Download A Phase 1, First-in-Human Study of MGD006/S80880 (CD123 x CD3

A Phase 1, First-in-Human Study of MGD006/S80880 (CD123 x CD3) in AML/MDS
Norbert Vey1, Jan Kenneth Davidson-Moncada2, Geoffrey L. Uy3, David Rizzieri4, Hanna Jean Khoury5, Matthew Charles Foster6,
John E. Godwin7, Max S. Topp8, Giovanni Martinelli9, Fabio Ciceri10, Matteo Giovanni Carrabba10, Gerwin A Huls11,
Antje Wegener12, Kathy Tran2, Michele Shannon2, Jichao Sun2, Jon M. Wigginton2, John F. DiPersio3
ASCO 2017
Abstract TPS7070
Institut Paoli Calmettes, Centre Régional de Lutte Contre le Cancer, Marseille, France; 2MacroGenics, Rockville, MD; 3Washington University School of Medicine, St Louis, MO; 4Duke University Medical Center, Durham, NC;
5
Winship Cancer Institute, Emory University, Atlanta, GA; 6University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; 7Providence Cancer Center, Portland, OR;
8
Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany; 9AOU di Bologna Policlinico S. Orsola Malpighi, Bologna, Italy; 10Ospedale San Raffaele, Milan, Italy;
11
Universitair Medisch Centrum Groningen, Groningen, Netherlands; 12Institut de Recherches Internationales Servier, Suresnes, France
1
NCT02152956
[email protected]
Background
CD45med+/CD33+
COOH
Redirected T-cell killing against targeted leukemia cells
■■
d28
Mouse
Not
Imaged
Irradiated NSG mice (n=5/group) injected with K562GFP-CD123 cells and treated with DARTs. Bioluminescence imaging
on days 3, 12, 19, and 28 showed significant inhibition (p<0.0001) of tumor growth in CD3 × CD123 DART1.
Rationale
CD123 is highly expressed in >90% of AML patients and at least 50% of
MDS patients, making these diseases a reasonable target for T-cell-based
immunotherapy
■■
MGD006 is a novel CD123 x CD3 DART molecule designed to target
CD123-positive cells for recognition and elimination by CD3-expressing
T lymphocytes as effector cells
■■
MGD006 shows potent activity to redirect T cell killing against CD123-expressing
cell lines and primary AML blasts in vitro, inhibition of the growth of leukemic
cell lines in mice and depletion of CD123-positive plasmacytoid dendritic cells
in cynomolgus macaques
■■
Large unmet need remains given toxicity and high rates of relapse with
standard therapy
■■
Single Patient Dose Escalation
3 ng/kg/day*
Characterize dose limiting toxicities (DLTs) and determine the maximum
tolerated dose and schedule (MTDS) for MGD006 when given by continuous
intravenous (IV) infusion over a broad dose range in two dosing schedules
in patients with relapsed or refractory acute myeloid leukemia (AML) or
intermediate-2/high risk myelodysplastic syndrome (MDS)
10 ng/kg/day*
CD25 MFI
ng
/
G
01 mL
D
00
ng
6
44
0. /mL
1
20
ng
hX
/m
L
M R32
G
0.
D
1
00
ng
6
M
/
0
.
G
01 mL
D
00
ng
6
0. /mL
1
ng
/m
L
0.
0.
00
M
M
G
hX
R
M
D
D
6
32
0.
0.
00
32
G
hX
R
M
20
44
1
1
1
4420 hXR32
0.1 ng/mL
MGD006
0.01 ng/mL
MGD006
0.1 ng/mL
AML patient primary PBMCs (containing 82% blasts) were treated with MGD006, 4420-hXR32, or phosphate buffered
saline (PBS) for 144 hours. The E:T cell ratio was approximately 1:300 as determined from blast and T cell percentages
in PBMCs at the start of the study. The absolute numbers of leukemic blast cells (CD45+/CD33+) and T cells (CD4+ and CD8+)
are shown on the top panel. Cytokines measured in culture supernatants are shown in the bottom panel.
100 ng/kg/day*
Week 4
MGD006
Disease
Evaluation
7 days
Lead-in
CIV*
4 days on,
3 days off
or
7 days on
4 days on,
3 days off
or
7 days on
4 days on,
3 days off
or
7 days on
(CR, CRi, PR, or
improvement
in PB/BM AML
blast count)
C2D1
4 days on,
3 days off
Up to 12 cycles
AML
DOSE EXPANSION
MTD/MAD
24 Patients Each
MDS
*Continuous IV infusion Days 1–3 at 30 ng/kg/day; Days 4–7 at 100 ng/kg/day.
Entry Criteria
■■
■■
Presented at The 2017 ASCO Annual Meeting, June 2–6, 2017, Chicago, IL
30 ng/kg/day*
Week 3
MGD006
Key Inclusion Criteria
Multi-center Phase 1, open-label 3+3 design dose escalation and cohort
expansion study
■■
All patients start with a lead-in continuous IV infusion (CIV) of 30 ng/kg/day
for 3 days followed by 100 ng/kg/day for 4 days; dosing occurs in 28-day
cycles. Subsequent weeks (2–4) are dosed in two different schedules.
(see Study Schema)
■■
Beginning with second cycle, all patients receive MGD006 for 4 days on/3
days off at the maximal dose/cohort
■■
Treatment continues until 2 cycles after attainment of complete response,
maximum of 12 cycles, DLT, or treatment failure
■■
CRS graded according to Lee criteria; response assessed by IWG (AML) or
IPSS (MDS) criteria
■■
Once MTDS or MAD is identified, two cohorts of 24 patients each, one in AML
and one in MDS, will be enrolled
Cytokines
Enrollment ongoing in U.S. and Europe.
