Updates in Myeloproliferative Disorders, including Chronic Myeloid Leukemia Katherine Walsh, MD

No conflicts of interest to disclose Off-label use: pacritinib, radotinib, PegIFN, ABL001, and combinations with ruxolitinib

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

A 72 year old gentlemen is referred to hematology for treatment recommendations for newly diagnosed JAK2 positive primary myelofibrosis. He reports symptoms of fatigue and decreased appetite. On exam, he appears pale and has palpable splenomegaly. The most recent CBC values were WBC 11K with 2% circulating blasts, hemoglobin 9, and platelet count of 30K. What agent has been submitted to the FDA for new drug application for myelofibrosis with thrombocytopenia (platelet count <50K)? A) Azacitidine B) Imetelstat C) Momelotinib D) Pacritinib E) Pomalidomide

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

A 32 year old woman with chronic phase CML has had a good response to tyrosine kinase inhibitor therapy with imatinib for the past 3 years comes to clinic for routine follow-up. While she has met her milestones on time and overall tolerated therapy well, she doesn’t like the idea of being on medicine lifelong and is considering having children in the next year. Her last PCR confirms continued MMR which she has maintained for 2 years. What advice can we give her based on current TKI discontinuation data? A) Imatinib can be safely stopped now B) Imatinib can be stopped after 1 more year of MMR C) Imatinib should not be stopped due to TKI withdrawal syndrome D) Imatinib should not be stopped outside of a clinical trial E) Imatinib can’t be stopped due to molecular recurrence resistant to

treatment

3

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Objectives

To discuss clinical updates in diagnosis and treatment of the myeloproliferative disorders (MPD, BCR-ABL negative) and chronic myeloid leukemia (CML). To discuss new agents in development and new

combination approaches being investigated for MPD and CML.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Updates in BCR-ABL Negative Myeloproliferative Disorders

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Mutations in MPNs

Klampfl, T et al. NEJM, December 2013 CALR added to WHO 2015 Abstract 350: 88% “triple negative” MF cases had a non-driver mutation

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Abstract 2804: Continued Treatment with Ruxolitinib Provides Additional Hematocrit Control and Spleen Volume Responses in Patients with PV Treated in the RESPONSE Study

Jean-Jacques Kiladjian, MD, Tamas Masszi, MD, PhD, Mark M. Jones, MD, Brian Gadbaw MD, Jingjin Li, PhD, Dany Habr, MD, Alessandro M. Vannucchi, MD, and, Srdan Verstovsek, MD, PhD

Vannucchi A, et al, NEJM 2015

Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib With Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results

Claire N. Harrison,1 Alessandro M. Vannucchi,2 Jean-Jacques Kiladjian,3

Haifa Kathrin Al-Ali,4 Heinz Gisslinger,5 Laurent Knoops,6 Francisco Cervantes,7 Mark M Jones,8 Kang Sun,8 Laurence Descamps,9 Viktoriya Stalbovskaya,10

Prashanth Gopalakrishna,10 Tiziano Barbui11

On Behalf of the COMFORT-II Investigators 1Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, UK; 2University of Florence, Florence, Italy; 3Hôpital Saint-

Louis et Université Paris Diderot, Paris, France; 4University of Leipzig, Leipzig, Germany; 5Medical University of Vienna, Vienna, Austria; 6Cliniques universitaires Saint-Luc and de Duve Institute, Université catholique de Louvain, Brussels, Belgium; 7Hospital

Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 8Incyte Corporation, Wilmington, DE; 9Novartis Pharma S.A.S., Rueil-Malmaison, France; 10Novartis Pharma AG, Basel, Switzerland; 11Hospital Papa Giovanni XXIII, Research

Foundation, Bergamo, Italy

COMFORT-II Study Design • Randomized, open-label, multicenter phase 3 study1 • Patients were stratified based on baseline IPSS risk category2

Ruxolitinib 15 or 20 mg oral BID

n = 146

Best available therapy (BAT) n = 73

Randomize Patients with

PMF, PPV-MF, or PET-MF with ≥ 2 IPSS risk

factors2

N = 219

2:1

1. Harrison C, et al. N Engl J Med. 2012;366(9):787-798; 2. Cervantes F, et al. Blood. 2009;113(13):2895-2901.

• Treatment continued until progressive splenomegaly, unless discontinued earlier for splenectomy, toxicity, or death

– Progressive splenomegaly was defined as ≥ 25% increase in spleen volume over on-study nadir (including baseline)

– Patients in the BAT arm were allowed to crossover and receive ruxolitinib following progressive splenomegaly; some crossed over without progressive splenomegaly following primary analysis

BID, twice daily; IPSS, International Prognostic Scoring System; PET, post–essential thrombocythemia; PMF, primary MF; PPV. post–polycythemia vera.

