Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes � Clinical Studies I
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.
Disclosures: Silverman: Onconova Therapeutics Inc: Honoraria , Patents & Royalties: co-patent holder on combination of rigosertib and azacitdine , Research Funding . Daver: ImmunoGen: Other: clinical trial , Research Funding . DiNardo: Novartis: Research Funding . Konopleva: Novartis: Research Funding ; AbbVie: Research Funding ; Stemline: Research Funding ; Calithera: Research Funding ; Threshold: Research Funding . Pemmaraju: Stemline: Research Funding ; Incyte: Consultancy , Honoraria ; Novartis: Consultancy , Honoraria , Research Funding ; LFB: Consultancy , Honoraria . Fenaux: CELGENE: Honoraria , Research Funding ; JANSSEN: Honoraria , Research Funding ; AMGEN: Honoraria , Research Funding ; NOVARTIS: Honoraria , Research Funding . Fruchtman: Onconova Therapeutics Inc: Employment . Azarnia: Onconova Therapeutics Inc: Employment .
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