Don Benson, MD, PhD1, Craig C. Hofmeister, MD1*, Courtney E Bakan, BS1, Yvonne Efebera, MD1*, Swaminathan Padmanabhan, MD, MBBS2,
A phase I study of IPH 2101, a novel anti-inhibitory KIR
# 8139
Rafat Abonour, MD3, Attaya Suvannasankha, MD4, Yvonne Efebera1, Patrick Squiban, MD4, Pascale André, PhD,4 Jérôme Tiollier, PhD4*, Ajai Chari, MD5,
Sundar Jagannath, MD5, Michael A. Caligiuri, MD1 and Sherif Farag, MBBS, PhD3
Board 38-A
1 Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH;
mAb - Interim Phase 1 Trial Results in patients with
2 The Institute for Drug Development, CTRC at the University of Texas Health Science Center San Antonio, San Antonio, TX;
3 Division of Hematology/Oncology, Indiana University Cancer Center, Indianapolis, IN;
4 Innate Pharma, Marseille, France;
5 St Vincent & Mount Sinai, New York, NY.
multiple myeloma
ASCO 2010
Scientific & medical rationales
Study design
Interim Phase I clinical trial results
Rationale for Clinical Development of IPH 2101
and assessments
Study on-going 32 patients included
Pharmacokinetics
Pharmadynamics
Serum concentration (0 to 28 days)
KIR occupancy (0 to 28 days)
Dose
Dose
No. of
· Dose level 1:
Safety
Method
· In allogeneic bone-marrow transplantation of high-risk patients with
Level
(mg/kg)
Patients
1 patient replaced but
100000
MM, AML or CML, KIR-HLA mismatched NK cells can provide
treated
IPH 2101 (1-7F9) was well tolerated
1
0.0003
n=4
100
· Open-label,
single-agent,
dose-escalation,
significant anti-tumour efficacy, leading to reduced relapse rates and
2
0.003
n=3
· Dose level 4:
· Related Adverse Events (AEs) were seen in
)
multiple dose safety and tolerability study of
L
10000
90
Full KIR Occupancy
7/25 patients (28%).
improved survival (Ruggeri, Capanni et al. 2002; Giebel, Locatelli et
3 additional patients
3
0.015
n=3
/m
3 mg/kg
IPH 2101 conducted in heavily pre-treated
· 13/25 pts received at least 2 doses (7 pts
g
1 mg/kg
enrolled due to a DLT
)) 80
al. 2003; Leung, Iyengar et al. 2004; Hsu, Keever-Taylor et al. 2005;
(n
patients with relapsed/refractory MM.
4
0.075
n=6
had 2, 1 pt had 3 and 5 pts had 4 cycles-
0.3 mg/kg
(%(%
.
1000
(SAE possibly related)
yy
c
cc
Kroger, Shaw et al. 2005).
median 2).
n
0.075 mg/kg
aa
70
· Dose escalation with IPH 2101 (0.0003,
5
0.3
n=3
n
o
· Dose level 7:
0.015 mg/kg
p
c
u
· In vitro, tumour cells are sensitive to killing by NK cells whose KIR fail
· Most AE are grade 1 to 3.
c
0.003, 0.015, 0.075, 0.3, 1.0, 3.0 mg/kg as IV
6
1
n=3
1
100
0.003 mg/kg
cc
60
3 mg/kg, ongoing,
c
1 cycle
0
O
to recognise HLA class I on the target cells (KIR-HLA mismatched),
1
infusion) using a 3+3 scheme. Re-dosing
O
7
3
n=10
10 patients included
2
0.0003 mg/kg
IRIRK 50
but not by KIR-HLA matched (Ruggeri, Capanni et al. 2002).
Only one Serious Adverse Event (SAE)
H
criteria (1/month x 4 months) based on safety
K
10
IP
Grade 4
Patients baseline characteristics
event was considered as
40
· Anti-KIR mAbs can induce, dose-dependently, killing of HLA-C-
data from previous dosing.
positive tumour cells by NK cells that are inhibited by HLA-C in the
Data on 25 patients ­ Dose levels 1-7
possibly related
1
Cut off
· Monitoring of KIR occupancy, pharmaco-
30
Sex
(M/F)
15/10
· Acute renal failure one week post dosing.
0
7
14
21
28
0
7
14
21
28
absence of mAb (Moretta, Vitale et al. 1993).
kinetics
(PK),
pharmacodynamics
(PD),
Tim e ( d ays )
Patient dosed with 0.075mg/kg (dose level
Time post-dose (days)
Time (days)
· IPH 2101 enhances patient NK cell cytotoxicity against autologous
effects on NK cell maturation, and biological
Age
Median
61
Time (days)
4). Patient was hospitalized and put on
tumor cells in vitro (Romagne et al. 2009).
(years)
min Max
47 - 81
effects of IPH 2101 in all patients.
dialysis then discharged from hospital one
Duration of disease
Mean
4
week after admission.