Crossover to ruxolitinib

Best Percentage Change in Spleen Volume for Individual Patients

• 97.1% of patients (132/136) experienced some degree of spleen volume reduction

• 78 patients (53.4%) in the ruxolitinib arm achieved a ≥ 35% reduction in spleen volume at any time on treatment

a Only patients with baseline and postbaseline spleen volume assessments are included; for crossover patients, the spleen volume at the time of crossover was used as the new baseline value.

-100

-80

-60

-40

-20

0

20

40

60

35% decrease

Bes

t Cha

nge

From

Bas

elin

e

in S

plee

n Vo

lum

e, %

Ruxolitinib randomizeda

(n = 136)

After crossovera

(n = 39)

Overall Survival

• Median OS was not yet reached in the ruxolitinib arm (ie, > 5 years)

— ITT: HR, 0.67 (95% CI, 0.44-1.02); P = .06 — RPSFT: HR, 0.44 (95% CI, 0.18-1.04) in favor of ruxolitinib vs BAT

1.0

0.8

0.6

0.4

0.2

0.0 0 1 2 3 4 5 6

146 130 109 100 88 61 0 73 58 48 35 30 22 0

Ruxolitinib

BAT (ITT) BAT (RPSFT) P

roba

bilit

y

Time, years

n =

Median Overall Survival Ruxolitinib (ITT) = not reached BAT (ITT) = 4.1 years BAT (RPSFT) = 2.7 years

HR, hazard ratio; ITT, intent-to-treat; RPSFT, Rank-Preserving Structural Failure Time.

Conclusions

• These 5-year findings demonstrate that the immediate benefits of ruxolitinib treatment, such as improvements in spleen size, were maintained with long-term therapy

• Reductions in JAK2 V617F allele burden were apparent with longer-term treatment; improvement or stabilization of bone marrow fibrosis was seen in 48% of ruxolitinib-treated patients (18.5% worsening; 34% missing)

• Long-term safety and tolerability were consistent with previous findings

• Patients randomized to ruxolitinib treatment in the study had a relatively lower risk of death compared with patients on the BAT arm, most of whom switched to receive ruxolitinib at a later date

— In the ITT analysis, reduction in the risk of death with ruxolitinib was 33%

• This hypothetical benefit with earlier treatment with ruxolitinib is being evaluated through a phase 3 study in patients with early MF

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Investigational Agents and New Combinations for MPD

ANALYSIS OF OUTCOMES BY PATIENT SUBGROUPS IN

PATIENTS WITH MYELOFIBROSIS TREATED WITH PACRITINIB VS

BEST AVAILABLE THERAPY (BAT) IN THE PHASE III PERSIST-1 TRIAL

Alessandro M. Vannucchi1, Ruben A. Mesa2, Francisco Cervantes3, Ritam Prasad4, Janos Jakucs5, Anna Elinder6, Christian Recher7,

Peter A. te Boekhorst8, Steven Knapper9, Tim Somervaille10, James P. Dean11, Tanya Granston11, Adam Mead12 and Claire N. Harrison13

1University of Florence, Florence, Italy; 2Mayo Clinic, Scottsdale, AZ; 3Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain; 4Royal Hobart Hospital, Hobart, Australia; 5Békés Megyei Pándy Kálmán Kórház, Gyula, Hungary;

6North Shore Hospital, Takapuna, New Zealand; 7Institut Universitaire du Cancer Toulouse, Toulouse, France; 8Erasmus University Medical Center, Rotterdam, Netherlands; 9Cardiff University, Cardiff, United Kingdom; 10The Christie NHS Foundation Trust, Manchester, United Kingdom; 11CTI BioPharma Corp., Seattle, WA; 12Oxford University Hospitals, Oxford, United Kingdom; 13Guy's and St. Thomas' NHS Foundation Trust, Guy’s Hospital, London, United Kingdom

