The Inspire Study in Higher-Risk Myelodysplastic Syndrome (HR-MDS): A Novel Phase 3 Study Adaptive Design for Hematological Malignancies in Adults

Background: Patients with HR-MDS have a dismal prognosis after failure of hypomethylating agents (HMAs) (Zeidan 2014), with median overall survival (OS) of less than 6 months (Prebet 2011) and currently no approved second-line therapy (Garcia-Manero 2016). Targeted therapies with novel mechanisms of action, combination strategies, as well as innovative study designs, are all needed to expedite and address the high unmet medical need in patients with HMA refractory HR-MDS. Rigosertib is a unique targeted therapy that inhibits PI3K and PLK signaling pathways by binding directly to the Ras-binding domain (Athuluri-Divakar 2016) and in vitro cytotoxicity studies have demonstrated synergy with azacitidine (Cosenza 2015). INSPIRE study is an example of a study with a novel compound and unique mechanism of action as well as an innovative study design. Methods: INSPIRE (NCT02562443) is a global randomized Phase 3 trial in patients with HR-MDS after HMA failure. Patients are randomized in a 2:1 fashion to rigosertib or physician's choice of treatment. Key inclusion criteria: age Conclusions: Based on the results of interim analysis, the IDMC recommended continuation of the trial based on ITT result in promising zone with one-time expansion in enrollment, using a pre-planned sample size re-estimation, the sample size for the study was increased from 225 to 360 with unchanged eligibility criteria. The Adaptive Design used real time data from the IA to modify sample size and mitigate the risk of underpowering without undermining its validity and integrity, while preserving type-1 error. The study design used in INSPIRE may be advantageous for other novel agents in rare hematological diseases during the transition from phase 2 to phase 3 studies. Clinical trial information: (NCT02562443). Disclosures Luger: Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding. Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Woodman: Onconova Therapeutics, Inc.: Employment. Adesanya: Onconova Therapeutics, Inc.: Employment. Azarnia: Onconova Therapeutics, Inc.: Employment. Parris: Onconova Therapeutics, Inc.: Employment. Jedrzejczak: Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Novartis: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) . Diez-Campelo: Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.