Phase 2 Study of Oral Decitabine/Cedazuridine in Combination with Magrolimab for Previously Untreated Subjects with Intermediate to Very High-Risk Myelodysplastic Syndromes (MDS)

Rationale Hypomethylating agents (HMAs) are approved for higher risk MDS (azacitidine, decitabine, oral decitabine/cedazuridine US package insert). Parenteral therapy (subcutaneous or intravenous) is required 5-7 days each month, often resulting in hospital or clinic visits on a chronic basis and represents a substantial burden for this primarily elderly population and their caregivers. Not surprisingly, patients with higher risk MDS are often not started and/or have low compliance with parenteral HMAs, with patients preferring oral medications (Zeidan et al., CLML 2022). Magrolimab has demonstrated encouraging preliminary data in the higher-risk MDS population in combination with azacitidine and is currently being evaluated in a randomized Phase 3 study (ENHANCE, NCT04313881), comparing the efficacy and safety of magrolimab plus azacitidine with that of azacitidine plus placebo in previously untreated patients with higher-risk MDS. This phase 2 study examines the possibility of using an oral HMA (oral decitabine/cedazuridine) in combination with magrolimab which may provide the benefits without the burden of significant parenteral therapy (4-6 additional clinic days each month).

Study Design ASTX727-10 is a phase 2, international, single-arm, open-label study investigating the safety and efficacy of combination oral decitabine/cedazuridine and magrolimab treatment in intermediate to very high-risk MDS, based on the MDS International Prognostic Scoring System - Revised (IPSS-R). Secondary objectives include evaluating the pharmacokinetic profiles of oral decitabine/cedazuridine and magrolimab, other clinical efficacy of the combination, and safety and efficacy in prespecified subgroups (e.g. IPSS-Molecular, p53 mutant status). To be eligible, subjects with ECOG Performance Status ≤2 must have previously untreated MDS per WHO 2016 classification with < 20% bone marrow blasts and be willing to undergo red blood cell transfusions to achieve a hemoglobin >9 gm/dl at the start of study treatment. Subjects must also be willing to undergo blood transfusions as per the parameters of the protocol and as clinically necessary. Key exclusion criteria include significant medical issues (including uncontrolled diabetes and New York Heart Association Class III-IV heart failure), creatinine clearance < 50 ml/min, immediate eligibility for hematopoietic stem cell transplant, secondary MDS, or MDS / (myeloproliferative neoplasm) overlap syndromes.

As part of the study, tolerability of the combination regimen will be confirmed in the first 6-18 subjects. Dose and/or dosing decreases identified during this dose limiting toxicity assessment will be applied to the entire study.

Approximately 100 subjects will be enrolled.

Anticipated study opening is November 2022.

Zeidan:Novartis, Cardiff Oncology, Pfizer: Other: Travel Support; Celgene/BMS, Novartis, Cardiff Oncology, AbbVie, Pfizer, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Amgen, Aprea, Astex, Pfizer, Medimmune/AstraZeneca, ADC Therapeutics: Research Funding; Astex, Medimmune, Astrazeneca, ADC Therapeutics: Research Funding; Celgene/BMS, AbbVie, Pfizer, Boeringer-Ingelheim, Trovagene, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, Amgen, Otsuka: Consultancy, Honoraria, Research Funding; Gilead, Kura, Loxo Oncology: Consultancy, Honoraria, Other: Clinical Trial Committee; Celgene/BMS, Novartis, Cardiff Oncology, AbbVie: Consultancy, Honoraria, Other: Advisory Board; Celgene/BMS, Novartis, AbbVie, Gilead, Kura, Loxo Oncology, Geron: Other: Clinical Trial Committee; Jazz, Agios, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, Beyondspring, Gilead, Kura, Tyme, Janssen, Syndax, Geron, Ionis, Epizyme: Consultancy, Honoraria; Pfizer, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Amgen, Aprea, Gilead, Kura, Loxo Oncology, Otsuka, Jazz, Agios, Acceleron, Astellas, Daiichi-Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Ionis, Epizyme, Janssen, Syndax, Genentec: Consultancy, Honoraria, Other: Advisory Boards. Mosher:Astex Pharmaceuticals, Inc.: Current Employment. Souza:Astex Pharmaceuticals, Inc.: Current Employment. Mirakhur:Astex Pharmaceuticals, Inc.: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Taylor:Astex Pharmaceuticals, Inc.: Current Employment.

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 in combination with magrolimab. Magrolimab is an investigational drug and has not been approved by any regulatory agency anywhere in the world.