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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 [email protected]
Twitter:@Dr_AmerZeidan