A Phase II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndromes (MDS)

Background: Rigosertib (RIG) is a Ras-mimetic that inhibits the PI3K and PLK cellular signaling pathways by binding directly to the Ras-binding Domain found in Ras effector proteins.� It has been tested as a single agent in patients (pts) after failure of hypomethylating agents (HMAs).� In vitro, the combination of RIG with azacitidine (AZA) inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (RIG administered prior to AZA) (Skidan et al 2006).� Phase I results of this study in pts with MDS or AML showed combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). Phase II was initiated to further study the combination in pts with MDS.

Methods: Results from pts in Phase II with MDS previously untreated with an HMA, or who had failed to respond to or progressed on a prior HMA, are presented, while response data from Phase I MDS pts are updated.� Pts with CMML are analyzed separately.� Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM).� AZA 75 mg/m²/d SC or IV was administered for 7 days starting on Day 8.� A CBC was performed weekly and a bone marrow aspirate and/or biopsy was performed at baseline, day 29, and then every 8 weeks thereafter.

Results: The combination of oral RIG and AZA has been administered to a total of 45 pts within Phase I (N=18) and Phase II (N=27).� Pts were classified into the following MDS risk categories per the IPSS (Greenberg et al, Blood 1997):� intermediate-1 (4), intermediate-2 (10), high-risk (14), and IPSS classification pending (4).� Five pts had CMML and 8 had AML.� Median age was 66 years; 69% of pts were male; and ECOG performance status was 0, 1, and 2 in 27%, 67%, and 6%, respectively.� Twelve pts [MDS (9), CMML (3)] received prior HMA therapy: AZA (11 pts), decitabine (1 pts). �Patients have received 1-21+ cycles of treatment to date (median, 3 cycles), with median duration of treatment of 14 weeks.�

Among 15 evaluable MDS pts treated with the RPTD (1 pt in Phase I, 14 pts in Phase II), marrow responses were observed in 10: marrow CR (mCR) (8), marrow PR (mPR) (2).� Responses according to IWG criteria were observed in 10 pts: complete remission (CR) (1), mCR (7), hematologic improvement (HI) (2).�

Table 1: Responses for MDS Patients Treated at the Recommended Phase II Dose

Pt	Prior HMA	Best BMBL at Nadir1	IWG Response2	Hematologic Improvement
102-008	None	mCR	mCR	Platelet
101-010	None	mCR	CR	Erythroid & Neutrophil
101-011	None	mCR	mCR	None
101-013	None	mCR	mCR	Erythroid
102-010	None	SD	SD	None
101-014	AZA	PD	PD	None
102-011	AZA	mPR	HI	Erythroid & Platelet
101-016	AZA	SD	SD	None
101-017	AZA	mCR	mCR	None
102-013	None	NE	NE	NE
101-019	None	SD	SD	None
101-021	None	PD	PD	None
101-024	None	mCR	mCR	None
101-022	AZA	mCR	mCR	None
101-025	None	mCR	mCR	None
101-026	AZA	NE	NE	NE
101-027	None	NE	NE	NE
102-016	None	mPR	HI	Platelet
1Silverman et al, Hematol Oncol 2014 2IWG = International Working Group (Cheson et al, Blood 2006) NE = not evaluable BMBL = bone marrow blast

Overall, in pts with MDS treated on Phase I and Phase II, marrow responses were observed in 15 out of 20 evaluable pts: mCR (13), mPR (2).� Responses according to IWG 2006 criteria were observed in 14 out of 19 evaluable MDS pts: CR (2), mCR (10), HI (2). �Among the 7 evaluable pts with MDS in both the Phase I and Phase II who had failed to respond or progressed on prior treatment with an HMA, 5 had a response after RIG was added: CR (1), mCR (3), HI (1). Analyzed as a separate subgroup, 2 out of 5 (40%) pts with CMML had a mCR.

The most frequent adverse events (AEs) in Cycle 1 included nausea (21%) and fatigue (15%), which were also the most frequent AEs in all cycles (fatigue, 28%; nausea, 26%).�

Six deaths have been observed so far.� Three pts were treated for more than 1 year and continue on study.

Conclusions: The combination of oral rigosertib and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. �Marrow CR was observed in 65% of pts, both with de novo MDS and after failure of prior HMA therapy.� In pts who received the RPTD, 67% of pts with MDS had a bone marrow blast and IWG response. These results suggest potential synergistic interaction of the combination and support continued study of this unique combination in patients with MDS.