1. Rigosertib + Azacitidine in Patients With Higher-Risk MDS
New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
MDS, myelodysplastic syndrome.
This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

2. Rigosertib + Azacitidine in MDS: Background
Azacitidine, a hypomethylating agent, is the current SOC for high-risk MDS[1]
Treatment failure and relapse are common and are associated with poor outcomes (median OS: 5.6 mos)[2]
Rigosertib: novel anticancer agent with activity in MDS and AML[3]
Targets Ras-binding domain, PI3K/AKT, Raf/PLK and other downstream pathways
Phase I study of rigosertib + azacitidine suggested clinical activity of this regimen in MDS post-HMA failure with toxicity similar to single-agent azacitidine[4]
Current phase II study evaluated safety and efficacy of rigosertib + azacitidine in pts with high-risk MDS or CMML[5]
AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; HMA, hypomethylating agent; MDS, myelodysplastic syndrome; SOC, standard of care.
1. Silverman LR, et al. J Clin Oncol. 2006;24:
2. Prébet T, et al. J Clin Oncol. 2011;29:
3. Olnes MJ, et al. Leuk Res. 2012;36:
4. Navada SC, et al. ASH Abstract 3252.
5. Navada SC, et al. ASH Abstract 910.
Slide credit: clinicaloptions.com

3. Rigosertib + Azacitidine in MDS: Study Design
Open-label, multicenter phase II study[1]
Endpoints: CR, PR, bone marrow response, improvement in neutrophil, platelet, and erythroid counts, safety and tolerability
Bone marrow aspiration/biopsy: Wk 4, every 8 wks after
4-wk cycles
Adult pts with MDS or CMML;
IPSS int-1, int-2, or high;
ECOG PS 0-2;
adequate organ function;
untreated or relapsed/failed prior HMA; no prior rigosertib
(N = 37)*
Rigosertib
560 mg qAM/280 mg qPM† PO Wk 1-3 +
Azacitidine
75 mg mg/m2/day SC or IV Wk 2
No treatment Wk 4
*For this analysis, only MDS pts from phase I and II studies.
†Recommended dose from previous phase II study.[2]
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMML, chronic myelomonocytic leukemia; ECOG, Eastern Cooperative Oncology Group; HMA, hypomethylating agent; int, intermediate; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; PS, performance status; ULN, upper limit of normal.
1. Navada SC, et al. ASH Abstract 910.
2. Navada SC, et al. ASH Abstract 3252.
Slide credit: clinicaloptions.com

4. Rigosertib + Azacitidine in MDS: Baseline Characteristics
MDS Pts
(N = 37)
Age, median yrs (range)
64 (25-85)
Male, % 73
ECOG PS, % 1 2 24 3
Earlier HMA therapy, %
Azacitidine
Decitabine
Both
None 27 8 62
Characteristic
MDS Pts
(N = 37)
IPSS risk group, %
Intermediate-1
Intermediate-2
High 27 41 32
IPSS cytogenetic risk group, %
Good
Intermediate
Poor
Unknown 22 38 24 16
ECOG, Eastern Cooperative Oncology Group; HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; PS, performance status.
Slide credit: clinicaloptions.com
Navada SC, et al. ASH Abstract 910.

5. Rigosertib + Azacitidine in MDS: Response
Parameter
MDS Pts
(N = 37)
Evaluable for response,* n 30
Duration of treatment, median mos (range)
4 (1 to ≥ 27)
Overall response, % 77
Hematologic response,† % CR PR
Bone marrow response SD PD 20 53 3
Hematologic improvement,† %
Not evaluable, % 10
Too early to evaluate 13
Parameter
MDS Pts
(N = 37)
Overall‡ (n = 26)
Hematologic improvement, n (%)
Any lineage‡
Erythroid
Plt
Neutrophil
13 (50)
11 (42)
12 (46)
7 (27)
Bone Marrow CR (n = 16)
Evaluable for response, n
Too early to evaluate, n
Plt + erythroid + neutrophil
Plt + erythroid
None 12 4
3 (25)
6 (50)
IPSS, International Prognostic Scoring System; IWG, International Working Group; MDS, myelodysplastic syndrome; PD, progressive disease; Plt, platelet; SD, stable disease.
‡Includes pts with CR, hematologic improvement, and marrow CR.
*Phase I, n = 8; phase II, n = 22. †Per IWG 2006.
Slide credit: clinicaloptions.com
Navada SC, et al. ASH Abstract 910.

