Phase 2 Study of Selinexor in Patients with MDS Refractory to Hypomethylating

Agents: Interim Report

Klimek V, Coleman M, Alvarez K, Sen F, Pichardo J, Kashyap T, Klebanov B.

(MSKCC 14-005; NCT02228525)

Virginia Klimek, MD May 6, 2017 MDS 2017

Valencia, Spain

• Nuclear-cytoplasmic shuttling is a normal regulatory process mediated by a family of chaperones proteins (Karyopherins), including XPO1 (Exportin 1)

• XPO1 has > 200 cargos with a leucine-rich

nuclear export sequence (NES) • Up-regulated XPO1 function promotes

survival in cancer cells via accelerated nuclear export of Tumor Suppressor Proteins (TSP) and normal growth regulatory proteins.

Nucleocytoplasmic Shuttling & XPO1 Inhibition by SINE Compounds

• Selinexor – oral, reversible, first-in-class Selective Inhibitor of Nuclear Export (SINETM) that specifically blocks XPO1 function.

• Binds cysteine-528 of XPO1 (in cargo binding pocket), inducing

transient G1/G2 cell cycle arrest.T1/2= 6-7 hr.

• Selinexor forces nuclear retention of regulatory proteins, allowing them to carry out their normal functions

KPT-330/selinexor

Courtesy, Conforti et al.

Oncogenic Pathways Activated Tumor Suppressor Proteins Enhanced by XPO1 inhibition

PI3K ↑, AKT ↑, or PTEN↓ FOXO, p27, PP2A

Del p53, MDM2↑ FOXO, p14ARF

Ras/Raf/MEK/ERK↑ FOXO, PP2A

HER2, EGF-R (HER1) p21CIP1, p53

p16INK4A ↓and/or p14ARF ↓ pRB, p53

mTOR↑ p53, p27

Wnt / ß-Catenin ↑ APC, HMGBP1, FOXO

Del Rb P27, E2F4/5

CDK2-Cyclin E-E2F1 pRb, p27, p21CIP1

NPM Mutation (NPMc) p53, p14ARF, NPM1 nuclear

c-Myc ↑ PP2A, p21CIP1, HMGBP1

Bcr-Abl PP2A, c-Abl

Notch↑ FOXO

NF-κB ↑ IκB

Bcl2 ↑, Bcl-xL ↑ p53, p16INK4A

XPO1 Inhibition Modulates Multiple Oncogenic Pathways

Courtesy, Karyopharm Therapeutics

XPO1 over-expression is seen in MDS and AML and is associated with poorer survival in AML

XPO1 expression in MDS Bone marrow mononuclear cells

Courtesy, Dr. G. Schwartz

Courtesy, Dr. Kojima (Kojima, et al. 2013)

XPO1 over-expression is associated with poorer survival in AML

Cell Line KPT330 IC50 (μM) Cell Line KPT330 IC50 (μM)

EOL1 0.010 F36P 0.380 SIGM5 0.020 BDCM 0.435 CMK 0.030 TF-1 0.438

CMK115 0.073 HEL9217 0.440 MV-4-11 0.073 NB4 0.445 OCIM1 0.080 HL-60 0.530 GDM1 0.140 AML-193 0.540 PL21 0.160 KASUMI1 0.540

OCIAML2 0.180 P31FUJ 0.588 MOLM13 0.188 SKM1 0.660

MO7e 0.200 HEL 0.820 MOLM16 0.210 THP-1 0.820 OCIAML5 0.230 CMK86 0.910

KG1 0.240 NOMO-1 1.003 OCIAML3 0.270 KO52 2.053

ME1 0.343 KASUMI6 3.170 UT7 0.365 PBMC >10

Selinexor Activity in AML Cell Lines Potent, broad cytotoxicity in cancer cells with minimal effect on normal cells (PBMC)

Courtesy, Karyopharm Therapeutics

MDS Study Rationale • Standard treatment options are limited after HMA:

AML induction therapy (if appropriate) Allo SCT (if age, medical condition, and disease status allow)

