Download Cell Cytotoxicity against Multiple Myeloma (MM

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
Novel Monoclonal Antibody Enhances Natural Killer (NK)
Cell Cytotoxicity against Multiple Myeloma (MM):
Interim Phase 1 Trial Results
* ASH Non-Member
# 2880 Board II-806
Interim Phase I clinical trial results
Pharmacokinetics
Serum concentration (0 to 28 days)
Study on-going 25 patients included
Safety
• In allogeneic bone-marrow transplantation of high-risk patients with
MMy, AML or CML, KIR-HLA mismatched NK cells can provide
significant anti-tumour efficacy, leading to reduced relapse rates and
improved survival (Ruggeri, Capanni et al. 2002; Giebel, Locatelli et
al. 2003; Leung, Iyengar et al. 2004; Hsu, Keever-Taylor et al. 2005;
Kroger, Shaw et al. 2005).
• Infusion of KIR-HLA mis-matched NK cells appears to provide antitumour efficacy in AML patients (Miller, Soignier et al. 2005).
• In vitro, tumour cells are sensitive to killing by NK cells whose KIR fail
to recognise HLA class I on the target cells (KIR-HLA mis-matched),
but not by KIR-HLA matched (Ruggeri, Capanni et al. 2002).
• Anti-KIR mAbs can induce, dose-dependently, killing of HLA-Cpositive tumour cells by NK cells that are inhibited by HLA-C in the
absence of mAb (Moretta, Vitale et al. 1993).
• 1-7F9/IPH2101 enhances patient NK cell cytotoxicity against
autologous tumor cells in vitro (Romagne et al 2009).
From Scientific Rationale to Drug Candidate
Blocking NK inhibitory receptor (KIR)
1/ NK and tumor cells from patient
Method
• An open-label, single-agent, dose-escalation,
multiple dose safety and tolerability study of
IPH2101 is being conducted in heavily pretreated patients with relapsed/refractory MM.
Dose escalation with IPH2101 (0.0003,
0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg as IV
infusion) is being studied using a 3+3
scheme. Re-dosing criteria (1/month x 4
months) are based on safety data from
previous
dosing.
KIR
occupancy,
pharmacokinetics (PK), pharmacodynamics,
effects on NK cell maturation, and biological
effects of IPH 2101 are being monitored in all
patients.
Redosing criteria based
on safety data, PK, and
PD (including KIR
occupancy ) from
previous dosing
Dosing every 4 weeks
with a total of 4 doses
Safety
assessment
MHC from patient is
recognized by KIR of NK
cells
=> NK cell is not activated
Dose
Level
Dose
(mg/kg)
No. of
Patients
1
0.0003
n=4
2
0.003
n=3
3
0.015
n=3
4
0.075
n=6
5
0.3
n=3
6
1
n=3
7
3
• Dose level 7:
3 mg/kg, on-going, 10
patients to be included
at this level
IPH 2101 (1-7F9) was well tolerated
• Related Adverse Events were seen in
7/25 patients (28%).
• 13/25 pts received at least 2 doses (7 pts
had 2, 1 pt had 3 and 5 pts had 4 cyclesmedian 2).
• Most AE are grade 1 to 3.
• Dose level 1: 1 patient
replaced but treated
• Dose level 4: 3
additionnal patients
enrolled due to a DLT
(SAE possibly related)
n=3
Only one SAE Grade 4 event only was
considered as possibly related
Patients baseline characteristics
• Acute renal failure one week post dosing.
Patient dosed with 0.075mg/kg (dose
level 4).
Data on 25 patients – Dose levels 1-7
Sex
(M/F)
15/10
Age
(years)
Median
min Max
61
47 - 81
Duration of disease
(years)
Mean
Min-Max
4
0.7-11
Prior Therapy
Median
Min-Max
3
1-11
Time from last
treatment (months)
Median
Min-Max
5.6
0.1 - 33
ECOG
Median
Min-Max
1
0-2
SPEP baseline
(mg/dl)
Median
Min-Max
2000
100- 7300
• Patient was hospitalized and put on
dialysis then discharged from hospital
one week after admission.
