a phase 1 study of tazemetostat (epz-6438), an inhibitor ......2015 pd tazemetostat: response...
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A Phase 1 Study of Tazemetostat (EPZ-6438), an Inhibitor of EZH2: Preliminary Safety and Activity in Patients with Relapsed or Refractory NHL and
Advanced Solid Tumors
Vincent Ribrag, Jean-Charles Soria, Jean-Marie Michot, Anna Schmitt,
Sophie Postel-Vinay, Fontanet Bijou, Jean-Michele Coindre,
Maud Toulemonde, Stephen J Blakemore, Ben Suttle, Scott Ribich,
Blythe Thomson, John Larus, Harry Miao, Peter TC Ho, and Antoine Italiano
Participating Institutions Institut Gustave Roussy, Villejuif, France
Institut Bergonie, Bordeaux, France
Sponsor Epizyme, Inc
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2013 Accomplishments Methylation of H3K27me3 by PRC2 Mediates Transcriptional Repression
PRC2
Transcriptional Repression
• EZH2 is the catalytic subunit of the multi-protein PRC2 (Polycomb Repressive Complex 2)
• PRC2 is the only protein methyltransferase complex that can methylate H3K27
– Generates mono-, di- and tri-methylation of H3K27
– H3K27me3 is a transcriptionally repressive histone mark, and is the only significant substrate for PRC2
• Aberrant trimethylation of H3K27 is oncogenic in a broad spectrum of human cancers, such as B-cell NHL
• Mutations in other proteins that affect H3K27 and chromatin accessibility in general are prevalent across almost all cancer types
Compacted Chromatin
2
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2013 Accomplishments EZH2 Regulates B-cell Maturation and Cell Fate
3
Native B cell
EZH2 is the “gatekeeper” for
cell fate decisions
Plasma/Memory Cell
Apoptosis
Lymph Node
Maturing B Cell
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2013 Accomplishments EZH2 Gain of Function Mutations Result in Elevated H3K27me3 Levels
4
Y641 or Y646 Mutant EZH2
Wild-Type EZH2
NH2NH2
++ +/-
Heterozygous WT/Y641 or Y646 Mutant EZH2 ++++
H3K27Me3 Production
Wild Type Mutant
H3K27me3
H3K27me2
H3K27me1
Total H3
EZH2
Sneeringer et al, PNAS, 2010
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2013 Accomplishments Tazemetostat (EPZ-6438): Potent and Highly Selective EZH2 Inhibitor
PKMTs
PRMTs
Novel Structure, Potent Target Inhibition
Ki <2.5 nM
Antitumor Activity in EZH2 Mutant and WT Xenograft Models of DLBCL
KARPAS-422 (EZH2 Y646N) OCI-LY19 (EZH2 WT)
Knutson et al., Mol. Cancer Therapeutics, 2014 Thomenius et al. Molecular Targets Conference, 2015
Selective for EZH2
Selectivity >20,000-fold (100-fold for EZH1)
5
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2013 Accomplishments
• Population: relapsed or refractory B-cell lymphoma or solid tumors
• Study design: 3+3 dose-escalation completed
– Expansion cohorts (800 mg and 1600 mg BID) completed
– Food effect sub-study (400 mg BID) completed
– Drug-drug interaction sub-study (800 mg BID) completed
• Primary endpoint: determination of RP2D/MTD
• Secondary endpoints: safety, PK, PD and tumor response (every 8 wks)
• Data cut: 7-Nov-2015
Dose
(mg BID)
Patients
(n=58)
Solid tumors
(n=37)**
B-cell NHL
(n=21)
100* 6 5 1
200 3 1 2
400 3 2 1
800 14 6 8
1600 12 8 4
Food Effect 13 8 5
Drug-Drug 7 7 0
First-in-Human Phase 1 Trial E7438-G000-001 (NCT01897571)
* 2 formulations
**Solid tumor data presented by A. Italiano, ESMO/ECC 2015 6
from Ribrag et al., ASH 2015
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2013 Accomplishments Patient Tumor Types
Relapsed or refractory NHL n=21
Diffuse Large B cell Lymphoma (DLBCL)
GCB 5
Non GCB 6
undetermined 3
Follicular lymphoma (FL) 6
Marginal Zone lymphoma (MZL) 1
Relapsed or refractory solid tumors n=37
INI1-deficient or negative
Malignant rhabdoid tumor 5
Epithelioid sarcoma 3
Synovial sarcoma 4
SMARCA4-negative tumors 3
Other solid tumors 22
2/17 NHL patients tested to date are EZH2 mutant by cobas® test (in development, Roche Molecular Systems, Inc.)
