H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE,

AN NCI COMPREHENSIVE CANCER CENTER – Tampa, FL

1-888-MOFFITT (1-888-663-3488) www.MOFFITT.org

© 2018 H. Lee Moffitt Cancer Center and Research Institute, Inc.

001-001

Scree

n

C3

TP

53

VA

F (

%)

0.01

0.1

1

10

100

• Mutations in the TP53 gene (mTP53) are found in approximately 10% of MDS

and AML patients and predict for inferior OS (median OS 6-12 mo).

• Hypomethylating agents have emerged as a standard frontline therapy for

mTP53 MDS although with an overall response rate (ORR) of 30-50%,

complete response (CR) rate of 20-30%, and poor durability of response.

• TP53 VAF clonal suppression with treatment predicts for improved OS as well

as improved OS with allo-HSCT (see ASH Abstract #1817)

• APR-246 is a small molecule that stabilizes mutant p53 protein in its wild-type

conformation, activating downstream anti-tumor cell death pathways.

Phase Ib/II Combination Study of APR-246 and Azacitidine (AZA) in Patients with

TP53 Mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

Safety

Background

Study Design

Treatment Duration and Response

Conclusions

1Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.; 2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA; 3Department of

Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 4Cote D’azur University, Nice Sophia Antipolis University, Hematology Department, CHU Nice, Nice, France; 5Department of

Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA; 6Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA; 7Weill Cornell Medical College, New York, NY, USA; 9Cancer Informatics

Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; 10Aprea Therapeutics, Stockholm, Sweden; 11Hospital St Louis, Paris 7 University, Paris, France.

David A Sallman1, Amy DeZern2, David P Steensma3, Kendra Sweet1, Thomas Cluzeau4, Mikkael Sekkeres5, Guillermo Garcia-Manero6, Gail Roboz7, Amy McLemore1, Kathy McGraw1,

John Puskas1, Ling Zhang1, Chirag Bhagat8, Jiqiang Yao9, Najla H Al Ali1, Eric Padron1, Roger Tell10, Jeffrey E. Lancet1, Pierre Fenaux11, Alan F List1 and Rami S Komrokji1

Abstract # 3091

• APR-246 + AZA combination is well tolerated in mutant TP53 MDS/AML. No DLTs occurred in the Phase 1b part of the trial.

• The RP2D of APR-246 was 4500 mg days 1-4 in combination with standard 7 day azacitidine 75mg/m2

• In Phase 1b part, overall response rate of 100% in response evaluable patients with 82% CR rate

• Serial p53 IHC and NGS for TP53 VAF indicative of deep molecular remissions.

• Enriched pathway analysis via Reactome following APR-246 lead-in phase showed transcriptional activation of p53 targets (FDR =

9.16E-09), including pathways involved in cell cycle arrest, apoptosis, DNA repair, and regulation of TP53 activity.

• Responses to date support planned Phase 3 registrational trial of APR-246+AZA versus AZA alone in TP53 mutant MDS.

mTP53 Assessment

Baseline Characteristics

Phase 1b Phase 2

Pts with serial assessment, n 12 9

Age, years, median (range) 66 (38-73) 67 (46-75)

Gender, n (%)

Male 5 (42) 2 (22)

Female 7 (58) 7 (78)

WHO Classification, n (%)

MDS-SLD 1 (8) 1 (11)

MDS-MLD 1 (8) 2 (22)

MDS-RS-MLD 0 (0) 1 (11)

MDS-EB1 5 (42) 0 (0)

MDS-EB2 2 (17) 2 (22)

MDS-MPN 0 (0) 1 (11)

AML-MRC 3 (25) 2 (22)

Complex cytogenetics, n (%) 10 (83) 6 (67)

Cytogenetic risk status, n (%)

Good 0 (0) 3 (33)

Poor 2 (17) 1 (11)

Very poor 10 (83) 5 (56)

IPSS-R Score, n (%)

Intermediate 0 (0) 1 (11)

High 3 (25) 5 (56)

Very high 9 (75) 3 (33)

Bone marrow blast %, median (range) 10 (1-30) 8 (0-25)

Hematology, median (range)

ANC .96 (0.02-5.3) 1.32 (0.23-5.9)

Hgb (g/dL) 8.8 (7.6-12.0) 8.8 (6.7-11.1)

