1. Combination Ruxolitinib + Sonidegib in Myelofibrosis
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.
This program is supported by educational grants from Amgen, Celgene Corporation, Merck, Incyte, Seattle Genetics, and Takeda Oncology.

2. Ruxolitinib + Sonidegib in MF: Background
Ruxolitinib: JAK1/2 inhibitor approved to treat MF-related symptoms and splenomegaly
Sonidegib: Hedgehog pathway inhibitor targeting SMO[1]
Addition of sonidegib to ruxolitinib improved splenomegaly and bone marrow fibrosis in murine MF model[2]
Current trial evaluates combination of ruxolitinib and sonidegib in pts with intermediate- or high-risk MF
Phase Ib results established recommended phase II dose of sonidegib mg/day + ruxolitinib 20 mg BID[3]
Updated safety/efficacy for 27 pts who received the recommended phase II dose presented here[4]
MF, myelofibrosis; SMO, smoothened.
1. Pan S, et al. ACD Med Chem Lett. 2010;1: Bhagwat N, et al. ASH Abstract 666.
3. Gupta V, et al. ASH Abstract Gupta V, et al. ASH Abstract 825.
Slide credit: clinicaloptions.com

3. Ruxolitinib + Sonidegib in MF: Study Design
Open-label phase Ib/II trial
Analysis performed 24 wks after last enrollment at recommended phase II dose (RP2D)
Endpoints: Safety/tolerability, pharmacokinetics, efficacy (splenomegaly/bone marrow fibrosis reduction, JAK2 V617F)
Dose Escalation[1]
Determine MTD/RP2D
Dose Expansion[2]
Treat additional pts at RP2D
IPSS, International Prognostic Scoring System; MF, myelofibrosis; MTD, maximum tolerated dose; PET-MF, postessential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; SMO, smoothened.
PMF, PPV-MF, or PET-MF;
int- or high-risk IPSS; palpable splenomegaly;
JAK/SMO inhibitor naive
(N = 50)
Sonidegib
400 mg PO QD +
Ruxolitinib
10, 15, or 20 mg PO BID
(n = 23)
Sonidegib
400 mg PO QD +
Ruxolitinib
20 mg PO BID
(n = 27)
1. Gupta V, et al. ASH Abstract Gupta V, et al. ASH Abstract 825.
Slide credit: clinicaloptions.com

4. Ruxolitinib + Sonidegib in MF: Key Baseline Characteristics
MF classification, %
Primary MF
Post polycythemia vera MF
Post essential thrombocythemia MF
59.3
14.8
25.9
Median palpable spleen length, cm (range)
10 (1-29)
Median spleen volume by MRI/CT, cm3 (range)
2093 ( )
IPSS risk, %
Low
Intermediate-1
Intermediate-2
High
3.7
66.7
JAK2 V617F +, %
85.2
IPSS, International Prognostic Scoring System; MF, myelofibrosis.
Slide credit: clinicaloptions.com
Gupta V, et al. ASH Abstract 825. Reproduced by permission.

5. Ruxolitinib + Sonidegib in MF: Safety
26% pts discontinued treatment: treatment-related AEs (n = 3), other AEs (n = 2), death (n = 1), pt decision (n = 1)
AEs in > 20% Pts, %
All Grades (n = 27)
Grade 3/4 (n = 27)
Hematologic
Anemia
Thrombocytopenia 52 26 33 11
Nonhematologic
Muscle spasms*
Elevated creatine phosphokinase*
Myalgia*
Dysgeusia*
Diarrhea
Fatigue
Pyrexia
Alopecia* 48 37 30 22 4 19 7 -
AE, adverse event; MF, myelofibrosis.
*AE not typically observed with ruxolitinib.
Slide credit: clinicaloptions.com
Gupta V, et al. ASH Abstract 825. Reproduced by permission.

6. Ruxolitinib + Sonidegib in MF: Reduction in Splenomegaly
Spleen Length Response at Week 24
+400%
100
Maximum Change From Baseline in Spleen Length by Palpation, % 60 20
-20
-60
50% reduction
-100
Sonidegib 400 mg QD + Ruxolitinib 20 mg BID
(n = 21)
Spleen Volume Response at Week 24 20
MF, myelofibrosis; tx, treatment.
Change From Baseline in Spleen Volume by MRI/CT at Week 24, %
-20
-40
35% reduction
-60
-80
-100
Slide credit: clinicaloptions.com
Gupta V, et al. ASH Abstract 825. Reproduced with permission.

7. Ruxolitinib + Sonidegib in MF: Efficacy
55.6% pts achieved ≥ 50% reduction in palpable spleen length at end of Wk 24; 92.6% at any time on treatment
55.6% achieved nonpalpable spleen at any time on treatment
44.4% pts achieved ≥ 35% reduction in MRI/CT spleen volume at end of Wk 24; 55.6% at any time during treatment
JAK2 V617F allele burden absolute changes from baseline to Wk 24 ranged from -56.5% to 7.0% with mean of -9.0%
Bone marrow fibrosis change from baseline to Wk 24: improved (n = 2), stable (n = 8), worsened (n = 3)
Pharmacokinetics of combination tx similar to individual agents
Bone marrow sonidegib concentrations comparable to plasma
MF, myelofibrosis; tx, treatment.
Slide credit: clinicaloptions.com
Gupta V, et al. ASH Abstract 825.

8. Ruxolitinib + Sonidegib in MF: Conclusions
Combination of ruxolitinib and sonidegib generally well tolerated with no observable PK interactions
Early efficacy results similar to ruxolitinib monotherapy
Majority of pts achieved resolution of palpable splenomegaly, ≥ 35% reduction in spleen volume
JAK2 V617F allele burden and bone marrow fibrosis improved in some patients
Wk 24 efficacy failed to attain predetermined benchmark for additional patient enrollment
Study will pursue longer-term follow-up of current patients
MF, myelofibrosis; PK, pharmacokinetic.
Slide credit: clinicaloptions.com
Gupta V, et al. ASH Abstract 825.

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