+
Week 2
MGD006
Exploratory Objectives:
■■
IFN-γ
TNF-α
IL-10
IL-6
IL-4
IL-2
Study Status
Week 1
MGD006
Secondary Objectives:
Study Design
ng
/
G
01 mL
D
00
ng
6
44
0. /mL
1
20
ng
hX
/m
L
M R32
G
0
D
00 .1 n
g
M 60
.0 /mL
G
D
1
00
ng
6
0. /mL
1
ng
/m
L
0
6
Absolute Cell Number
0
L
1000
Multi-Patient Dose Escalation Segment and Dose
Expansion Phase
■■
Evaluate the utility of CD123 expression on blast cells in AML and MDS as
a biomarker
■■
Evaluate cytokine production by immune effector cells
■■
Evaluate changes in T lymphocyte populations and activation markers
■■
Evaluate changes in leukemic and normal cells in PBMCs
■■
Evaluate changes in leukemic cells, leukemic stem cells and normal
progenitor cells in bone marrow
■■
Evaluate molecular markers of minimal residual disease
■■
Examine changes in T lymphocyte repertoire
■■
Gain experience with the use of certain anti-cytokine agents in the
prevention and/or treatment of cytokine release symptoms
2000
*One patient mini-cohorts, increase to 4 patient cohort if AE ≥ Grade 2; proceed to next dose if DLT <33 %.
+Completed.
Primary Objective:
Describe preliminary safety profile of MGD006 over a broad dose range in
two dosing schedules
■■
Characterize pharmacokinetics (PK) and immunogenicity of MGD006 over a
broad dose range in two dosing schedules
■■
Describe any evidence of anti-neoplastic activity in AML and MDS
3000
80
0
Study Schema
Key Study Objectives
■■
4000
5000
0.
6
00
D
G
M
Radiance x 106
photons/g/cm2/sr
■■
*Also known as S80880 and flotetuzumab
CD8+
40
––Elimination of leukemic stem cells
––Capable of engaging any T cell without HLA-restriction
Potent in vivo preclinical activity in preclinical models
■■
Extremely low clinical dosing (ng/kg)
CD4+
5000
10000
400
pg/mL
Proposed Function/Mechanism of Action
CD8+
15000
800
Radiance x 106
photons/g/cm2/sr
d19
T-cell Activation
20000
S–S
COOH
CD4+
25000
ng
/m
L
ng
/m
0.
M
NH2
01
1
0.
hX
R
VH
20
NH2
VH
Radiance x 103
photons/g/cm2/sr
d12
VL
0
44
VL
10000
6
Anti-CD123
Anti-CD3
(hXR32)
20000
00
Radiance
photons/g/cm2/sr
d3
30000
T Cells
20
CD3 x CD123
D
FITC x CD123
G
CD3 x FITC
ng
/m
L
No DART
32
MGD006*
T Cells Only
MGD006 Activity in Primary AML Patient Samples
44
MGD006 Suppresses CD123+ Leukemia Xenografts
Absolute Cell Number
MGD006: Humanized CD123 x CD3 DART® Molecule
Confirmed diagnosis of primary or secondary AML (any subtype except APL
according to WHO classification) or MDS with an IPSS risk category of Int-2
or High Risk
■■
Refractory AML unlikely to benefit from cytotoxic chemotherapy as defined
by any one of the following criteria:
––newly diagnosed leukemia refractory to ≥2 induction attempts,
––leukemia in 1st relapse with initial CR duration <6 months,
––leukemia in 1st relapse following ≥1 unsuccessful salvage attempts, or
––leukemia in 2nd or higher relapse
Patients with MDS must have experienced treatment failure with induction
therapy or at least one cycle of hypomethylating therapy and have ≥10%
marrow blasts
■■
Eastern Cooperative Oncology Group (ECOG) performance status ≤2 with
adequate hepatic and renal function and organ reserve
■■
Peripheral blast count ≤20,000/mm3 at the time of initiation of infusion on
Cycle 1 Day 1
■■
Key Exclusion Criteria
Prior history of allogeneic stem cell transplantation
■■
Prior treatment with an anti-CD123-directed agent
■■
Need for concurrent other cytoreductive chemotherapy
■■
History of or suspected current autoimmune disorders with certain exceptions
■■
Second primary malignancy that requires active therapy (adjuvant hormonal
therapy allowed)
■■
Prior treatment with radiotherapy, immunotherapy, or other investigational
agent within 4 weeks; use of immunosuppressant medications, granulocyte
colony stimulating or granulocyte-macrophage colony stimulating factor
within 2 weeks
■■
Known central nervous system leukemia
■■
Location
Principal Investigator
Washington University
Geoffrey L. Uy
Duke University
David Rizzieri
Emory University
Hanna Jean Khoury
University of North Carolina
Mathew C. Foster
Providence Cancer Center
John Godwin
Institut Paoli-Calmettes
Norbert Vey
Universitätsklinikum Würzburg
Max S. Topp
Università di Bologna
Giovanni Martinelli
University Vita-Salute San Raffaele
Fabio Ciceri
University Medical Center Groningen
Geert Abraham (Gerwin) Huls
Erasmus University Medical Center
Bob Löwenberg
References
1. Al-Hussaini, et al. Blood 2016,127:122-31
Copies of this poster obtained through Quick Response (QR) Code are for
personal use only and may not be reproduced without permission from
ASCO® and the author of this poster.