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 investigated in additional cohorts (Raza ASH 2017). Risk-mitigation strategies were employed to reduce GU AEs (Navada ASH 2018).
Oral rigosertib was administered on Day 1–21 of a 28-day cycle (840 mg or 1120 mg total); parenteral (SC or IV) azacitidine 75 mg/m2/day was given for 7 days starting on Day 8 in patients with MDS including both HMA naive and HMA failures.
Of those patients receiving ≥840 mg rigosertib, 55 were evaluable for response. 26 were treated with 840 mg rigosertib and 29 were treated with 1120 mg.
Median duration of response was 12.2 months (range, 0.1–24.2+) and 10.8 months (range, 0.1–11.8+) for HMA naive and HMA-failure pts, respectively. Median number of cycles to initial/best response was 1/4 and 2/5, respectively.
Responses per IWG 2006 occurred in all IPSS-R subgroups. In low/intermediate (N = 17), CR occurred in 4 (24%), PR was 0, mCR was 5 (29%), stable disease was 2 (12%), progression was 0, not evaluable was 3 (18%), HI in 9 (53%). In high risk (N = 23), CR occurred in 2 (9%), PR in 1 (4%), mCR was 8 (35%), stable disease was 6 (26%), progression was 1 (4%), not evaluable was 4 (17%), and HI in 7 (30%). In very high risk (N = 33), CR occurred in 5 (15%), PR was 0, mCR was 10 (30%), stable disease was 2 (6%), progression was 4 (12%), not evaluable was 11 (33%), and HI in 11 (33%).
The following Safety-optimization strategies were employed to minimize genitourinary toxicities of hematuria and dysuria:
- 1. Second rigosertib dose must be taken at 3 PM (±1 hour) at least 2 hours after lunch to avoid a nocturnal bladder dwell time (Maniar M, et al. ASCO 2018 Sub for Pub)
- 2. Oral hydration of at least two liters of fluid per day is encouraged
- 3. Mandatory bladder emptying prior to bedtime
- 4. Urine pH approx. 2 hours after AM dose. Sodium bicarbonate suggested 650 TID if pH < 7.5
1. Second rigosertib dose must be taken at 3 PM (±1 hour) at least 2 hours after lunch to avoid a nocturnal bladder dwell time (Maniar M, et al. ASCO 2018 Sub for Pub)2. Oral hydration of at least two liters of fluid per day is encouraged3. Mandatory bladder emptying prior to bedtime4. Urine pH approx. 2 hours after AM dose. Sodium bicarbonate suggested 650 TID if pH < 7.5
Oral rigosertib with azacitidine demonstrated efficacy in HMA-naive patients. The combination markedly improved hematopoiesis and reduced blasts in HMA-failure patients. The combination was well-tolerated in repetitive cycles for 25+ months. Risk mitigation strategies reduced urinary AEs in the expansion cohort. A pivotal Phase 3 trial is planned in an HMA-naive patient population.