PERSIST-1 Study Design

Best Available Therapy (BAT)a excluding ruxolitinib

(n=107)

Pacritinib 400 mg qd (n=220)

aCross-over from BAT allowed after progression or after Week 24 assessment

Key Eligibility Criteria PMF, PET-MF, or PPV-MF

Intermediate- or high-risk disease

Palpable spleen ≥5 cm

No exclusion for baseline platelet levels; stratified by platelet counts ≥100,000/µL, ≥50,000-<100,000/μL, and <50,000/µL No exclusion for baseline Hgb levels

No prior treatment with JAK2 inhibitors

R (2:1) N=327

• Stratification at randomization: platelet count category, risk category, and region • Study endpoints

– Primary: proportion of patients achieving a ≥35% reduction in spleen volume (by MRI/CT) from baseline to Week 24

– Secondary: proportion of patients with a ≥50% reduction in Total Symptom Score (TSS) from baseline to Week 24 on the Myeloproliferative Neoplasm Symptom Assessment Form v 2.0

• Trial conducted in US, Europe, Russia, and Oceania

CT, computed tomography; Hgb, hemoglobin; JAK, Janus kinase; MRI, magnetic resonance imaging; PET-MF, post-essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; R, randomized. Mesa RA, et al. ASCO 2015. Abstract LBA7006.

aBy central laboratory. bBased on linear regression using mixed model. BAT, best available therapy; BL, baseline; Hgb, hemoglobin; PAC, pacritinib; RBC, red blood cell. 1. Mesa RA, et al. ASCO 2015. Abstract LBA7006. 2. Gale RP, et al. Leuk Res. 2011;35:8-11.

Patients With Baseline Hgb <10 g/dL Mean Hgb (g/dL) (± SEM)1,a

Mea

n H

gb (g

/dL)

(± S

EM)

Weeks

10

9.5

9

8

8.5

PAC

BL 3 4 8 12 16 20 24

BAT

Patients With Baseline Platelets <50,000/μL Mean Platelets×109/L (± SEM)1,a

Mea

n Pl

atel

ets×

109 /L

(± S

EM)

Weeks

60

50

40

0

30

20

10

p=0.0034b

p=0.1927b

BL 3 4 8 12 16 20 24

PAC

BAT

25.7%

0% 0%

5%

10%

15%

20%

25%

30%

PACBAT

p=0.043

Patie

nts

Patients Achieving RBC Transfusion Independence1

• At baseline, 15.9% of PAC and 14.0% of BAT patients were RBC transfusion dependent, per Gale criteria (≥6 units/90 days2)

Changes in Platelet Levels, Hemoglobin, and RBC Transfusion Dependence Over Time

Conclusions

• Treatment with pacritinib resulted in consistent rates of SVR ≥35% and TSS reduction ≥50%, irrespective of baseline characteristics, including baseline platelet count

• Comparisons of pacritinib vs BAT were favorable for all patient subgroups examined for both endpoints

• These results support the use of pacritinib across all

intermediate- and high-risk myelofibrosis patient subgroups analyzed

BAT, best available therapy; SVR, spleen volume reduction; TSS, total symptom score.

18

PRM-151 in Myelofibrosis: Durable Efficacy and Safety at 72 Weeks

Srdan Verstovsek1, Olga Pozdnyakova2,Robert Hasserjian3, Mohamed Salama4, Ruben Mesa5, Lynda Foltz6, Vikas Gupta7, John Mascarenhas8, Ellen Ritchie9, Ronald Hoffman8, Richard

Silver9, Marina Kremyanskaya8, Zeev Estrov1, Elizabeth Trehu10, Hagop Kantarjian1, Jason Gotlib11

1MD Anderson Cancer Center, Houston, TX, 2Brigham and Women’s Hospital, Boston, MA, 3Massachusetts General Hospital, Boston, MA, 4University of Utah, Salt Lake City, UT, 5Mayo Clinic, Scottsdale, AZ, 6St. Paul’s Hospital, University of British Columbia, BC, CA, 7Princess Margaret Hospital, Toronto, ON, CA, 8Mt Sinai Medical Center, New York, NY, 9Weill Cornell

Medical Center, New York, NY, , 10Promedior, Inc., Lexington, MA, 11Stanford Cancer Institute, Stanford, CA