6. Rigosertib + Azacitidine in MDS: Response With Previous HMA Failure
Hematologic response in 64% of pts with previous HMA failure vs 84% of HMA-naive pts
Parameter
MDS Pts
(N = 11*)
Prior HMA cycles, range
4-20
HMA, n
Azacitidine
Decitabine
Both 8 2 1
Hematologic response,† % CR PR
Bone marrow response
BM response + HI SD PD 4 3
Trilineage hematologic improvement, %
BM, bone marrow; HI, hematologic improvement; HMA, hypomethylating agent; IWG, International Working Group; MDS, myelodysplastic syndrome; PD, progressive disease; SD, stable disease.
*Evaluable for response: phase I, n = 3; phase II, n = 8. †Per IWG 2006.
Slide credit: clinicaloptions.com
Navada SC, et al. ASH Abstract 910.

7. Rigosertib + Azacitidine in MDS: Response by IPSS Subgroup
Intermediate-1
Intermediate-2
High
Overall
(n = 10)
HMA Failure
(n = 3)
(n = 15)
(n = 7)
(n = 12)
(n = 4)
CR, n 3 2 1
PR, n
Marrow CR, n 6 8
Hematologic improvement, n 3* 1*
SD, n 4
PD, n
Not evaluable, n
Response rate, % 75 67 62 40
100
HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; PD, progressive disease; SD, stable disease.
*Concurrent marrow CR and hematologic improvement.
Slide credit: clinicaloptions.com
Navada SC, et al. ASH Abstract 910.

8. Rigosertib + Azacitidine in MDS: Bone Marrow Complete Remission Duration
Pts With Marrow CR
No prior HMA
Prior HMA failure
Bone marrow response ongoing at last assessment*
HMA, hypomethylating agent; MDS, myelodysplastic syndrome; mCR, marrow complete response. 5 10 15 20
Months
*12 pts excluded due to pending post-mCR bone marrow assessment.
Slide credit: clinicaloptions.com
Navada SC, et al. ASH Abstract 910. Reproduced with permission.

9. Rigosertib + Azacitidine in MDS: Safety
TEAE, %
(N = 37)
Cycle 1
Cycles ≥ 2
All
Grade ≥ 3
Fatigue 27 -- 19
Nausea 16
Pyrexia 24 8
Thrombocytopenia 14
Constipation 22
Diarrhea 3
Cough
Decreased appetite
Dysuria
Dizziness 11
Hematuria 5
Hypokalemia
Injection-site rxn
Neutropenia
Tachycardia
3 fatal serious AEs, none considered treatment related
Multiorgan failure, n = 1
Worsening of AML, n = 1
Sepsis, n = 1
AE, adverse event; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; rxn, reaction; TEAE, treatment-emergent AE.
Slide credit: clinicaloptions.com
Navada SC, et al. ASH Abstract 910.

10. Rigosertib + Azacitidine in MDS: Conclusions
Rigosertib + azacitidine is associated with ORR of 77% in pts with intermediate- and high-risk MDS
64% of pts with prior HMA failure responded to this therapy
Combination is well-tolerated with low incidence of grade ≥ 3 AEs, except neutropenia and thrombocytopenia
Toxicity profile similar to that of single-agent azacitidine
No increase in toxicity reported with ≥ 2 cycles of treatment
Authors conclude that this combination should continue to be investigated for the treatment of MDS
HMA, hypomethylating agent; MDS, myelodysplastic syndrome.
Slide credit: clinicaloptions.com
Navada SC, et al. ASH Abstract 910.

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