Platelets (109/L) 67 (8-230) 44 (28-845)

Mutations / patient, median (range) 1 (1-3) 2 (1-2)

TP53 VAF %, median (range) 17% (5%-79%) 28 (14-47)

p53 IHC positivity > 5%, n (%) 10 (83) 7 (78)

Other somatic mutations, n (%) 3 (25%) 3 (33)

p53 Pathway Activation Analysis

Most common TEAEs with any relation to APR-246 or AZA, n (%)

G1 G2 G3 G4 G5

Nausea 9 (42) 3 (14) 0 (0) 0 (0) 0 (0)

Peripheral neuropathy 8 (38) 0 (0) 0 (0) 0 (0) 0 (0)

Vomiting 6 (29) 2 (10) 0 (0) 0 (0) 0 (0)

Dizziness 4 (19) 2 (10) 0 (0) 0 (0) 0 (0)

Thrombocytopenia 0 (0) 1 (5) 0 (0) 5 (24) 0 (0)

Neutropenia 0 (0) 0 (0) 0 (0) 6 (29) 0 (0)

Pruritus 4 (19) 1 (5) 0 (0) 0 (0) 0 (0)

Tremor 4 (19) 0 (0) 0 (0) 0 (0) 0 (0)

Constipation 3 (14) 1 (5) 0 (0) 0 (0) 0 (0)

Headache 4 (19) 0 (0) 0 (0) 0 (0) 0 (0)

Leukopenia 0 (0) 0 (0) 1 (5) 3 (14) 0 (0)

TEAEs in > 1 patient with any relation to APR-246 only, n (%)

G1 G2 G3 G4 G5

Peripheral neuropathy 6 (29) 0 (0) 0 (0) 0 (0) 0 (0)

Nausea 3 (14) 0 (0) 0 (0) 0 (0) 0 (0)

Dizziness 2 (10) 1 (5) 0 (0) 0 (0) 0 (0)

Tremor 3 (14) 0 (0) 0 (0) 0 (0) 0 (0)

Edema 1 (5) 1 (5) 0 (0) 0 (0) 0 (0)

G3/G4 Hematologic TEAEs by APR-246 dose level, n (%)

Ph1b DL1 Ph1b DL2 Ph1b DL3 Ph2

Febrile neutropenia 1 (33) 0 (0) 3 (50) 2 (10)

Neutropenia 2 (66) 3 (100) 1 (17) 2 (10)

Thrombocytopenia 1 (33) 2 (66) 2 (33) 1 (5)

Leukopenia 2 (66) 1 (33) 1 (33) 1 (5)

Anemia 1 (33) 0 (0) 2 (33) 0 (0)

• No DLTs experienced to date.

• No correlation of TEAE frequency, severity with increasing APR-246 dose

• No increase in G3/G4 hematologic TEAEs above that expected for AZA

Funding

Top 10 Pathways Following APR-246 TreatmentPathway FDR (%)RNA Pol II transcription 7.8 E-10

Signal transduction 7.8 E-10

Transcriptional regulation by TP53 9.2 E-09

Intracellular signaling by second messengers 2.2 E-08

S phase 3.0 E-08

Cell cycle, mitotic 1.2 E-07

G1/S transition 2.7 E-07

Cell cycle 6.6 E-07

Signaling by activated point mutants of FGFR3 1.4 E-06

TP53 regulated transcription of death receptors and ligands 1.9 E-06

001-005

Scr

een

C3

C6

C9

001-008

Scr

een

C3

C6

001-009

Scree

n

C3

C6

003-025

Scree

n

C3

001-003Scr

een

C3

C6

C9

TP

53

VA

F (

%)

0.01

0.1

1

10

100001-007

Scree

n

C3

C6

C9

003-012

Scr

een

C3

C6

003-014

Scree

n

C3

C6

003-026

Scree

n

C3

DL1 DL2 DL3 Ph2

MRD Assessment (NGS Negative Patients)

mCRCR MRD negative

mCR / HICR

mCR / HICR

Best Response at Cutoff

Ph1b Ph2 MDS AML All AZA Historical

Evaluable Patients 11 9 15 5 20

Response Rate 100% 89% 93% 100% 95% 30-50%

CR Rate 82% 56% 67% 80% 70% 20-30%