Microsoft PowerPoint - ASH_Sallman_APR-246 + AZA in MDS AML_2019-12-04_FINAL_IHC separatedPhase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in
Patients with TP53 Mutant Myelodysplastic Syndromes (MDS) and
Acute Myeloid Leukemia (AML)
David A. Sallman1, Amy E. Dezern2, Guillermo Garcia-Manero3, David P. Steensma4, Gail J. Roboz5, Mikkael A. Sekeres6, Thomas Cluzeau7, Kendra Sweet1, Amy McLemore1, Kathy McGraw1, John Puskas1, Ling Zhang1, Jiqiang Yao8, Qianxing Mo8, Lisa Nardelli1, Najla H Al Ali1, Eric Padron1, Greg Korbel9, Eyal C. Attar9, Hagop M. Kantarjian3, Jeffrey E. Lancet1, Pierre Fenaux10, Alan F. List1, and Rami S. Komrokji1
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 Leukemia, MD Anderson Cancer Center, Houston, TX, USA; 4Department of Medical Oncology, Dana Farber Cancer
Institute, Harvard Medical School, Boston, MA, USA; 5Weill Cornell Medical College, New York, NY, USA; 6Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA; 7Hematology
Department, Cote D'azur University, Nice Sophia Antipolis University, Nice, France; 8Department of Biostatistics &
Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA; 9Aprea Therapeutics, Boston, MA, USA, 10Hospital St Louis, Paris 7 University, Paris, France
Impact of TP53 mutations in MDS/AML
• TP53 mutations in myeloid malignancies
– Occur in 15-25% of patients with MDS and AML
– Occur in 30-40% of therapy related disease
• Prognostic Impact of TP53 mutations
– Strongest independent predictor of inferior OS in MDS with increased risk of AML transformation
– In complex karyotype patients, TP53 is the driver of inferior OS (7.2 months)
– Increasing TP53 variant allele frequency (VAF) is an independent predictor of inferior OS
• Current therapies in TP53 mutant MDS/AML
– Hypomethylating agents (HMA) result in 15-20% CR and 40-45% ORR, similar to TP53 wildtype patients
– Despite HMA responses, significantly inferior OS in TP53 mutant patients (6-8 months)
– In TP53 mutant AML, Ven+HMA regimens in AML provide 47% ORR with median DoR 5.6 mos and median OS of 7.2 months
– In 10 TP53 mutant AML patients treated with Ven+LDAC there were 0 CR and 3 CRi
– TP53 is the only gene uniformly identified across large cohorts to predict for inferior OS
Bally C, et al. Leuk Res. 2014; Welch JS, et al. NEJM 2016; Haase D, et al. Leukemia 2019; Bejar R, et al. JCO. 2014; Lindsley R et al. NEJM 2017; Della
Porta MG et al. JCO 2016; Yoshizato T, et al. Blood 2017; Sallman et al. Leukemia 2016; DiNardo C ,et al. Blood 2019; Wei A, et al. J Clin Oncol, 2019.