from Ribrag et al., ASH 2015 7
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2013 Accomplishments Clinical Pharmacokinetics
● Rapid absorption (tmax = 1-2 h) with a mean terminal t1/2 = 3 - 5 h
● Dose-proportional Cmax and AUC0-12h at steady-state (day 15) through 1600 mg BID
● Decrease in systemic exposure between day 1 and day 15 with no further reduction afterwards
‒ 42% decrease in AUC0-12h on day 15 vs. day 1 at 800 mg BID
‒ Ctrough levels reach steady-state by day 15
Day 1
12 h
Day 1
5 0
h
Day 1
5 1
2 h
Day 2
9 0
h
0
1 0 0
2 0 0
3 0 0
4 0 0
T ro u g h p la s m a c o n c . a t R P 2 D 8 0 0 m g B ID
EP
Z-6
43
8 p
las
ma
co
nc
. (n
g/m
L)
0 3 6 9 1 21
1 0
1 0 0
1 0 0 0
1 0 0 0 0
D a y 1 5
T im e (h )
EP
Z-6
43
8 p
las
ma
co
nc
. (n
g/m
L)
1 0 0 m g (s u s p ) , n = 3
1 0 0 m g ( ta b ) , n = 3
2 0 0 m g , n = 3
4 0 0 m g , n = 3
8 0 0 m g , n = 1 3
1 6 0 0 m g , n = 1 1
from Ribrag et al., ICML 2015 8
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2013 Accomplishments PK-PD: EZH2 Inhibition in Surrogate Tissue
Target inhibition in skin:
● Reduction of H3K27me3 by IHC at week 4 at all doses
● Exposure-dependent reductions in H3K27me3
● Differential effects by epithelial layer
‒ Stratum basale - minimal change
‒ Stratum spinosum – pronounced change
‒ Full epidermis – composite signal of stratums spinosum and basale
● Reduction in H3K27me3 signal equivalent at 800 and 1600 mg BID
100mg 200mg 400mg 800mg 1600mg
9 from Ribrag et al., ASH 2015
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2013 Accomplishments Safety Profile in All Patients (n=55: 20 NHL and 35 Solid Tumors)
All Events All Treatment-Related
All Grades * Grade >3 All Grades Grade >3 **
Asthenia 23 0 13 0
Decreased appetite 9 1 4 0
Thrombocytopenia 8 2 7 1
Nausea 8 0 8 0
Constipation 7 0 2 0
Diarrhea 6 0 4 0
Vomiting 6 0 5 0
Anemia 5 0 3 0
Dry skin 5 0 4 0
Dysgeusia 5 0 5 0
Dyspnea 5 0 0 0
Muscle spasms 5 0 3 0
Abdominal pain 4 1 1 0
Hypophosphatemia 4 0 1 0
Anxiety 3 0 1 0
Depression 3 2 1 0
Hypertension 3 1 2 1
Insomnia 3 0 0 0
Neutropenia 3 1 3 1
Night sweats 3 0 3 0
Peripheral edema 3 0 2 0
Hepatocellular injury 2 1 1 1
* All AEs with frequency >5% regardless of attribution shown
** All grade >3
treatment-related events shown
from Ribrag et al., ASH 2015 10
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2013 Accomplishments NHL Patient Demographics
Characteristic n=21 (%)
Median age, years [range] 63 [24-84]
Sex (M / F) 15/6
# of prior therapeutic systemic regimens
1 2 (10)
2 1 (5)
3 8 (38)
4 3 (14)
>5 7 (33)
Prior autologous hematopoietic cell transplant 8 (38)
Prior radiotherapy 17 (57)
from Ribrag et al., ASH 2015 11
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2013 Accomplishments Objective Response in NHL All Patients (n=21)
Food Effects (FE): 200 mg on day -8 and day -1 400 mg BID from day 1
12 Data as of 27-May 2015
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2013 Accomplishments
15 mos
Response in EZH2-mutated DLBCL
PD PR PR 4 mos PR 2014 2011 2010
SD 2012 2013
PD SD SD 2015 PD
Tazemetostat: Response through 15 months
53 year old female (EZH2Y646H) treated at RP2D (800 mg BID)
Images courtesy of A. Italiano, Institut Bergonie
CR
Baseline SPD: 8282mm2 Wk 16 SPD: 3864 mm2 (PR) Wk 40 SPD: 3506 mm2 (PR)
13 Data as of 27-May 2016