(years)
Min-Max
0.7-11
1
2
3
4
1
2
3
4
Cycle:
Cycle:
Redosing criteria based
· The acute renal failure was deemed
Median
3
From Scientific Rationale to Drug Candidate
Prior Therapy
on safety data, PK and
Min-Max
1-11
probably related to trial drug and considered
100
Dosing every 4 weeks
PD (including KIR
Blocking NK inhibitory receptor (KIR)
as a potential Dose Limiting Toxicity (DLT).
occupancy ) from
Time from last
Median
5.6
100000
with a total of 4 doses
Full KIR
90
previous dosing
treatment (months)
Min-Max
0.1 - 33
Occupancy
1/ NK and tumor cells from patient
Median
1
)
10000
)
80
ECOG
17 additional patients have been since
Safety
L
3 mg/kg
(%
Min-Max
0-2
/m
1 mg/kg
y
MHC from patient is
assessment
included in the study and received up to
g
c
(n
0.3 mg/kg
a
70
SPEP (Serum protein
1000
.
n
recognized by KIR of NK
Median
2000
3 mg/kg. No additional related SAE
c
0.075 mg/kg
p
repeated
electrophoresis) baseline
n
u
cells
Min-Max
100- 7300
o
0.015 mg/kg
c
(mg/dl)
has been reported up to now.
c
c
60
cycles
=> NK cell is not activated
1
0.003 mg/kg
O
100
01
0.0003 mg/kg
IR
Safety results
2
K
50
1
2
3
4
H
all patients stay in trial for safety
Cycles
IP
follow-up until KIR-occupancy
· 25 patients have been exposed and followed until the cut off date
10
40
2/ NK cell from donor
can no longer be detected
(3 first patients of dose level 7 - 3 mg/kg) ­ (unvalidated data).
1
30
Cut off
> 146 AEs reported, 25 considered as possibly or probably related to the trial product.
0
14
28
42
56
70
84
98
112
126
140
MHC from transplanted
0
14
28
42
56
70
84
98
112
126
patient is not recognized by
Assessments
· Related AEs according to dose-level (N patients reporting at least once the AE) were
Time (days)
Time (days)
KIR of NK cells from donor
reported only at 3 doses levels.
due to genetic difference
· Safety and tolerability (NCI-CTC) of
CTC AE
0.075
1
3
Total
between donor and recipient
Grade
mg/kg
mg/kg
mg/kg
IPH 2101 (1-7F9)
KIR-ligand
Tumor cell from
=> NK cell is activated
CARDIAC DISORDERS
M protein / Serum concentrations
Conclusions
mismatch
transplanted patient
· PK & PD: KIR-occupancy , cytokines,
TACHYCARDIA
Grade 2
1
0
0
1
immune cell regulation markers, functional
3/ NK and tumor cells from patient
GASTROINTESTINAL DISORDERS
For some patients, kinetics of serum monoclonal protein
assay of NK cytotoxicity, NK and T cell
· Accrual of the study completed : Last Patient Last Visit expected Dec 2010.
were altered. A representative example is shown of a
receptors
ABDOMINAL PAIN
Grade 1
1
0
0
1
patient with Durie-Salmon stage 3, ISS stage 2, MM with
Mimicking mismatch
NAUSEA
Grade 1
0
1
0
1
· Early signs of efficacy: reduction in serum
· Maximum Tolerated Dose (MTD) has not been reached. Only one SAE (Grade 4
situation with a blocking
high-risk cytogenetics enrolled in dose level 7 (3mg/kg)
and/or M-protein, Progression Free Survival
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
antibody targeting KIR
who had previously received induction therapy with
acute renal failure) event was considered as possibly related. Safety data from the
CHILLS
Grade 1
0
1
2
3
=> NK cell is activated
(PFS)
FATIGUE
Grade 1
0
0
1
1
lendex, high-dose melphalan and autologous stem cell
first 25 treated patients suggests a satisfactory safety profile with manageable
IPH 2101
KIR
Main selection criteria
PYREXIA
Grade 1
0
0
3
3
transplantation followed by maintenance therapy with len.
adverse events.
the anti-KIR antibody
blockade
INVESTIGATIONS
· MM patients in relapse or progression after
at least one prior systemic treatment regimen
BLOOD CREATININE INCREASED
Grade 4
1*
0
0
1
· PK/PD show a clear relationship between exposure (Cmax) and KIR occupancy
IPH 2101 (1-7F9)
for MM
NEUTROPHIL COUNT DECREASED
Grade 3
0
0
1
1
and a low inter-patients variability. Half-life of IPH2101 ranges around 13 days at
METABOLISM AND NUTRITION DISORDERS
· Relapse or progression evidenced by at least
the highest doses.
· Non depleting full human IgG4 mAb
25% increase in the M-protein as compared to
HYPERKALAEMIA
Grade 4
1*
0
0
1
· Binds with high affinity to KIR2DL1 and KIR2DL2/3 (main KIR
the best response from the previous regimen
HYPERURICAEMIA
Grade 4
1*
0
0
1
· No deleterious effect on NK cell maturation has been seen.
inhibitory receptors expressed by NK cells and a subset of T cells)
· Peripheral NK cells (absolute CD16 + 56)
NERVOUS SYSTEM DISORDERS
>0,1X109/L (100 mm3), 0,05X109/L since
HEADACHE
Grade 1
0
1
1
2
· Blocks the interaction of KIR with HLA-C allotypes (their natural
· Protein M follow-up suggested transient disease stabilization while receiving
amendment 5
RENAL AND URINARY DISORDERS
ligands)
IPH 2101
IPH 2101 in several patients.
· Age range: min 18 years
RENAL FAILURE ACUTE
Grade 3
1*
0
0
1
dosing
· Prevents the inhibitory signals usually triggered by this KIR/HLA-C
VASCULAR DISORDERS
· ECOG* status: 0 -2
contact and thus fosters activation of NK cells
FLUSHING
Grade 1
0
0
1
1
* Eastern Cooperative Oncology Group
* Same patient 102006 acute renal failure

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