AZA (for cohorts with similar PK AUC exposures to SC AZA). Preliminary clinical efficacy assessments for patients with sufficient follow-up (36.2 months; n=33) from cohorts with comparable AUC exposures versus SC AZA had overall survival of 29.5 months, with 24% complete response, 24% marrow complete response, 33% stable disease, and 18% efficacy status unknown.

Conclusion:

All ASTX030 dose combinations evaluated were well tolerated and the safety profile was similar to SC AZA, with emerging clinical efficacy also consistent with parenteral AZA. Based on the results of the phase 1 trial, 140/20 mg AZA/CED was selected as the RP2D. Enrollment for the phase 2 randomized, crossover (oral vs SC) trial is ongoing and combination dosing is in preparation.

Garcia-Manero:Genentech: Research Funding; Astex: Research Funding; Curis: Research Funding; Helsinn: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; Amphivena: Research Funding; Merck: Research Funding; Aprea: Research Funding; Helsinn: Other: Personal fees; H3 Biomedicine: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; AbbVie: Research Funding; Astex: Other: Personal fees; Onconova: Research Funding; Genentech: Other: Personal fees. McCloskey:Jazz Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb/Pfizer: Consultancy; BluePrint Health: Speakers Bureau; BluPrint Oncology: Honoraria; Blueprint Medicines: Consultancy; Stemline Therapeutics: Speakers Bureau; Novartis: Consultancy; Incyte: Speakers Bureau. Scott:BMS, Celgene, Jazz Pharmaceuticals, and Novartis: Other: Advisory Board; Nektar, Johnson and Johnson: Other: data safety monitoring board; Alexion, Celgene, BMS, and Incyte: Consultancy; BMS, Novartis: Research Funding; Celgene, BMS: Honoraria. Griffiths:Genentech: Consultancy, Research Funding; Celldex Pharmaceuticals: Research Funding; Servier: Consultancy; Picnic Health: Consultancy; Partner Therapeutics: Consultancy; Novartis: Consultancy, Research Funding; Astex Pharmaceuticals/Taiho Oncology/Otsuka: Consultancy, Research Funding; ASH: Honoraria; MJH Health: Honoraria; MediCom Worldwide: Honoraria; MedscapeLive: Honoraria; NextCure: Research Funding; Blueprint Medicines: Research Funding; CTI Biopharma: Consultancy; MDS International Foundation: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Apellis Pharmaceuticals: Consultancy, Research Funding; Takeda Oncology: Consultancy; Abbvie: Consultancy; Physicians Educational Resource: Honoraria; Alexion Pharmaceuticals/ AstraZeneca Rare Disease: Consultancy, Research Funding; AAMDS: Honoraria. Kiner-Strachan:Esperion: Current equity holder in publicly-traded company; Gossamer: Current equity holder in publicly-traded company; Janssen: Current Employment; Johnson and Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Seagen: Current equity holder in publicly-traded company; Vaxart: Current equity holder in publicly-traded company; Viatris: Current equity holder in publicly-traded company. Brunner:Agios: Consultancy; BMS: Consultancy, Research Funding; i-Mab Biopharma: Consultancy; Keros Therapeutics: Consultancy; Lava Therapeutics: Consultancy; Novartis: Consultancy, Research Funding; Rigel Pharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Research Funding; Geron: Consultancy; AstraZeneca: Research Funding; Servier: Consultancy. Zeidan:Sumitomo: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Vinerx: Consultancy, Honoraria; Astex: Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Hikma: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Orum: Consultancy, Honoraria; Treadwell: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Lava Therapeutics: Consultancy, Honoraria; Medus: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Shattuck Labs: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Schroedinger: Consultancy, Honoraria; Faron: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Kura: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Akeso Pharma: Consultancy, Honoraria; Geron: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Keros: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria. Traer:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Schrödinger: Research Funding; Rigel Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Servier Laboratories: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Research Funding; Prelude Therapeutics: Research Funding. Madanat:BMS, Kura Oncology, Blueprint Medicines, Geron: Consultancy; Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences, and Novartis: Other: Advisory Board; Blueprint Medicines, MD Education and Morphosys: Other: Supporting or attending meetings and/or travel. Meyer:Biodesix: Research Funding; Celcuity: Research Funding; G1 Therapeutics: Research Funding; Genenrech/Roche: Research Funding; Janssen: Research Funding; Lilly: Research Funding; Mirati: Research Funding; Tempus: Research Funding; UpToDate: Patents & Royalties; VastBiome: Research Funding; Abbvie: Research Funding; Astex Pharmaceuticals: Research Funding; Astra Zeneca: Research Funding; Natera: Research Funding; BillionToOne: Research Funding. Erba:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Chair, Independent Review Committee for VIALE A and VIALE C, Research Funding; Macrogenics: Consultancy, Other: Advisory Board/Consultant, Research Funding; Astellas: Consultancy, Other: Advisory Board; BMS: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Speakers Bureau; Immunogen: Consultancy, Other: Advisory Board/Consultant; Glycomimetics: Consultancy, Other: Advisory Board; Steering Committee member, Research Funding; Jazz: Consultancy, Other: Advisory Board/Consultant, Speakers Bureau; Incyte: Consultancy, Other: Advisory Board/Consultant; Novartis: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Pfizer: Consultancy, Other: Advisory Board/Consultant; Schrodinger: Consultancy, Other: Advisory Board/Consultant; Servier: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Stemline: Consultancy, Other: Advisory Board/Consultant; Syros: Consultancy, Other: Advisory Board/Consultant; Takeda: Consultancy, Other: Advisory Board/Consultant; Trillium: Consultancy, Other: Advisory Board/Consultant; Ascentage: Research Funding; Oryzon: Research Funding; PTE: Research Funding; Taiho Oncology: Research Funding; Sumitomo Pharma: Consultancy, Other: Advisory Board/Consultant, Research Funding; ALX Oncology: Research Funding; Aptose: Research Funding; Genentech: Consultancy, Other: Advisory Board; Daiichi Sankyo: Consultancy, Other, Research Funding; Celgene: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Research Funding, Speakers Bureau; Kura Oncology: Consultancy, Other: Advisory Board/Consultant, Research Funding. Baratam:MBS and ONO Pharmaceutical: Consultancy; Rigel Pharma, BMS, and GSK: Honoraria; Kite Pharma and Rigel Pharma: Other: travel; Protagonist Therapeutics and Kite Pharma: Other: participated on data safety monitoring/advisory boards . Borate:Genentech: Consultancy; Abbvie: Consultancy; Sumitomo: Consultancy; Rigel: Consultancy; Ryvue: Other: IDMC; Novartis: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: IDMC; Beigene: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Incyte: Consultancy. Sano:Taiho Oncology Inc: Current Employment. Oganesian:Taiho Oncology Inc: Current Employment. Zhu:Taiho Oncology Inc: Current Employment. Keer:Taiho Oncology Inc: Current Employment. Savona:Karyopharm, Ryvu, Empath Biosciences: Current equity holder in publicly-traded company; Abbvie, BMS, CTI, Forma, Geron, GSK, Rigel, Taiho, and Treadwell: Consultancy; Astex: Other: Grants or Contracts from entity; MDSF Foundation BOD: Membership on an entity's Board of Directors or advisory committees; Boehringer, Empath Biosciences: Patents & Royalties; Incyte: Other: Grants or Contracts from entity.