19

PRM-151: Recombinant Human Pentraxin-2 (PTX-2)

X

X X

Pro-inflammatory macrophages

Pro-fibrotic macrophages

Pro-resolutive macrophages

Hypothesis: Reduction of bone

marrow fibrosis will restore hematopoiesis

and improve cytopenias

• PTX-2 ( ) is an endogenous regulator of tissue repair • PTX-2 binds to damaged tissue ( ) and monocytes/macrophages • PTX-2 prevents and reverses fibrosis

in pre-clinical models • PTX-2 levels are low in MF patients

– Also low in patients with renal, pulmonary and liver fibrosis

20

Weekly PRM-151 10 mg/kg IV

Monthly PRM-151 10 mg/kg IV

Weekly PRM-151 10 mg/kg IV + ruxolitinib

Monthly PRM-151 10 mg/kg IV + ruxolitinib

27 Patients Enrolled

PRM-151G-101 Stage 1 and Extension

• 24 week treatment period – Patients with clinical benefit may continue beyond 24 weeks

• PRM-151 + RUX: stable RUX dose ≥3 months with no decrease in splenomegaly for ≥ 4 weeks

• No eligibility restrictions for anemia, thrombocytopenia, leukopenia, or spleen size

7

8

6

6

20 Patients completed 24 weeks

13 patients completed 72 weeks

5 9

5

6 4

4

1 PD 2 deaths

1 PD 1 lack of benefit

1 death 1 splenectomy

2 stopped < 72 weeks

5 switched to monthly

1 stopped rux

3 stopped < 72 weeks

2 stopped < 72 weeks 5 switched to monthly

21

Bone Marrow Fibrosis Improvement as Measured by WHO Criteria

• Response assessment by central hematopathologists blinded to patient, treatment and time point. WHO MF Response = % of patients with ≥1 grade reduction in MF score at any time point

• Reduction in BM fibrosis was associated with normalization of bone marrow architecture: Normal erythroid clustering, Normal or decreased myeloid:erythroid ratio, Fewer paratrabecular megakaryocytes

% P

atie

nts w

ith

Bo

ne M

arro

w Im

prov

emen

t

Patient n 13 10 6 6 6 5

0

10

20

30

40

50

60

70

80

Wk 12 Wk 24 Wk 36 Wk 48 Wk 60 Wk 72

WHO MF Response

22

Platelets and Platelet Transfusions Pl

atel

ets x

109 /

L an

d

% o

f pat

ient

s with

PLT

tran

sfus

ions

Patients with Baseline Platelets < 100 x 109/L who completed ≥ 72 weeks (n=9)

0

10

20

30

40

50

60

Baseline Week 12 Week 24 Week 36 Week 48 Week 60 Week 72

Median PLT (x 109/L) % pts receiving plt transfusions

23

Conclusions

• 13 patients have completed 72 weeks of PRM-151 treatment • Reductions in bone marrow fibrosis have been accompanied by

– Median increase in Hgb in patients with baseline Hgb < 100 g/L – Decreased RBC transfusions – Median increase in PLT in patients with baseline PLT < 100 x 109/L – Decreased PLT transfusions – > 50% reduction in symptoms in 62% of patients – > 50% reduction in splenomegaly in 2 patients on PRM-151 alone

• PRM-151 was well-tolerated – 13 related adverse events, 11 Grade 1 – 6 SAEs, none related

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Combination Therapy in MPN

Ruxolitinib plus:

N Descriptors Toxicity Results

Pomalidomide 25 Immunomodulation for cytopenia (MF)

Anemia (G4) Neuropathy (G3)

3 CI

AZA 24 MDS/MPN overlap Myelosuppression (G3/4) 12 CI

IFN 30 Better tolerate IFN for PV or MF

Myelosuppression (G2/3) Infection (G2/3)

CI for most

Buparlisib (PI3K) (HARMONY)

42 Both agents active in MF (prior treatment allowed)

Myelosuppression (G3/4) Spleen reduced in most

Sonidegib (Hedgehog)

27 Animal models: combo reduced spleen size

Anemia (G3/4) Muscle spasms (G3/4)

Spleen reduced in 25 pts

24

CI = clinical improvement

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Updates in Chronic Myeloid Leukemia:

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Combination Therapy: TKI plus PegIFN

