Microsoft PowerPoint - 091130_PosterASH_IPH 2101-103 [Mode de compatibilité]

Novel Monoclonal Antibody Enhances Natural Killer (NK)
Don Benson, MD, PhD1, Craig C. Hofmeister, MD2*, Swaminathan Padmanabhan, MD, MBBS3, Rafat Abonour4, Attaya Suvannasankha, MD5, Alain Mita6*, Patrick Squiban, MD7*,
Megan K Smith, MS, CNP, RN8*, Courtney E Bakan9*, Marc Marzetto7*, Pascale Andre, PhD7, Jerome Tollier7*, Michael A. Caligiuri, M.D.10 and Sherif Farag, MBBS, PhD11
1 Division of Hematology/Oncology, Ohio State University, Columbus, OH; 2 Hematology and Oncology, Ohio State University, Columbus, OH; 3 The Institute for Drug Development, CTRC at the University of Texas Health Science
Cell Cytotoxicity against Multiple Myeloma (MM):
Center San Antonio, San Antonio, TX; 4 Indiana University Cancer, Indianapolis, IN; 5 Division of Hematology and Oncology, Department of Internal Medicine, Indiana University School of Medicine and Simon Cancer Center,
Indianapolis, IN; 6 CTRC, San Antonio, TX; 7 Innate Pharma, Marseille, France; 8 The Ohio State University, Columbus, OH; 9 Division of Hematology/Oncology, The Ohio State University, Columbus, OH;
10 The Ohio State University Comprehensive Cancer Center, Columbus, OH; 11 Indiana University School of Medicine, Indianapolis, IN.
Interim Phase 1 Trial Results
* ASH Non-Member
# 2880 Board II-806
Scientific & medical rationales
Study design
Interim Phase I clinical trial results
Rationale for Clinical development of IPH 2101
and assessments
Study on-going 25 patients included
Pharmacokinetics
Pharmadynamics
Safety
Serum concentration (0 to 28 days)
KIR occupancy (0 to 28 days)
· In allogeneic bone-marrow transplantation of high-risk patients with
Dose
Dose
No. of
· Dose level 7:
Method
MMy, AML or CML, KIR-HLA mismatched NK cells can provide
Level
(mg/kg)
Patients
3 mg/kg, on-going, 10
IPH 2101 (1-7F9) was well tolerated
100000
1
0.0003
n=4
patients to be included
· Related Adverse Events were seen in
100
significant anti-tumour efficacy, leading to reduced relapse rates and
· An open-label, single-agent, dose-escalation,
7/25 patients (28%).
improved survival (Ruggeri, Capanni et al. 2002; Giebel, Locatelli et
at this level
multiple dose safety and tolerability study of
2
0.003
n=3
Full KIR Occupancy
· 13/25 pts received at least 2 doses (7 pts
3
0.015
n=3
· Dose level 1: 1 patient
10000
al. 2003; Leung, Iyengar et al. 2004; Hsu, Keever-Taylor et al. 2005;
IPH2101 is being conducted in heavily pre-
mL)
80
had 2, 1 pt had 3 and 5 pts had 4 cycles-
3 mg/kg
replaced but treated
y
Kroger, Shaw et al. 2005).
treated patients with relapsed/refractory MM.
4
0.075
n=6
median 2).
(ng/
1 mg/kg
Dose
escalation
with
IPH2101
(0.0003,
· Dose level 4: 3
50.3
n=3
· Most AE are grade 1 to 3.
1000
· Infusion of KIR-HLA mis-matched NK cells appears to provide anti-
0.3 mg/kg
60
additionnal patients
tumour efficacy in AML patients (Miller, Soignier et al. 2005).
0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg as IV
6
1
n=3
Conc
0.075 mg/kg
enrolled due to a DLT
Occupanc
infusion) is being studied using a 3+3
0.015 mg/kg
· In vitro, tumour cells are sensitive to killing by NK cells whose KIR fail
73
n=3
(SAE possibly related)
Only one SAE Grade 4 event only was
100
R
40
scheme. Re-dosing criteria (1/month x 4
H2101
considered as possibly related
0.003 mg/kg
KI
to recognise HLA class I on the target cells (KIR-HLA mis-matched),
IP
months) are based on safety data from
0.0003 mg/kg
%
Patients baseline characteristics
Cut off
but not by KIR-HLA matched (Ruggeri, Capanni et al. 2002).
· Acute renal failure one week post dosing.
10
20
previous
dosing.
KIR
occupancy,
Data on 25 patients Dose levels 1-7
Patient dosed with 0.075mg/kg (dose
· Anti-KIR mAbs can induce, dose-dependently, killing of HLA-C-
pharmacokinetics (PK), pharmacodynamics,
Sex
(M/F)
15/10
level 4).
positive tumour cells by NK cells that are inhibited by HLA-C in the
effects on NK cell maturation, and biological
1
0
Age
Median
61
· Patient was hospitalized and put on
absence of mAb (Moretta, Vitale et al. 1993).
effects of IPH 2101 are being monitored in all
0
7
14
21
28
0
7
14
21
28
(years)
min Max
47 - 81
dialysis then discharged from hospital
Time (days)
· 1-7F9/IPH2101
enhances
patient
NK
cell
cytotoxicity
against
patients.
one week after admission.
Duration of disease
Mean
4
Time (days)
autologous tumor cells in vitro (Romagne et al 2009).
