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POLO-LIKE KINASE 1 (PLK1) INHIBITOR, ONVANSERTIB, IN COMBINATION WITH LOW-DOSE CYTARABINE OR

DECITABINE IN PATIENTS WITH RELAPSED/REFRACTORYACUTE MYELOID LEUKEMIA

Presentation Number 10660Lecture Time: 14:57 – 15:09Speaker: Amer M. Zeidan, MBBS, MHSYale University, New Haven, CT., USA

28-September-2019

Amer Zeidan, MBBS, MHS; Alexander Spira, MD; Pamela Becker, MD; Prapti Patel, MD; Gary Schiller, MD; Michaela Tsai, MD; Tara Lin, MD; Eunice Wang, MD; Maya Ridinger, PhD; Peter Croucher, PhD;

Sandra Silberman, MD, PhD; Mark Erlander, PhD

DISCLOSURE SLIDE• A.M.Z. received research funding (institutional) from Trovagene, Celgene, Abbvie,

Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics.

• A.M.Z had a consultancy with and received honoraria from Trovagene, AbbVie, Otsuka, Pfizer, Celgene, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Takeda, Ionis, and Epizyme.

• A.M.Z received travel support for meetings from Pfizer, Novartis, and Trovagene.

BACKGROUNDPOLO-LIKE KINASE 1 (PLK1)

q Serine/threonine kinase, master regulator of cell-cycle progression1

q Operates at G2/M checkpoint1

q Inhibition of PLK1 causes mitotic arrest and subsequent cell death1

q Over-expressed in blasts cells from AML patients2

q The pan-PLK inhibitor, volasertib, showed some efficacy in combination with LDAC in AML

q In a phase 2 randomized study volasertib + LDAC showed a significant increase in overall survival in comparison to LDAC alone3. However, the Phase 3 study was negative4

q Unfavorable features of volasertib may have contributed to this outcome: a long half-life (~5 days), the lack of specificity, the dosing regimen and the absence of biomarker strategy

1Zitouni et al., Nat Rev Mol Cell Biol. 2014 Jul;15(7):433-522Renner et al, Blood 2009 Jul 16;114(3):659-623Döhner et al, Blood 2014 Aug 28;124(9):1426-334Döhner et al, 21st Congress of EHA, Volume: Haematologica 101(suppl.1): 185-186, abstract S501

pTCTP

TCTP

BACKGROUNDONVANSERTIBq Orally-bioavailable, highly-selective PLK1 inhibitor, with ~24-hour half-life q Potent anti-tumor activity in AML preclinical models

q Induces G2/M arrest and apoptosis in the nanomolar range in leukemic cellsq Induces tumor growth inhibition in mouse models as a single agent and in combination with

LDAC q PLK1 inhibition by onvansertib can be monitored in-vitro and in-vivo through changes

in the phosphorylation of its direct substrate, the translational controlled tumor protein, TCTP 5,6

5 Cucchi et al., Anticancer Res. 2010 Dec;30(12):4973-856 Valsasina et al., Mol Cancer Ther. 2012 Apr;11(4):1006-16

Onvansertib (µM) 0 .01 .032 .1 .32 1 3 10

MV4-11 cell line (1h-treatment)

0 mg/kg 60 mg/kg 90 mg/kg 120 mg/kgOnvansertib

Tumor-bearing mice treated with one dose of Onvansertib (sacrificed 2h later)

pTCTP

H3

PHASE 1B TRIAL DESIGNMain eligibility criteriaq Relapsed and refractory AML patients who have received ≤3 prior treatment regimens q Treatment-related AML or APL excludedq ECOG ≤2Dosing schedule:q Onvansertib for 5 days + decitabine 20mg/m2 IV for 5days OR low dose cytarabine (LDAC) 20mg/m2 SC for 10daysq 21-28-day cycles

Primary and Secondary Objectives q Assess safety (incidence and severity of AEs)q Define dose-limiting toxicities (DLTs)q Define MTD or RP2D q Evaluate preliminary anti-leukemic activity

Exploratory objectives q Evaluate predictive biomarkers associated with response

to treatmentq Assess PLK1 inhibition in circulating leukemic cells by

measuring pTCTP levels

Dose escalation (3+3 design) 50% incremental dose increase in successive cohorts of 3 patientsq Dose limiting toxicities (DLTs) evaluated during the 1st cycle

TREATMENT SUMMARYData Cutoff: June 1st, 2019

N or Median [range]

Number of patients treated 33

Cleared doses in Decitabine arm 12, 18, 27, 40 and 60mg/m2

Cleared doses in LDAC arm 12, 18, 27 and 40mg/m2

Number of DLTs 0

Number of patients completing ≥1 cycle

27

Number of cycles 2 [1-13]

Patients (N=33)N (%) or Median

[range]

Age (years) 68 [33-88]

Male gender 25 (76%)

ECOG 1 [0-2]

Previous treatments 2 [0-3]

Cytogenetic Risk Status (N=33)

