Inspire: A Randomized Phase Iii Trial Of Intravenous Rigosertib In Patients With Higher-Risk Myelodysplastic Syndromes (Hr-Mds) After Failure Of Hypomethylating Agents (Hmas) Study Design Informed By Subgroup Analyses Of Ontime.

TPS7077 Background: Encouraging effects of rigosertib on overall survival (OS) seen in subgroups of pts in ONTIME informed the design of a new pivotal trial (Study 04-30; INSPIRE). This Phase III, randomized study has been initiated in pts with HR-MDS failing HMA treatment, testing the hypothesis that a more homogenous HR-MDS pt population (based on prognostic factors defined in ONTIME) will benefit from rigosertib. Methods: Major inclusion criteria: age 18-79 years; RAEB-1, RAEB-2, or RAEB-t; ≥ 1 cytopenia; failure of prior HMA; duration of prior HMA of ≤ 9 months; last dose of HMA ≤ 6 months before screening; ECOG status 0-2. Randomization is stratified by the revised International Prognostic Scoring System (IPSS-R; Greenberg et al, 2012) very high risk (VHR) vs non-VHR and by geographic region. These criteria were influenced by OS results observed in the subgroups of ONTIME listed in the table below. Rigosertib is administered as an 1800 mg/24 hr infusion for 72 hr every 2 weeks for 16 weeks, then every 4 weeks (N~150) vs physician’s choice of treatment (N~75). Primary endpoints: OS in the ITT population and in the IPSS-R VHR subgroup. Secondary endpoints: OS in pts with monosomy 7 and/or trisomy 8 chromosomal aberrations, overall response and bone marrow blast response per IWG 2006, quality-of-life per EuroQol EQ-5D, hematologic improvement, and rigosertib population pharmacokinetics. Genomic studies will be performed at baseline and monitored in both arms. Enrollment opened in December 2015 and is ongoing. Clinical trial registry number: NCT02562443. Clinical trial information: NCT02562443. Rigosertib Best supportive care Log-rank p-value Hazard ratio (Rigosertib / BSC) (95% CI) N Median (months) N Median (months) Months of last HMA ≤ 9 103 7.7 46 4.5 0.0025 0.55 (0.37, 0.81) > 9 96 9.2 52 8.1 0.42 1.18 (0.79, 1.74) Age (years) < 80 155 8.6 86 5.4 0.068 0.76 (0.57, 1.02) ≥ 80 44 4.5 14 6.8 0.21 1.57 (0.77, 3.20) Months since last dose of HMA ≤ 6 173 7.9 91 5.4 0.24 0.84 (0.63, 1.12) > 6 26 9.8 8 11.9 0.99 1.00 (0.41, 2.44) IPSS-R risk level Intermediate/Low 15 9.7 14 12.6 0.21 1.71 (0.56, 5.24) Very high 93 7.6 41 3.2 0.015 0.61 (0.36, 1.03) Very high 93 7.6 41 3.2 0.015 0.61 (0.36, 1.03)