Abstract 134 (Roy et al): French Intergroup of CML Treatment plan: Dasatinib alone x 3 months; then

combination with PegIFN for 21 months maximum

Abstract 477 (Hjorth-Hansen et al) Treatment plan: Dasatinib alone x 3 month; then

combination with PegIFN for 12 months Potential AE benefit = pleural effusions rare

26

N=61 3 months 6 months 9 months 12 months MMR 16% 51% 70% 70%

N=40 3 months 6 months 9 months 12 months MMR 8% 53% 66% 82%

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Combination Therapy: Nilopeg Study

27

The Lancet Haematology 2015 2, e37-e46DOI: (10.1016/S2352-3026(14)00027-1)

In future, combination of 2nd generation TKI plus PegIFN may have a role for TKI discontinuation attempts after MMR.

ASH 2015 RERISE 12 Months Follow-up ASH 2015 RERISE 12 Months Follow-up

Abstract 476

Efficacy and Safety of Radotinib versus Imatinib

for Newly Diagnosed CML-CP Patients

Jae-Yong Kwak1, Hawk Kim2, Jeong-A Kim3, Young Rok Do4, Hyeoung Joon Kim5, Joon Seong Park6, Joo Seop Chung7, Ho Jin Shin7, Sung-Hyun Kim8, Dae-Young Kim9, Udomsak Bunworasate10, Chul Won Choi11, Narcisa Sonia Comia12, Dae Young Zang13, Suk Joong Oh14, Saengsuree Jootar15, Ary Harryanto Reksodiputro16, Won Sik Lee17, Yeung-Chul Mun18, Jee Hyun Kong19, Priscilla B. Caguioa20, Jinny Park21, Chol Won

Jung22, Dong-Wook Kim23

1Chonbuk National University Medical School & Hospital, Jeonju, South Korea, 2Ulsan University Hospital, Ulsan, South Korea, 3St. Vincent

Hospital, The Catholic University of Korea, Suwon, South Korea, 4Dongsan Medical Center, Keimyung University, Daegu, South Korea, 5Chonnam National University, Hwasun Hospital, Hwasun, South Korea, 6Ajou University Hospital, Suwon, South Korea, 7Pusan National

University Hospital, Pusan, South Korea, 8Dong-A University Medical Center, Busan, South Korea, 9Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, 10King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand, 11Korea

University, Guro Hospital, Seoul, South Korea, 12Mary Mediatrix Medical Center, Batangas, Philippine, 13Hallym University Sacred Heart Hospital, Anyang, South Korea, 14Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea, 15Faculty of Medicine,

Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 16Rumah Sakit Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia, 17Inje University Busan Paik Hospital, Busan, South Korea, 18Ewha Womans University Mokdong Hospital, Seoul, South Korea, 19Wonju Severance Christian Hospital, Wonju, South Korea, 20St.Luke’s Medical Center, Manila, Philippine, 21Gachon University Gil Medical Center, Seoul, South

Korea, 22Samsung Medical Center, Seoul, South Korea, 23Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea

ASH 2015 RERISE 12 Months Follow-up ASH 2015 RERISE 12 Months Follow-up

Study Design

Radotinib 300 mg BID (n = 79)

Radotinib 400 mg BID

(n = 81)

Imatinib 400 mg QD (n = 81)

Extension follow-up 3 years after 1 year treatment

*Stratified by Sokal risk score.

Randomized*

≤3 months after diagnosis of chronic-phase Ph+ CML (n=241)

24 sites

4 Asian countries (KR, TH, PH & IDN)

Enrollment

: 2011.08 – 2014.02

Primary endpoint: MMR by 12 months Secondary endpoints: CCyR & CMR by 12 months, MMR at 12 months Disease Progression Other endpoints: OS, PFS

ASH 2015 RERISE 12 Months Follow-up ASH 2015 RERISE 12 Months Follow-up

Major Molecular Response at Each Time P

atie

nts

with

MM

R, %

MMR: Major Molecular Response, BCR-ABL1 transcript level ≤ 0.1% (MR3.0)

(N=79) (N=81) (N=81)

Data cut-off: 17Mar2015

MMR At 12 months MMR By 12 months

p=0.0342

p=0.0044

p=0.0667

p=0.0065

ASH 2015 RERISE 12 Months Follow-up ASH 2015 RERISE 12 Months Follow-up

Conclusion Radotinib demonstrated significantly higher molecular response rate

at both 300mg BID and 400mg BID group compared with imatinib

- Radotinib 300mg BID, 400mg BID vs Imatinib 400mg QD:

52%, 46% vs 30%

Treatment failure and suboptimal response in all radotinib groups were fewer than imatinib group and no progression in all groups was occurred

The safety profiles of the radotinib and imatinib were different, and most AEs were manageable and well-controlled by dose reduction.