Supportive care • Survival is short following HMA failure:

IPSS Int-2/High Risk/RAEBt - 5-6 months 1

IPSS Low/Int-1 Risk – 16-17 months 2,3

• New treatments are needed for pts who progress on HMA

1Prebet T, et.al., J Clin Oncol. 2011; 29(24):3322-7 2Prebet T, et.al., Haematologica 2013; 98(2): e18-e19 3Jabbour EJ, et.al., Cancer 2015; 121(6): 876-82

Study Design

Allowable selinexor dose reductions on 3-week schedule: 40 mg twice weekly for 2 weeks 80 mg once weekly for 2 weeks

Phase 2, single arm, two-stage design. 25% RR is promising. Accrual goal=20 Primary Objective: ORR (CR+mCR+PR+HI)1 in HMA-refractory MDS Secondary Objectives: Response duration, Survival, Tolerability of chronic therapy, Pharmacodynamics (PDn) Study procedures: Serial response assessments Continuous toxicity monitoring Serial PB/BM collection for PDn Treatment allowed indefinitely, barring POD or excessive toxicity

1Cheson, BD, et.al., Blood, 2006;108, 419–425.

Patient Baseline Characteristics (n=16)

# Pts % Pts # Pts % Pts Median Age (yrs) 76 (50 - 83) Female 3 19% Male 13 81% De novo 15 94% Therapy-related 1 6% WHO Subtype

RAEB-1 2 13% RAEB-2 6 38% AML 5 31% RCUD 1 6% RCMD 1 6% MDS/MPN 1 6%

IPSS-R Risk Group Very Low 0 0% Low 2 13% Intermediate 4 25% High 5 31% Very High 5 31%

BM Blasts

< 5% 2 13% 5-10% 3 19% 11-20% 9 56% 21-30% 2 13%

IPSS-R Cytogenetics Very Good 1 6% Good 2 13% Intermediate 3 19% Poor 2 13% Very Poor 3 19% Unknown 5 31%

Prior therapy Median # cycles 11 (3 - 58) Decitabine 9 56% 5-azacytidine 2 13% Both 5 31%

ID#

Time to Best Resp

(days)

Time on Study (days)

IPSS-R Risk

Category IPSS-R Cyto

WHO Subtype

TP53

FLT3

RUN

X1

NPM

1

TET2

ASXL

1

SF3B

1

CBL

mCR 8 21 52 ≥ Int Unk RAEB-1

21 126 300

(ongoing) Int Very Good RAEB-2

12 70 70 Very High Poor RAEB-2

1 28 72 High Good RAEB-2

SD 19 20 133 ≥ Int Unk RCMD

15 21 90 Very High Very Poor RAEB-2

2 28 28 ≥ High Unk AML (20%)

18 42 62 Very High Very Poor RAEB-2

20 21 217 High Intermediate AML (25%)

7 20 259 High Good MDS/MPN

PD 22 n/a 28 Very High Poor AML (20%)

3 n/a 21 High Intermediate AML (20%)

9 n/a 28 Very High Very Poor RCUD

• Selinexor induced mCRs in 4/13 (30%) evaluable patients • Two pts (#7, #20) with SD had improved BM blast % and/or CBC values

Responses and Associated Disease-Related Parameters (Evaluable for response, n=13)

Pt #7

WBC

(K/m

cL)

Abs M

ono

(K/m

cL)

Plat

elet

s (K

/mcL

)

Pt #20

Effects on CBC parameters/BM blast % in patients with SD

Plat

elet

s (K

/mcL

)

ANC

(K/m

cL)

MDS/MPN (12 cycles selinexor)

AML/RAEB-t (25% blasts; 10 cycles selinexor)

0

10

20

30

40

50

60

70

SCR C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 EOT

0

0.5

1

1.5

2

2.5

SCR C1 C2 C3 C4 C5 C6 C7 C8 C9 C10C11C12 EOT0

50

100

150

200

250

300

350

SCR C1 C2 C3 C4 C5 C6 C7 C8 C9 C10C11C12 EOT

Blas

ts (%

)