Targeting TP53 Mutations in MDS/AML via APR-246
APR-246 binds
APR-246
A. Fersht et al. (2010) Prot. Sci; Q. Zhang et al, (2018) Cell Death Disease; H. Furukawa et al, (2018) Cancer Sci.
…restores wt p53
arrest and apoptosis
Frontline Combination Therapy with APR-246 + Azacitidine:
Study Design and Objectives • IIT evaluating frontline APR-246 + azacitidine in TP53 MT HMA-naïve MDS, oligoblastic AML (≤ 30% blasts) and MDS-MPN
• Phase 1b Results (Sallman D et al., ASH 2018)
– RP2D of 4500mg days 1-4 (~100mg/kg) azacitidine (75mg/m2)
– Manageable G1/G2 nausea and transient neurological AEs (dizziness/altered sensation) to APR-246
– Activation of p53-dependent pathways following monotherapy treatment (1 mCR+partial cytogenetic remission in lead-in phase)
• Phase 2
– Primary: CR rate
– Secondary: Safety, ORR, DoR, OS, p53 IHC, and Serial NGS (0.1% VAF sensitivity)
ClinicalTrials.gov NCT03072043; i.v., intravenous; s.c., subcutaneous; RP2D, recommended Phase 2 dose; CR, complete
remission; DoR, duration of response
Baseline Characteristics
(N=55)
Female, n (%) 29 (53) 17 (43) 8 (73) 4 (100)
Age in years, median (range) 66 (34 – 85) 66 (34 – 80) 68 (47 – 85) 57 (41 – 79)
Age Category, n (%)
ECOG PS at treatment start, n (%)
0 17 (31) 15 (37) 2 (18) 0 (0)
1 34 (62) 22 (55) 8 (73) 4 (100)
2 4 (7) 3 (8) 1 (9) 0 (0)
Disease type, n (%)
MDS 40 (73)
IPSS-R: Very high 28 (51) 28 (70)
AML 11 (20)
Therapy-related, n (%) 18 (33) 14 (35) 4 (36) 0 (0)
Complex karyotype, n (%) 47 (85) 36 (90) 8 (73) 3 (75)
Transfusion dependence, n (%) 38 (69) 27 (68) 8 (73) 3 (75)
Baseline Characteristics
All Patients
(N=55)
CMML (N=4)
TP53 mutations, n (%) 55 (100) 40 (100) 11 (100) 4 (100)
Mutations per patient, median (range) 1 (1 – 3) 1 (1 – 3) 2 (1 – 2) 2 (2)
p53 IHC ≥ 10%, n (%) 42 (76) 33 (83) 6 (55) 3 (75)
TP53 VAF %, median (range) 21 (0.5 – 72) 20 (1 - 72) 15 (0.5 – 50) 44 (5 – 47)
Other somatic mutations, n (%) 21 (38) 15 (38) 5 (45) 1 (25)
0%
5%
10%
15%
include gastrointestinal (nausea/vomiting)
– 30 and 60 day mortality of 2% (n=1) and
5% (n=3), respectively.
to adverse events (none secondary to
APR-246 related AEs)
Nausea 35 (64) 0 (0)
Vomiting 25 (45) 1 (2)
Fatigue 24 (44) 0 (0)
Constipation 23 (42) 0 (0)
Edema 21 (38) 2 (4)
Dizziness 20 (36) 1 (2)
Diarrhea 18 (33) 1 (2)
Febrile neutropenia 18 (33) 18 (33)
Peripheral sensory neuropathy 17 (31) 0 (0)
White blood cell decreased 17 (31) 16 (29)
Dyspnea 16 (29) 1 (2)
Headache 16 (29) 0 (0)
Lung infection 16 (29) 14 (25)
Neutrophil count decreased 16 (29) 16 (29)
Platelet count decreased 16 (29) 14 (25)
Cough 15 (27) 1 (2)
Pruritus 14 (25) 0 (0)
Anorexia 13 (24) 0 (0)
Ataxia / unsteady gait 13 (24) 2 (4)
Fever 12 (22) 1 (2)
Alanine aminotransferase increased 11 (20) 1 (2)
Mucositis oral 11 (20) 0 (0)
Tremor 11 (20) 1 (2)
Serious Adverse Event, n (%)
Febrile neutropenia 14 (25)
Lung infection 11 (20)
Respiratory failure 4 (7)
Sepsis 4 (7)
Dehydration 3 (5)
Most common AEs (≥20% of patients) Most common SAEs (≥5% of patients)
Response to Treatment All Patients (N=55) Evaluable Patients (N=45)
ORR, n (%) [95% CI] 39 (71) [57 – 82] 39 (87) [73 – 95]
Time to first response in months, median (range) 2.1 (0.1 – 5.4)
Duration of response in months, median [95% CI] 8.0 [6.5 – 11.2]
Best response by IWG, n (%)
CR 24 (44) 24 (53)
PR 0 (0) 0 (0)
mCR + HI 8 (15) 8 (18)
mCR / MLFS 4 (7) 4 (9)
HI 3 (5) 3 (7)
SD 4 (7) 4 (7)
NR 11 (20) 1 (2)
PD 1 (2) 1 (2)
CR, n (%) [95% CI] 24 (44) [30 – 58] 24 (53) [38 – 68]
Time to CR in months, median (range) 3.1 (2.5 – 6.1)
Duration of CR in months, median [95% CI] 7.3 [5.8 – N.E.]