(years)
Min-Max
0.7-11
· The acute renal failure was deemed
Redosing criteria based
on safety data, PK, and
Median
3
probably related to trial drug and
From Scientific Rationale to Drug Candidate
Prior Therapy
PD (including KIR
Min-Max
1-11
considered as a potential dose limiting
Blocking NK inhibitory receptor (KIR)
occupancy ) from
Dosing every 4 weeks
Time from last
Median
5.6
toxicity (DLT).
previous dosing
Conclusions
with a total of 4 doses
treatment (months)
Min-Max
0.1 - 33
1/ NK and tumor cells from patient
12 additional patients have been since
PK/PD conclusions
Median
1
· After dose escalation, the study
ECOG
included in the study and received up to
Safety
Min-Max
0-2
MHC from patient is
assessment
3 mg/kg, no additional related SAE was
is now entering into the extension
· PD
SPEP baseline
Median
2000
·PK
recognize
ogniz d
e by
by KIR
KI
of NK
reported and no relevant
relev
change in
(mg/dl)
Min-Max
100- 7300
· Low inter-patients variability
· Moderate inter-patients variability
coht
hort 3 mg/k
/kg. Data from th
the
cells
creatinine was observed.
=> NK cell is not activated
· Half-life of IPH2101 ranges
· Clear dose-response relationship
first 25 treated patients are
Safety results
around 17 days at the highest
for full KIR occupancy and
1
2
3
4
available and presented.
all patients stay in trial for safety
doses
duration of KIR occupancy.
Cycles
· 25 patients have been exposed and followed until the cut off date
follow-up until KIR-occupancy
2/ NK cell from donor
can no longer be detected
(3 first patients of dose level 7 - 3 mg/kg) (unvalidated data).
> 146 AEs reported, 25 considered as possibly or probably related to the trial product
· No Dose Limiting Toxicity (DLT)
MHC from transplanted
· Related AEs according to dose-level (N patients reporting at least once the AE)
has been observed.
patient is not recognized by
Assessements
were reported only at 3 doses levels.
KIR of NK cells from donor
M protein / Serum concentrations
due to genetic difference
· Safety and tolerability (NCI-CTC) of IPH
CTC AE
0.075
1
3
Total
between donor and recipient
Grade
mg/kg
mg/kg
mg/kg
· KIR full occupancy (> 90%) for at
2101 (1-7F9)
KIR-ligand
Tumor cell from
=> NK cell is activated
CARDIAC DISORDERS
For some patients kinetics of serum monoclonal protein level was altered.
least 3 weeks is reached at 1mg
mismatch
transplanted patient
· PK
TACHYCARDIA
Grade 2
1
0
0
1
This is seen in 2 patients of dose level 4 (0.075mg/kg) who both had 4 lines of prior therapy and
/kg. In accordance with the pre-
3/ NK and tumor cells from patient
· PD (KIR-occupancy , cytokines, immune cell
GASTROINTESTINAL DISORDERS
high risk cytogenetics.
regulation markers, functionnal assay of NK
clinical PK/PD model there is a
ABDOMINAL PAIN
Grade 1
1
0
0
1
cytotoxicity,NK and T cell receptors)
NAUSEA
Grade 1
0
1
0
1
clear relationship between
Mimicking mismatch
· Early signs of efficacy (reduction in serum
situation with a blocking
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
exposure (Cmax) and KIR
antibody targeting KIR
and/or M protein, PFS)
CHILLS
Grade 1
0
1
2
3
=> NK cell is activated
occupancy.
FATIGUE
Grade 1
0
011
IPH 2101
KIR
Main selection criteria
PYREXIA
Grade 1
0
0
3
3
the anti-KIR antibody
blockade
· No deleterious effect on NK cell
INVESTIGATIONS
· Multiple myeloma patients in relapse or
BLOOD CREATININE INCREASED
Grade 4
1*
0
0
1
maturation has been seen.
progression after at least one prior systemic
IPH 2101 (1-7F9)
treatment regimen for MM
NEUTROPHIL COUNT DECREASED
Grade 3
0
0
1
1
METABOLISM AND NUTRITION DISORDERS
· Relapse or progression evidenced by at least
· In two heavily pre-treated
· Non depleting full human IgG4 mAb
25% increase in the
HYPERKALAEMIA
Grade 4
1*
0
0
1
patients, both with high-risk
· Binds with high affinity to KIR2DL1 and KIR2DL2/3 (main KIR
M-protein as compared to the best response
HYPERURICAEMIA
Grade 4
1*
0
0
1
cytogenetics, protein M follow-up
inhibitory receptors expressed by NK cells and a subset of T cells)
from the previous regimen
NERVOUS SYSTEM DISORDERS
HEADACHE
Grade 1
0
1
1
2
suggested transient disease
· Peripheral NK cells (absolute CD16,56)
· Blocks the interaction of KIR2DL with HLA-C allotypes, their
>0,1X109/L (100 mm3), 0,05X109/L since
RENAL AND URINARY DISORDERS
stabilization while receiving
natural ligands
amendment 5
RENAL FAILURE ACUTE
Grade 3
1*
0
0
1
IPH 2101.
· Prevents the inhibitory signals usually triggered by this
· Age range: min 18 years
VASCULAR DISORDERS
KIR2DL/HLA-C contact and thus fosters activation of NK cells
· ECOG status: 0 -2
FLUSHING
Grade 1
0
0
1
1
* Same patient 102006 accute renal failure
Disclosures: Benson: Innate Pharma: Consultancy, Honoraria Padmanabhan, Farag : Innate Pharma: Honoraria - André, Marzetto, Squiban, Tiollier: Innate Pharma: Employment - Hofmeister, Abonour, Suvannasankha, Mita, Smith, Bakan, Caligiuri: Nothing to disclose.
innate pharma ASH December 2009