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1538 Oral Decitabine/Cedazuridine Vs Intravenous Decitabine for Acute Myeloid Leukemia: Final Results of a Randomized, Crossover, Registration-Enabling, Pharmacokinetics Study

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, Myeloid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Klaus Geissler, MD1,2*, Zdenek Koristek, MD, PhD3*, Teresa Bernal Del Castillo, MD, PhD4*, Jan Novak5*, Gabriela Rodriguez Macias, MD6, Stephan Metzelder7*, Arpad Illes, MD8*, Agnes Nagy, MD9*, Jiří Mayer, MD10, Montserrat Arnan Sangerman, MD, PhD11*, Mary-Margaret Keating, MD12, Jürgen Krauter13*, Monia Lunghi, MD, PhD14*, Nicola Fracchiolla, MD15*, Uwe Platzbecker, MD16, Valeria Santini17, Danna Chan, PhD18*, Beloo Mirakhur, MD, PhD18, Yuri Sano, MD, PhD18, Aram Oganesian, PhD18*, Harold N. Keer, MD, PhD18 and Michael Lübbert, MD19

1Clinic Hietzing, Vienna, Austria
2Sigmund Freud University, Vienna, AUT
3University Hospital Ostrava, Ostrava, CZE
4Hospital Universitario Central de Asturias, ISPA, IUOPA, Oviedo, Spain
5Charles University and Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic
6Hospital Universitario Gregorio Maranon, Madrid, ESP
7Philipps-Universität Marburg, Marburg, Germany
8Department of Hematology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
9University of Pécs, University of Pécs, Hungary
10Masaryk University and University Hospital Brno, Brno, Czech Republic
11Hematology Department. Institut Català d’Oncologia, Hospital Duran i Reynals. Institut d’Investigació Biomèdica de Bellvitge (IDIBELL). Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain
12Queen Elizabeth II (QEII) Health Sciences Centre, Halifax, NS, CAN
13Department of Hematology and Oncology, Städtisches Klinikum Braunschweig, Braunschweig, Germany
14Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
15Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy
16Department of Hematology, University Hospital of Leipzig, Leipzig, Germany
17MDS Unit, AOU Careggi, DMSC, University of Florence, Firenze, Italy
18Astex Pharmaceuticals, Inc., Pleasanton, CA
19University Medical Center Freiburg, Freiburg, Germany

Background:

Parenterally administered hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are approved in Europe for adult patients with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy as single agent or in combination with venetoclax. Cedazuridine(C) is a novel, potent, and safe inhibitor of cytidine deaminase (CDA) and when given in combination with decitabine, cedazuridine enables efficient oral availability of decitabine. ASTX727 (DEC-C) is a fixed-dose combination (FDC) tablet of 35 mg DEC and 100 mg cedazuridine, DEC-C has been approved for MDS in the US, Canada, and Australia. Here we present final results using DEC-C in an AML population appropriate for single-agent decitabine treatment.

Aims:

Describe the final clinical outcomes of patients with AML with additional analysis of genetic profiles.

Methods:

The ASCERTAIN study used a randomized two-period, two-sequence, two-treatment, crossover study design. Patients were randomized 1:1 to either Sequence A: DEC-C (35 mg DEC/100 mg cedazuridine) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B: receiving IV-DEC in Cycle 1 followed by DEC-C on Cycle 2 to compare pharmacokinetics (PK) [primary endpoint Area Under the Curve (AUC) equivalence over 5 days of dosing]. All patients received DEC-C from Cycle 3 until treatment discontinuation to assess safety and clinical efficacy. Patients were eligible as per the EMA-approved decitabine label (newly diagnosed AML who are not candidates for standard induction chemotherapy). Clinical responses were assessed according to modified International Working Group (IWG) 2003 response criteria. Pre-treatment peripheral blood was used for DNA isolation from leukocytes, and molecular abnormalities identified using a NGS hematologic malignancy panel. Cox-regression analysis on the various factors (eg binary mutational status, CR, etc.) was used for analyses of risk-factors for overall survival (OS).