N (%)

Favorable 3 (9%)

Intermediate 4 (12%)

Adverse 23 (70%)Unknown 3 (9%)

SAFETY SUMMARYFor patients who received ≥ 1 doseData Cutoff: June 1st, 2019q Treatment was well tolerated; no

unexpected toxicities were reported

q No DLTs, SAEs or trial-related deaths attributed to onvansertib

q 3 deaths on trial were not attributed to onvansertib (2 due to progression; 1 intracranial hemorrhage due to fall)

q MTD not reached through 60mg/m2

dose level

q Grade 3/4 AEs possibly related to onvansertib: hematological AEs (n=10; 30%); non-hematological (n=1; 3%)

*reported as SAE

Table of All Adverse Events Reported in ≥ 10% of Patients (N=33)

Grade 1 Grade 2 Grade 3 Grade 4 All Grades

Fatigue 3 8 11 (33%)

Thrombocytopenia 2 1 7 10 (30%)

Febrile Neutropenia 9* 9 (27%)

Anemia 1 7 1* 9 (27%)

Neutropenia 1 7 8 (24%)

Dyspnea 3 3 1 7 (21%)

Nausea 4 3 7 (21%)

Constipation 6 6 (18%)

Rash 2 3 1 6 (18%)

Cough 3 2 5 (15%)

Diarrhea 5 5 (15%)

Dizziness 4 4 (12%)

Epistaxis 3 1 4 (12%)

Headache 4 4 (12%)

Stomatitis 1 2 1 4 (12%)

WBC Decrease 1 3 4 (12%)

PRELIMINARY EFFICACY LDAC ARM

q 12 patients evaluable for efficacy (treated for ≥1 cycle) at onvansertib 12 – 40mg/m2 plus LDAC

q 1 patient achieved objective response 1 CRi at onvanserib 40mg/m2

q LDAC arm discontinued following completion of onvansertib 60mg/m2

cohort

01 00

2 00

3 00

1 2 -0 4 1

1 1 -0 4 0

0 3 -0 3 7

0 9 -0 3 2

0 8 -0 2 7

0 1 -0 2 4

0 3 -0 1 5

0 5 -0 1 6

1 1 -0 1 9

0 7 -0 0 4

0 7 -0 1 0

0 1 -0 0 2

D a y s o f tre a tm e n t

12

mg

/m2

18

mg

/m2

27

mg

/m2

40

mg

/m2

M L F S

C R p

O n g o in g

L D A C

PR

C R i

C R

N o e va lua b leb o n e m a rro w

P a tie n t d e c is io n

P ro g re s s iv e d is e a s e

M D d e c is io n

P ro g re s s iv e d is e a s e

D e a th

P ro g re s s iv e d is e a s e

L a c k o f e ffic a cy

D e a th

L a c k o f e ffic a cy

P ro g re s s iv e d is e a s e

LDAC ARMFor patients who completed ≥ 1 cycleData Cutoff: June 1st, 2019

01 00

2 00

3 00

4 00

0 5 -0 4 3

0 7 -0 3 6

0 7 -0 3 5

0 9 -0 3 4

0 7 -0 3 3

0 5 -0 3 0

0 7 -0 1 8

0 9 -0 2 6

0 1 -0 2 1

0 7 -0 1 3

0 7 -0 1 1

0 7 -0 0 9

D a y s o f tre a tm e n t

12

mg

/m2

18

mg

/m2

27

mg

/m2

40

mg

/m2

C R

PR

C R i

O n g o in g

C R p

M L F S

N o e va lua b leb o n e m a rro w

P a tie n t d e c is io n

P a tie n t d e c is io n

P a tie n t d e c is io n

L a c k o f e ffic a cy

P ro g re s s iv e d is e a s e

L a c k o f e ffic a cy

1 8 m g /m 2 2 7 m g /m 2

L a c k o f e ffic a cy

L a c k o f e ffic a cy

P ro g re s s iv e d is e a s e

PRELIMINARY EFFICACY DECITABINE ARM

q 12 patients evaluable for efficacy (treated for ≥1 cycle) who received onvansertib12 – 40mg/m2 plus decitabine

q 3 patients achieved objective responses2 CR: 1 at onvansertib 27mg/m2 and 1 at onvansertib 40mg/m2

1 CRi at onvansertib 27mg/m2

DECITABINE ARMFor patients who completed ≥ 1 cycleData Cutoff: June 1st, 2019

PRELIMINARY EFFICACY Onvansertib + Decitabine Patient Cases of Complete Response

q 75 year-old male, diagnosed with AML in 2009; treated with induction chemotherapy followed by alloBMT; relapsed in March 2018

q Mutations: RUNX1, GATA2, SF3B1, FLT3-TKDq Entered trial April 2018 on onvansertib 12mg/m2 + decitabineq Onvansertib dose increased to 18mg/m2 cycle 6; 27mg/m2 cycle 11q Patient reached PR at end of cycle 4 and CR at end of cycle 11q Patient is currently on cycle 14 (as of 01 June 2019) q % BM blasts decreased from 94% (at screening) to <5% (cycle 11) 0