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2013 Accomplishments Tazemetostat Phase 2 Dose Selection
Dose BID
Efficacy Safety PK/PD
Response in NHL (%) Grade ≥3 TEAE * H3K27me3
Inhibition Emax **
<800 mg 2/9 (22%) 7/24 (29%) -
800 mg 5/8 (62%) 3/19 (16%) 81%
1600 mg 2/4 (50%) 4/12 (33%) 91%
* Treatment Emergent Adverse Events in all patients (n=55)
** H3K27me3 Emax vs. Exposure
Day 15 AUC0-last (h*ng/mL)
100mg 200mg 400mg 800mg
1600mg
200 mg 800 mg 1600 mg
Base
line
Week 4
H3K27me3 in Skin
from Ribrag et al., ASH 2015 14
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2013 Accomplishments Subunits of SWI/SNF Complexes Are Mutated Across Many Indications
Adapted from Kadoch 2015 15
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2013 Accomplishments Antagonism of PRC2 and SWI/SNF-Dependent Chromatin Remodeling Regulates Pluripotency
SWI/SNF PRC2
PRC2 target genes
Stem cell programs
Self-renewal and Block in differentiation
Stem or Progenitor Cells
INI1
SMARCA4
Highly dependent on EZH2 activity
Adapted from Wilson 2010 16
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2013 Accomplishments EZH2 Activity Is Down-regulated as Progenitor Cells Become Differentiated
SWI/SNF PRC2
PRC2 target genes
Stem cell programs
Self-renewal and Block in differentiation
Stem or Progenitor Cells
Highly dependent on EZH2 activity
INI1
SMARCA4
SWI/SNF PRC2
PRC2 target genes
Stem cell programs
Quiescence and Differentiation
Differentiated Cells
EZH2 activity down-regulated
INI1
EZH2 Activity
SMARCA4
Adapted from Wilson 2010 17
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2013 Accomplishments INI1 or SMARCA4 Loss Can Creates an Oncogenic Dependency on EZH2 in Tumors
on EZH2 in Tumors
SWI/SNF PRC2
PRC2 target genes
Stem cell programs
Oncogenic Transformation
Stem or Progenitor Cells
Highly dependent on EZH2 activity
INI1
INI1 or SMARCA4-negative tumors ● Malignant rhabdoid tumor (MRT)
● Malignant rhabdoid tumor of the ovary (MRTO/SCCOHT)
● Epithelioid Sarcoma (ES)
● Renal Medullary Carcinoma (RMC)
Hyper-repression of
PRC2 targets
Potentiation of stem
cell programs INI1fl/fl CD4-Cre (n=8) INI1fl/fl EZH2fl/fl CD4-Cre (n=23)
EZH2 knockout reverses
oncogenesis induced by INI1 loss
Adapted from Wilson 2010 18
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2013 Accomplishments
Malignant Rhabdoid Tumors (MRT)
● Often pediatric, however adult cases reported
● Occur in the kidney, CNS and soft tissue
● Chemo-resistant
● Dismal prognosis with survival rates <25%
INI1- and SMARCA4-negative Rhabdoid Tumors are Aggressive in Children and Young Adults
MRT in an Infant
Image courtesy of S. Goldman, MD Bailey et al., 2014
MRTO in a 15-Yr Old
Malignant Rhabdoid Tumor of the Ovary (MRTO)
● Also known as Small Cell Carcinoma of the Ovary Hypercalemic Type (SCCOHT)
● Average age of diagnosis at 24 years
● Chemo-resistant
● Dismal prognosis with survival rates <35%
19
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2013 Accomplishments INI1- and SMARCA4-Negative Rhabdoid Tumor Models are Sensitive to Tazemetostat
D a y s
Tu
mo
r v
olu
me
SE
M (
mm
3)
0 1 0 2 0 3 0 4 0 5 0 6 0
0
4 0 0
8 0 0
1 2 0 0
1 6 0 0
2 0 0 0
2 4 0 0
2 8 0 0
3 2 0 0V e h ic le
1 2 5 m g / k g
2 5 0 m g / k g
5 0 0 m g / k g
E P Z -6 4 3 8
0 .0 1
0 .1
1
1 0
1 0 0
