Phase 2 expansion study of oral rigosertib combined with azacitidine (AZA) in patients (Pts) with higher-risk (HR) myelodysplastic syndromes (MDS): efficacy and safety results in HMA treatment naïve & relapsed (Rel)/refractory (Ref) patients. Presented at 2019 EHA Congress; June 13-16, 2019; Amsterdam, The Netherlands.
Abstract S488.Sekeres MA, Othus M, List AF, et al. In vitro, the combination of rigosertib and azacitidine inhibits growth and induces apoptosis of leukemic cells. The Phase II, Part 2 Expansion will assess if treatment with rigosertib in combination with azacitidine, has measurable effects in patients with myelodysplastic syndrome (MDS). The median duration of treatment was 7.8 months (range, 7.0-25.2+) and median duration of response (DoR) was 12.2 months (range, 0.1-24.2+).Among patients with HMA-refractory MDS who received rigosertib ≥840 mg daily, 26 patients were evaluated for response. The ORR was 54%, including 1 patient (4%) each who achieved CR or partial response (PR); 5 patients (19%) had marrow CR and hematologic improvement, 2 (8%) with only hematologic, and 5 (19%) with marrow improvement.
However, an increase in genitourinary (GU) adverse events (AEs) was noted.Based on the observation that rigosertib at a higher dose of 1120 mg/day provided improved ORR in patients with lower-risk MDS,In this phase II trial, patients with MDS were treated with rigosertib at 840 mg or 1120 mg plus standard-dose parenteral azacitidine at 75 mg/mOf 55 patients treated with ≥840 mg rigosertib, 29 received 1120 mg, and 26 received 860 mg (morning/evening split doses). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle.
Adherence to these guidelines provided successful management in 70% of patients with grade ≥2 hematuria.Safety was evaluated in 79 patients receiving rigosertib at all dose levels; 100% of patients had an adverse event (AE) of any grade. Rigosertib, Onconova’s lead candidate, is a proprietary Phase 3 small molecule. Rigosertib, Onconova’s lead candidate, is a proprietary Phase 3 small molecule. Rigosertib was given at 840mg/day (560 mg in the morning & 280mg in the afternoon); or 1120mg/day (560 mg in the morning & 560mg in the afternoon or 840 mg in the morning and 280 mg in the afternoon) (Maniar ASH 2018). Rigosertib is the sodium salt of (E)-2,4,6-trimethoxystyryl-e-carboxymethylamino-4-methoxybenzyl sulfone, an unsaturated sulfone kinase inhibitor [ 11 ]. Phase II study of oral rigosertib combined with azacitidine in patients with higher-risk myelodysplastic syndromes (MDS). It is a small molecule that inhibits cellular signaling by targeting the Ras binding domain with downstream effects on the PI3K/AKT and Raf/PLK pathways [ 12 ].
The median duration of treatment was 4.9 months (range, 1.1-20.8+) and DoR was 10.8 months (range, 0.1-11.8+).Navada pointed out: “The median duration of response in patients failing HMA was approximately 11 months, which is important since the historic median overall survival is approximately 4 to 6 months.”In the HMA-naive and HMA-failed cohorts, the median time to initial response was 1 and 2 cycles and the median time to best response was 4 and 5 cycles, respectively, which was quicker than observed with single-agent azacitidine.Responses were observed at all levels of cytogenics that ranged from 73% in patients with very poor to 76% in patients with good cytogenetics; notably, the response was 100% in 4 HMA-naïve patients having poor cytogenetics.In 46 transfusion-dependent patients, 30% of HMA-naïve and 15% of HMA-failed patients achieved transfusion independence.“The combination regimen was well-tolerated and was given in continuing cycles for >2 years, even in those who did not respond to HMA therapy,” said Navada.“Safety management guidelines for genitourinary toxicities work and allowed patients to continue on combination therapy,” she added.
Azacitidine (AZA) is first-line therapy for pts with higher-risk MDS. These guidelines included split rigosertib doses, hydration, mandatory pre-bedtime bladder emptying, and adjustment of urine PH with sodium bicarbonate when needed. Among responding patients, 10 patients (34%) achieved a complete response (CR), 5 (17%) showed marrow CR with hematologic improvement, 3 (10%) showed only hematologic improvement, and 8 (28%) showed only marrow improvement. Safety of patients is an objective throughout all parts of the study.