S839 phase Ii Study of Oral Rigosertib Combined With Azacitidine in Patients With Higher‐risk Myelodysplastic Syndromes (Mds)

Abstract

Background: Azacitidine based combination trials have not demonstrated improved response or outcome over single agent azacitidine (Sekeres JCO 2017; Ades ASH 2018). Results of a Phase I/II study in MDS patients demonstrated oral rigosertib and standard-dose azacitidine to be well-tolerated with efficacy in HMA-naive and HMA-failure patients: at 560 mg qAM/280 mg qPM rigosertib dosing, overall response rate (ORR) was 77%; 88% for HMA-naive group, 60% for HMA-failure group. An increase in genitourinary (GU) adverse events was noted with the combination. Rigosertib at higher doses (1120 mg/day) yielded maximum ORR in lower-risk MDS and was thus

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“…Of the 55 patients evaluable for response, median duration of response was 12.2 months in HMAnaïve patients and 10.8 months in HMA-failure patients. 16 Responses to treatment occurred in all IPSS-R subgroups. In the low/intermediate-risk subgroup (n = 17), complete response (CR) occurred in 4 patients and marrow CR (mCR) occurred in 5 patients.…”

“…The 5-year OS did not differ significantly between groups: 94.7% vs 95.9% in the 9-week and 12-month groups, respectively (HR,1.36 90% CI, 0.98-1.89). 16 (Table 2) Of these 5 trials, only PERSPEHONE's results showed noninferiority. In a meta-analysis of the 5 trials, there was a statistically significant difference in the DFS and OS between the shorter duration of treatment-both 9 weeks and 6 months, pooled-compared with the 12-month duration of treatment, with a HR of 1.21 (95% CI, 1.08-1.37) for DFS and an HR of 1.31 (95% CI, 1.08-1.59) for OS.…”

“…KIT function is also critical for the development and maintenance of different cell types, including hematopoietic cells, mast cells, melanocytes, gametocytes, and ICCs. [14][15][16] Based on immunophenotypic, ultrastructural, and cell signaling similarities, GISTs are believed to originate from KIT-expressing progenitor ICCs through somatic KIT or PDGFRα mutations, which are believed to be an early step in GIST pathogenesis.…”

“…In the very high-risk subgroup (n = 33), CR occurred in 5 patients and mCR in 10 patients. 16 Four safety optimization strategies were used to minimize genitourinary toxicities, including taking rigosertib at least 2 hours after lunch to avoid nocturnal bladder dwell time, encouraging oral hydration of at least 2 liters of fluid per day, mandatory bladder emptying before bedtime, and assessing urine pH around 2 hours after the morning dose of rigosertib. 16…”

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“…The 5-year OS did not differ significantly between groups: 94.7% vs 95.9% in the 9-week and 12-month groups, respectively (HR,1.36 90% CI, 0.98-1.89). 16 (Table 2)…”