Da
y 1
4 I
C5
0 (
M)
SMARCA4 Mutant
MRTO
Non-MRTO
Ovarian
0 .0 1
0 .1
1
1 0
1 0 0
Da
y 1
4 I
C5
0 (
M)
INI1 Mutant
MRT
INI1 WT
Non-MRT
In vitro and in vivo cell killing
of mutant INI1 MRT cells
In vitro and in vivo cell killing of
mutant SMARCA4 MRTO cells
D a y s
Tu
mo
r v
olu
me
SE
M (
mm
3)
0 1 0 2 0 3 0 4 0 5 0 6 0
0
4 0 0
8 0 0
1 2 0 0
1 6 0 0
2 0 0 0V e h ic le
1 2 5 m g / k g
5 0 0 m g / k g
E P Z -6 4 3 8
Knutson et al. PNAS , 2013 Penebre et al, EORTC, 2015
20
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2013 Accomplishments EZH2 Target Inhibition in Tumor Tissue
Rhabdoid Tumor of Kidney
INI1-negative
H3K27me3 Diffuse positive 1+: 100% tumor
H3K27me3 Negative: 100% tumor
Pre-Dose
Epithelioid Sarcoma
INI1-negative
H3K27me3 Diffuse positive 1+: 100% tumor
Post-Dose: Week 4
H3K27me3 Negative: 50% tumor
21
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2013 Accomplishments Patient Tumor Types
Relapsed or refractory solid tumor N=30
INI1-negative (SMARCB1)*
Malignant rhabdoid tumor 5
Epithelioid sarcoma 3
SMARCA4-negative*
Malignant rhabdoid tumor of ovary (SCCOHT)
2
Thoracic sarcoma 1
Synovial sarcoma 3
GI malignancy 9
GU malignancy 2
GYN malignancy (non-SCCOHT) 2
CNS tumor/other sarcoma 3
Relapsed or refractory NHL N=21
* INI1- or SMARCA4-negative by IHC
from Italiano et al., ECC 2015 22
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2013 Accomplishments Best Response in Patients with Solid Tumors
* Patients censored at time of progression ** Four additional other solid tumor patients with pending disease evaluation
% c
hange fro
m b
ase
line
75%
25%
0%
-25%
-75%
50%
-50%
INI1-negative
SMARCA4-negative
Other solid tumor**
*
*
*
from Italiano et al., ECC 2015 23
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2013 Accomplishments CR in Patient with INI1-Negative Malignant Rhabdoid Tumor
55 y.o. male 800 mg BID
PD
Surgery + XRT
CR Week 8: CR 2014 2015
Diagnosis
2013
Tazemetostat: ongoing response week 65+
Week 4 Baseline
INI1 IHC
Week 20 Week 8: CR
Week 20: pathologic CR from Italiano et al., ECC 2015
24
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2013 Accomplishments PR in Patient with SMARCA4-Negative Malignant Rhabdoid Tumor of Ovary
PD CR Week 8: PR 2014 2015 2013
Tazemetostat: ongoing week 24+
27 y.o. female 1600 mg BID
Baseline Week 8 Week 16
CR Week 16: PR from Italiano et al., ECC 2015
25
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2013 Accomplishments Clinical Pharmacology: Food Effect and Drug-Drug Interaction
• The effect of food on tazemetostat pharmacokinetics
– Patients (n=13) received tazemetostat 200 mg after an overnight fast and immediately after a high-fat breakfast in a randomized crossover fashion with 7 days between doses
– Plasma tazemetostat concentrations were determined over 24 hours after each dose
– Patients received tazemetostat 400 mg BID after completing the food effect component of the study
• The effect of tazemetostat on CYP3A4/5-mediated metabolism
– Patients (n=13) received an oral dose of midazolam 2 mg on Day -1 and Day 15
– Tazemetostat 800 mg BID administration started on Day 1 and continued throughout the study
– Plasma midazolam concentrations were determined over 24 hours after each dose
26