However, laboratory AEs were high in radotinib 400mg BID group

These phase 3 data suggest that radotinib can become a new promising 1st line therapy for patients with newly diagnosed chronic phase CML

ABL001, a Potent, Allosteric Inhibitor of BCR-ABL1, Exhibits Safety and Promising Single- Agent Activity in a Phase 1 Study of Patients With

CML and Failure of Prior TKI Therapy

Oliver Ottmann, Giuliana Alimena, Daniel J. DeAngelo, Yeow-Tee Goh, Michael Heinrich, Andreas Hochhaus, Timothy P. Hughes,

Francois-Xavier Mahon, Michael Mauro, Hironobu Minami, Marie Huong Nguyen, Delphine Rea, Juan-Luis Steegmann, Arkendu Chatterjee,

Varsha Iyer, Noelia Martinez, Gary J. Vanasse, Dong-Wook Kim

American Society of Hematology Annual Meeting 2015

Abstract 138

• Developed to gain greater BCR-ABL1 inhibition, with activity against BCR-ABL1 mutations conferring resistance to TKIs

• Potential to combine with TKIs for greater pharmacological control of BCR-ABL1

BCR-ABL1 Protein

Nilotinib (ATP Site)

ABL001 (Myristoyl Site)

ABL001 Is a Potent, Specific Inhibitor of BCR-ABL1 With a Distinct Allosteric Mechanism of Action

SH2

SH3

BCR

ACTIVE

ABL001 Allosterically Inhibits BCR-ABL1 Kinase Activity

Kinase

ABL001

t(9;22) BCR

SH3

Kinase

INACTIVE

ABL001

SH2

ABL001X2101: Study Design A multicenter, phase 1, first-in-human study

Dose Escalation Dose Expansion

MTD/RDE CML, Resistant/Intolerant to

Prior TKI

ABL001 BID, Oral

Combo Dose Escalation – CML ABL001 40 mg BID +

Nilotinib 300 mg BID, Oral

Dose Expansion – CML ABL001 40 mg BID +

Nilotinib 300 mg BID, Oral

CML, Resistant/Intolerant ABL001 QD, Oral

MTD/RDE

MTD/RDE

CML, Resistant/Intolerant ABL001 QD, Oral

CML, Resistant/Intolerant to Prior TKI

ABL001 BID, Oral

• •

Primary outcome: estimation of MTD/RDE Secondary outcomes: safety, tolerability, preliminary anti-CML activity, pharmacodynamics, pharmacokinetic profile

Ph+ ALL, Resistant/Intolerant to Prior TKI

ABL001 BID, Oral

Responses in Patients With ≥ 3 Months of Follow-up on Study (n = 29)

100 90 80 70 60 50 40 30 20 10 0 Hematologic relapse

(n = 12) Cytogenetic relapse (> 50% Ph+; n = 12)

Molecular relapse (no MMR; n = 29)

Patie

nts

With

Res

pons

e, %

CHR within 2 months:

100% (12/12) CCyR:

66.7% (8/12)

MMR: 34.5% (10/29)

≥ 1-log reduction:

24.1% (7/29)

< 1-log reduction:

31.0% (9/29)

None: 33.3% (4/12)

None: 10.3% (3/29)

Hematologic Response Within 2 Months

Cytogenetic Response Within 3-6 Months

Molecular Response Within 6 Monthsa

Status at Baseline a BCR-ABL1IS reduction achieved.