2 5

5 0

7 5

1 0 0

% o

f b

las

ts

C 1 C 2 C 3 C 4

C irc u la tin g b la s ts

C 5 C 6 C 7 C 8 C 9 C 1 0 C 1 1 C 1 2

B o n e m a rro w b la s ts

C R

P R

C 1 3

18 mg/m227 mg/m2

12 mg/m2

q 82 year-old male, diagnosed with AML in 2015; treated with induction and consolidation chemotherapy; relapsed in December 2018

q Mutations: ASXL1, SRSF2, IDH2q Entered trial in January 2019 on onvansertib 40mg/m2 + decitabineq Patient reached CR as of the end of cycle 2. Patient was in cycle 5 (as

of 01June 2019) with ongoing CRq % BM blasts decreased from 22% (at screening) to less than 5% at the

end of cycles 2 and 40

5

1 0

1 5

2 0

2 5

% b

las

ts

C 1 C 2 C 3 C 4

B o n e m a rro w b la s ts

C irc u la tin g b la s ts

C R

C 5

BIOMARKER STRATEGYAssessing inhibition of PLK1 in patients

q Blood samples collected on day 1hr pre (0h) and 3hr post (3h) dose (corresponding to onvansertib ~Cmax)

q pTCTP and TCTP assessed by capillary Western-Blot in isolated peripheral mononuclear cells

q Biomarker+ defined as ≥ 50% decrease in pTCTP/TCTP at 3h versus 0h

q Nine of 24 evaluable patients (38%) were biomarker positive for both arms

q Biomarker positivity was not correlated with onvansertib blood concentration (PK), dose level, % blasts, or

combination (onvansertib plus LDAC or decitabine)

12mg/m2

01-0020h 3h

pTCTPTCTP

07-009

27mg/m2

08-027 05-030

pTCTP inhibition: Biomarker positive40mg/m2

07-0360h 3h 0h 24h 0h 3h 0h 3h

12mg/m2

07-0040h 3h

pTCTPTCTP

07-01827mg/m2

01-024 07-033

No pTCTP inhibition: Biomarker negative 40mg/m2

12-0410h 3h 0h 3h 0h 3h 0h 3h

18mg/m2

1 2 1 8 2 7 4 0 6 00

5 0 0 0

1 0 0 0 0

1 5 0 0 0

2 0 0 0 0

2 5 0 0 0

O n v a n s e r t ib A U C 0 -2 4

o n D a y 5 in th e d e c ita b in e a rm

D o s e o f O n v a n s e r tib (m g /m 2 )

AU

C0

-24

(h

*ng

/mL

)

B io m a rk e r p o s it iv e

BIOMARKER STRATEGYBiomarker positivity is associated with response to treatment

-1 5 0-1 0 0

-5 00

5 01 0 01 5 02 0 02 5 05 0 07 5 0

1 0 0 0

%ch

ang

e fr

om

bas

elin

e B io m a rk e r p o s it iv e

B io m a rk e r n e g a t iv e

Waterfall plot of %bone marrow blast change relative to baseline

* Patient sample showed a 40% reduction in pTCTP

*

CR/CRi

q 20 patients evaluable for anti-leukemic efficacy and biomarker+ (defined as ≥ 50% decrease1 in pTCTP/TCTP at 3h versus 0h)

q 6 of 9 biomarker positive patients had a decrease in BM blasts ≥ 50%, versus 1 of 11 in the biomarker negative patients

q Among the 4 patients with OR (CR+CRi), 3 were biomarker positive and 1 was borderline biomarker positive (40% decrease in pTCTP)

q Further biomarker validation is ongoing; development of a more sensitive and quantitative assay

1The ability to observe two-fold differences by methodology has been analytically validated

CONCLUSIONSOnvansertib Treatment of Relapsed/Refractory AML

q Dose escalation as of 01June 2019 demonstrated safety of onvansertib up to 60mg/m2

q Anti-leukemic activity was observed at the 2 highest evaluable doses: 27 and 40mg/m2

q 2 patients reached a CR (at 27 and 40mg/m2) and 2 patients a CRi (at 27 and 40mg/m2)q Biomarker positivity was defined as a ≥ 50% decrease in pTCTP (PLK1 substrate) 3h post first

dose of onvansertibq 40% of patients were biomarker positive q Biomarker positivity was associated with an increase in response to treatment, as

measured by decrease in BM blasts and rate of OR (CR+CRi)q Phase 2 will enroll 32 patients to further assess the safety, efficacy, biomarker positivity and

correlation with response of onvansertib plus decitabine

ACKNOWLEDGMENTS

We would also like to extend a special thanks to our patients and their families for participating in this trial

Happy to answer any questionsAmer.zeidan@yale.edu

Twitter:@Dr_AmerZeidan