0%

5%

10%

15%

20%

25%

30%

SCR C1 C2 C4 C8 EOT0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

SCR C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 EOT

0

10

20

30

40

50

60

SCR C1 C2 C3 C4 C5 C6 C7 C8 C9 C10C11C12 EOT

Side Effects Attributed to Selinexor (evaluable for toxicity, n=16)

Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) cycle length 4wk 3wk 4wk 3wk 4wk 3wk 4wk 3wk

Anemia - - - 8 40 - - - Anorexia/Weight Loss - 33 40 8 - - - - Dehydration - - 20 - - - - - Diarrhea 20 8 - 8 - - - - Dysgeusia - 8 - 8 - - - - Dyspnea 20 - - - - - - - Fatigue 20 - 60 42 20 17 Febrile Neutropenia - - - - 8 - - Hyperglycemia 40 17 20 17 - 17 - - Hyperkalemia 40 - - - - - - - Hypoalbuminemia 60 - - - - - - - Hypocalcemia - - 20 - - 8 - - Hyponatremia 40 33 - - 20 33 - - Hypotension - - - - - - - 8 Lethargy - - 20 - - - - - Lung Infection - - - - - 8 - - Malaise 20 - 20 - - - - - Mucosal Infection - - - 8 - - - - Nausea 40 33 - 17 20 - - - Neutrophil Count Decreased - - - 17 - 17 20 - Platelet Count Decreased 20 8 - 8 - 17 40 17 Weakness - - 20 - - - - - White Blood Cell Decreased 20 - - 8 20 - 20 - using patients' highest grade per tox

Study Progress and Patient Disposition

Reason for coming off-study # % Toxicity - pt decision (4 wk schedule) 3 19% SAE, infection (unrelated) 2 13% Withdrawal (other) 2 13% Progressive Disease 6 38% SCT 2 13% N/A (on treatment) 1 6%

Study progress: Currently in second stage 13 pts evaluable for efficacy 16 pts evaluable for toxicity

Note: •Three pts who came off study for toxicity were on 4-week regimen. •NO pts withdrew from study due to toxicity on 3-week regimen •Median time on study: 4 week regimen: 35 days 3 week regimen: 139 days

Median survival: 8.6 months

# Pts % Pts ALIVE 2 13% AWD, off study 1 6%

On study 1 6%

DEAD 13 81% Died of Disease 10 63%

Died from Infection 2 13% Graft Failure post Allo-SCT 1 6%

Lost to f/u 1 6% n = 16

Pharmacodynamic studies

Selinexor preclinical data: • Selinexor modulates Wnt/β-catenin signaling (TCF1, LEF1,

and Frzd3) and proteins in the p53 pathway (c-myc and FOXP3)

• Inhibits NF-κB transcriptional activity Initial planned pharmacodynamic assessments: • In MDS pts, can we see modulation of Wnt signaling, p53

and NF-κB activity as seen in other diseases? • BM immunohistochemical (IHC) stains to assess nuclear

localization of p53, β-catenin and p65 • Assess mechanism of selinexor: XPO1, p53, p21, PARP,

and caspase levels

Conclusions • Primary efficacy endpoint was achieved with RR 30% (4 mCRs;

total evaluable n=13) • Dose reduction and 1 week treatment break improved chronic

tolerability. Median time on study increased by 100 days • Interim median survival 8.6 months in this higher-risk cohort

(vs. expected 5-6 months) • XPO1 induction in all patients demonstrates selinexor target

engagement and confirms XPO1 mRNA as a selinexor PD biomarker

Future directions

• Complete study enrollment (end of 2017) • Complete correlative data analysis

– Serial PDn studies to assess modulation of NF-κB, WNT, and p53 signaling

– Mechanistic assays

Thank You ! • Morgan Coleman, MPH • Kelsey Alvarez, BSN, RN • Filiz Sen, MD • MSKCC Leukemia Service • MSKCC patients and their

families