Cytogenetic response, n (%) [95% CI] 26/44 (59) [43 – 74]
Partial 8/44 (18) [8 – 33]
Complete 18/44 (41) [26 – 57]
TP53
NGS negative, n (%) 20 (44)
Serial IHC ≤ 5% 22 (49)
Response to Treatment in Evaluable Patients (n=45) Cutoff: November 15, 2019
Median duration of follow-up = 10.8 months
Overall MDS AML
Evaluable patients, n 45 33 8 4
Overall response rate, n (%) 39 (87) 29 (88) 7 (88) 3 (75)
CR rate, n (%) 24 (53) 20 (61) 4 (50) 0 (0)
Duration of CR, months (median) [95% CI] 7.3 [5.8 – N.E.] 7.3 [5.8 – N.E.] 7.0 [3.3 – N.E.] N.E.
Discontinued for transplant, n (%) 22 (49) 17 (52) 4 (50) 1 (25)
Spectrum of TP53 Mutations in Evaluable Patients
• 66 TP53 mutations sequenced in 45 evaluable patients
– 53 (80%) are missense and 62 (94%) are in the DNA-binding domain
– 45 (100%) patients had at least one TP53 mutation in the DNA-binding domain
• Patients with TP53 mutation alone predicted for CR (69% vs 25%, P=0.0062) with trend for higher ORR (93% vs 69%, P=0.08)
Overall Survival (ITT)
O v e
ra ll S
Response 13.7 months (95% CI 10.8-16.5)
No Response 3.9 months (95% CI 1.9-6.0)
P < 0.0001
Time (months)
P < 0.0001
No BMT 10.1 Months (95% CI 6.2-14.0)
P = 0.1
Serial Analysis by p53 Immunohistochemistry (IHC)
• Patients with ≥ 10% p53 IHC+ BM-MNCs was predictive of CR (66% vs 13%; P =0.01)
Baseline
CR
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Serial Analysis by p53 Immunohistochemistry (IHC)
• Patients with ≥ 10% p53 IHC+ BM-MNCs was predictive of CR (66% vs 13%; P =0.01)
Baseline
CR
CR vs Non-CR vs Non-Responder
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Serial Variant Allele Frequency (VAF) and MRD Analysis
• 20 (44%) patients achieved NGS negativity with a VAF threshold of 5%
• In NGS negative patients, median MRD VAF at maximum clearance was 0.63% (0.0 – 5%) with 5 (11%) MRD
negative (0.1% sensitivity)
*
• APR-246 + AZA combination is well tolerated in mutant TP53 MDS/AML
• The primary endpoint of the phase 2 was achieved with an improved CR rate
(53% of patients, 61% in MDS) in comparison to historical HMA outcomes
• Biomarkers of CR include p53IHC+ BM-MNCs (≥ 10%) and absence of non-TP53
mutations
• 59% of patients achieved a partial or complete cytogenetic response
• Serial p53 IHC and NGS for TP53 VAF indicative of deep molecular remissions
Pivotal Phase 3 MDS Trial in TP53 Mutant MDS
• Randomized study of frontline azacitidine ± APR-246 in TP53 mutant MDS
• Status
– Currently targeting full enrollment in first quarter 2020
– Fast Track Designation for MDS: granted by FDA in April 2019
– Orphan Drug Designations for MDS: granted by FDA in April 2019 and EMA in July 2019
ClinicalTrials.gov NCT03745716
Primary endpoint: CR rate
Acknowledgements Moffitt Cancer Center