Conclusions

• ABL001 was generally well tolerated in heavily treated CML patients resistant to or intolerant of prior TKIs

• Preliminary pharmacokinetic exposures appear linear in the dose range tested

• Early evidence of single-agent efficacy at ≥ 10 mg BID – Clinical activity across TKI-resistant mutations (eg, V299L, F317L,

Y253H) – Myristoyl binding pocket mutations (V468H, I502L) may lead to clinical

resistance

• Allosteric inhibition of BCR-ABL1 is a promising therapeutic approach in patients with CML

• Enrollment ongoing to determine a recommended dose and to assess safety and tolerability

Long-term Follow-up of the French

Stop Imatinib Study (STIM1) in

Chronic Myeloid Leukemia Patients*

Gabriel Etienne, Delphine Réa, Joëlle Guilhot, François Guilhot, Françoise Huguet, Laurence Legros, Franck Nicolini Aude Charbonnier, Agnès Guerci, Bruno Varet, Philippe Rousselot, François-Xavier Mahon

on behalf of the Intergroupe Français des Leucémies Myéloïdes Chroniques (FILMC) on behalf of the STIM Investigators

*This study is registered with ClinicalTrials.gov, number NCT00478985

Orlando, ASH 2015, abstract 85121

STIM study design* N=100

STOP Molecular recurrence: positivity of BCR–ABL transcript confirmed by a second consecutive analysis point indicating a increase of one log or loss of MMR at one point. Molecular recurrence Imatinib rechallenge

Sustained CMR for ≥ 2 years on imatinib

(5 assessments)

Q- RT-PCR every month in the first year and every 2 months in the second year and every 3-4 months thereafter

* Mahon FX et al. The Lancet Oncology, 2010;11(11): 1029-1035.

Year 1 Year 2 Year 3 and after

Molecular Recurrence-free Survival (MRFS)

MRFS after imatinib discontinuation – Median Follow-up = 65 mo. accounting for competing events (death in complete molecular remission without any relapse, n=1)

43% (95% CI 33-52) at 6 months 38% (95% CI 32-51) at 24 months 38% (95% CI 28-47) at 84 months.

MRFS

0 6

Number at risk 100 44

12 18 24 30 36 42 48

41 38 38 38 38 37 29 25 19 11 5 1 0

54 60 66 72 78 84 90

Months since Imatinib Discontinuation

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

TKI Withdrawal Syndrome Upper extremity and shoulder pain lasting median of 7

months

Patient Preference Data emerging about predictors of which patients will

maintain MMR versus recur after stopping TKI therapy

Additional TKI Discontinuation Considerations

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

A 72 year old gentlemen is referred to hematology for treatment recommendations for newly diagnosed JAK2 positive primary myelofibrosis. He reports symptoms of fatigue and decreased appetite. On exam, he appears pale and has palpable splenomegaly. The most recent CBC values were WBC 11K with 2% circulating blasts, hemoglobin 9, and platelet count of 30K. What agent has been submitted to the FDA for new drug application for myelofibrosis with thrombocytopenia (platelet count <50K)?

A. Azacitidine B. Imetelstat C. Momelotini

b D. Pacritinib E. Pomalidom

ide

42

Azacitidine

Imetelst

at

Momelotinib

Pacritin

ib

Pomalidomide

50% 50%

0%0%0%

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

A 32 year old woman with chronic phase CML has had a good response to tyrosine kinase inhibitor therapy with imatinib for the past 3 years. While she has met her milestones on time and overall tolerated therapy well, she doesn’t like the idea of being on medicine lifelong and is considering having children in the next year. Her last PCR confirms continued MMR which she has maintained for 2 years. What advice can we give her based on current TKI discontinuation data?

A. Imatinib can be safely stopped now

B. Imatinib can be stopped after 1 more year of MMR

C. Imatinib should not be stopped due to TKI withdrawal syndrome

D. Imatinib should not be stopped outside of a clinical trial

E. Imatinib should not be stopped due to the risk of molecular relapse that would most likely be resistant to imatinib re-challenge

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Imatin

ib can be sa

fely st.

..

Imatin

ib can be st

opped ...

Imatin

ib should not b

e s...

Imatin

ib should not b

e s...

Imatin

ib should not b

e s...

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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

MPD Summary

Current therapy updates: Continued responses to ruxolitinib in the front line

myelofibrosis setting and second line polycythemia vera treatment

Application under review for approval of pacritinib for MF with thrombocytopenia, plt <50K (PERSIST)

TKI discontinuation still needs to be done in clinical trial setting for close PCR monitoring

Areas of ongoing and future investigation: MPD: ruxolitinib combinations, PRM-151 CML: TKI plus PegIFN, radotinib, ABL001

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