Results:

89 patients were randomized, of whom 87 were treated. The median age of patients was 78.0 years (range, 61 to 92) with 31 (35.6%) males and 56 (64.4%) females. Cytogenetic risk classification was poor-risk in 33 (37.9%), intermediate-risk in 45 (51.7%), and 9 (10.4%) not evaluated patients. For the primary endpoint, preliminary PK data was available from 69 patients who successfully completed PK assessments for both IV-DEC and DEC-C cycles, and the DEC AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 904 for DEC-C and 907 for IV-DEC resulting in an oral/IV geometric LSM AUC ratio of 99.64% (90% CI of 91.23-108.8%). Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 10% were thrombocytopenia, neutropenia, anaemia, and febrile neutropenia). As of the database lock (25May2023), median follow up was 24.5 (20.2, 25.0) months (25% of 19.7 and 75% of 25.2 months). The best response was complete response (CR) in 19/87 (21.8%, 95% CI: 13.7, 32.0%); CR with incomplete blood cell count recovery (CRi) in 5 patients (5.7%); and CR with incomplete platelet recovery (CRp) in 2 (2.3%); resulting in composite response rate [CR + CRi] of 27.6%. The median overall survival was approximately 8.9 months (95% CI: 6.0, 13.1).These results obtained with DEC-C are consistent with those observed for IV-DEC. Multiple genes, including ASXL1, TP53, RUNX1, and SRSF2 genes were present in more than 20% of the AML patients. TP53 mutation was associated with worse survival.

Summary/Conclusion:

This randomized phase 3 study in AML patients not candidates for standard induction chemotherapy demonstrates that Daily X 5 dosing of the oral FDC of DEC-C resulted in an equivalent DEC AUC exposure to IV-DEC at 20 mg/m2 over 5 days. Pharmacodynamic data showed similar demethylation rates (≤1.1% difference). In addition, safety findings and observed clinical activity (response rates and OS) are consistent with published data from IV-DEC, suggesting that DEC-C has the potential to be an oral alternative to the standard IV-DEC Daily×5 regimen. These findings support the use of DEC-C in patients with AML who are not candidates for standard induction chemotherapy.

Disclosures: Geissler: Celgene: Honoraria; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria. Bernal Del Castillo: AbbVie: Consultancy; Otsuka: Consultancy; Jazz: Consultancy. Novak: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses and accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: travel expenses and accommodations . Illes: Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: travel and conference support; Pfizer: Consultancy, Other: travel and conference support; Roche: Consultancy, Other: travel and conference support; Janssen: Consultancy, Other: travel and conference support; AbbVie: Consultancy. Mayer: MSD: Research Funding; Novartis: Research Funding. Keating: Janssen, Roche: Consultancy. Fracchiolla: AbbVie, Jazz, Pfizer, Amgen: Other: Travel grants, Speakers Bureau. Platzbecker: Jazz: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Research Funding; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; AbbVie: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Curis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; medical writing support, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Honoraria; Janssen Biotech: Consultancy, Research Funding; Fibrogen: Research Funding; Roche: Research Funding; BeiGene: Research Funding; BMS: Research Funding. Santini: Janssen: Other: Travel support; Syros: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Chan: Astex Pharmaceuticals, Inc.: Current Employment. Mirakhur: Astex Pharmaceuticals, Inc.: Current Employment. Sano: Astex Pharmaceuticals, Inc.: Current Employment. Oganesian: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Lübbert: Otsuka: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Cheplapharm: Other: Study drug; Imago BIosciences: Other: study drug.

OffLabel Disclosure: INQOVI (35 mg decitabine and 100 mg cedazuridine) is a prescription medicine approved in the United States to treat adults with myelodysplastic syndromes and chronic myelomonocytic leukemia. In this study, INQOVI is referred as ASTX727 or oral decitabine and cedazuridine due to the off-label investigational use in this study to explore treatment in AML patients.

*signifies non-member of ASH