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2013 Accomplishments Clinical Pharmacology: Food Effect
0
50
0
10
00
1
50
0
Cmax
Ta
ze
me
tosta
t C
max (
ng/m
L)
0
10
00
3
00
0
50
00
AUC(0-∞)
Ta
ze
me
tosta
t A
UC
(0-∞) (n
g*h
/mL
)
Fasted Fed Fed Fasted
70
00
Parameter Fed:Fasted
Ratio 90% CI
Cmax (ng/mL)
0.72 0.52, 1.00
AUC(0-∞) (ng*h/mL)
0.93 0.66, 1.30
• AUC(0-∞) and Cmax decreased by 7%
and 28%, respectively
• The 90% CI for both ratios contained 1
Administration of tazemetostat with a meal resulted in a non-clinically
relevant effect on systemic disposition and overall systemic exposure
from Suttle et al., AACR 2016 27
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2013 Accomplishments Clinical Pharmacology: CYP3A4/5 Interaction
0.2 0.5 0.8 1.0 Fold Change and 90% Confidence Intervals
Str
ong I
nduct
ion
Modera
te I
nduct
ion
Weak
Induct
ion
Change relative to administration of midazolam alone
Geometric Mean Ratio (90% CI)
0.79 (0.59, 1.06)
0.60 (0.47, 0.76)
Cmax
AUC(0-∞)
Induction Inhibition
Pharmacokinetic results after administration of midazolam with and without tazemetostat demonstrate that tazemetostat is a weak inducer of Cyp3A4/5
from Smith et al., AACR 2016 28
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2013 Accomplishments Phase 1 Summary
• Tazemetostat demonstrates clinical activity as monotherapy in patients with both B-cell NHL and solid tumors
• Relapsed or refractory DLBCL (both GCB and non-GCB), FL and MZL
– Objective responses in B-cell NHL with either wild-type or mutated EZH2
– Responses are durable – patients ongoing at 10+ to 21+ months
• Relapsed INI1- and SMARCA4-negative tumors
– Malignant rhabdoid tumor, malignant rhabdoid tumor of ovary (SCCOHT), epithelioid sarcoma
– Objective responses (CR and PR) and SD ≥6 months
• Pharmacodynamic inhibition of H3K27me3 demonstrated in tumor tissue and in surrogate tissue (skin)
• Safety profile as monotherapy is favorable for both monotherapy and combination development
• Pharmacokinetic results demonstrate that tazemetostat may be taken without regard to meals and is a weak inducer of CYP3A4/5
• RP2D dose of 800 mg BID supported by safety, efficacy, PK/PD
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2013 Accomplishments Current Tazemetostat Development
• Non-Hodgkin Lymphoma
– Phase 2 trial for DLBCL and FL – France, Australia, UK, Italy, Canada, US, Germany.
• Five cohorts – prospectively stratified according to cell-of-origin and EZH2 mutation status
– Phase 1/2 trial in DLBCL of tazemetostat in combination with R-CHOP in front-line elderly high-risk patients to start in 2016
– Phase 1b trial in DLBCL of tazemetostat in combination with a checkpoint inhibitor to start in 2016
• Rhabdoid and non-rhabdoid INI1-negative or SMARCA4-negative Tumors and Synovial Sarcoma
– Phase 2 trial in adults – US, Belgium, France, Italy, Australia, Canada, Germany, Taiwan
– Phase 1 trial in children (oral suspension formulation) – US, Australia, Denmark France, Canada, UK, Germany.
• Mesothelioma
– Phase 2 trial in mesothelioma with BAP1 loss of function to start in 2016 in US, France and UK
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2013 Accomplishments Acknowledgements
We thank our co-investigators and their teams
and, most importantly,
the patients and families who participated
in the study
31