100000
100
Full KIR Occupancy
10000
2
3
Cycles
4
2/ NK cell from donor
all patients stay in trial for safety
follow-up until KIR-occupancy
can no longer be detected
1 mg/kg
0.3 mg/kg
1000
0.075 mg/kg
0.015 mg/kg
100
0.003 mg/kg
0.0003 mg/kg
10
KIR-ligand
mismatch
Tumor cell from
transplanted patient
• PD (KIR-occupancy , cytokines, immune cell
regulation markers, functionnal assay of NK
cytotoxicity,NK and T cell receptors)
12 additional patients have been since
included in the study and received up to
3 mg/kg, no additional related SAE was
reported and no relevant change in
creatinine was observed.
Mimicking mismatch
situation with a blocking
antibody targeting KIR
=> NK cell is activated
IPH 2101
the anti-KIR antibody
IPH 2101 (1-7F9)
• Non depleting full human IgG4 mAb
• Binds with high affinity to KIR2DL1 and KIR2DL2/3 (main KIR
inhibitory receptors expressed by NK cells and a subset of T cells)
• Early signs of efficacy (reduction in serum
and/or M protein, PFS)
Main selection criteria
• Multiple myeloma patients in relapse or
progression after at least one prior systemic
treatment regimen for MM
• Relapse or progression evidenced by at least
25% increase in the
M-protein as compared to the best response
from the previous regimen
• Blocks the interaction of KIR2DL with HLA-C allotypes, their
natural ligands
• Peripheral NK cells (absolute CD16,56)
>0,1X109/L (100 mm3), 0,05X109/L since
amendment 5
• Prevents the inhibitory signals usually triggered by this
KIR2DL/HLA-C contact and thus fosters activation of NK cells
• Age range: min 18 years
• ECOG status: 0 -2
0.075
mg/kg
1
mg/kg
3
mg/kg
0
7
14
21
28
Grade 2
1
0
0
1
GASTROINTESTINAL DISORDERS
ABDOMINAL PAIN
Grade 1
1
0
0
1
NAUSEA
Grade 1
0
1
0
•PK
• Low inter-patients variability
• Half-life of IPH2101 ranges
around 17 days at the highest
doses
1
CHILLS
Grade 1
0
1
2
3
FATIGUE
Grade 1
0
0
1
1
Grade 1
0
0
3
3
Grade 4
1*
0
0
1
NEUTROPHIL COUNT DECREASED
Grade 3
0
0
1
1
HYPERURICAEMIA
Grade 4
1*
0
0
1
Grade 4
1*
0
0
1
1
1
2
0
0
1
0
1
1
Grade 1
0
RENAL AND URINARY DISORDERS
RENAL FAILURE ACUTE
Grade 3
1*
28
Conclusions
• PD
• Moderate inter-patients variability
• Clear dose-response relationship
for full KIR occupancy and
duration of KIR occupancy.
For some patients kinetics of serum monoclonal protein level was altered.
This is seen in 2 patients of dose level 4 (0.075mg/kg) who both had 4 lines of prior therapy and
high risk cytogenetics.
NERVOUS SYSTEM DISORDERS
HEADACHE
21
• After dose escalation, the study
is now entering into the extension
cohort 3 mg/kg. Data from the
first 25 treated patients are
available and presented.
M protein / Serum concentrations
METABOLISM AND NUTRITION DISORDERS
HYPERKALAEMIA
14
• No Dose Limiting Toxicity (DLT)
has been observed.
INVESTIGATIONS
BLOOD CREATININE INCREASED
7
Time (days)
PK/PD conclusions
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
PYREXIA
0
Time (days)
Total
CARDIAC DISORDERS
TACHYCARDIA
Cut off
• The acute renal failure was deemed
probably related to trial drug and
considered as a potential dose limiting
toxicity (DLT).
• Related AEs according to dose-level (N patients reporting at least once the AE)
were reported only at 3 doses levels.
CTC AE
Grade
40
0
1
• 25 patients have been exposed and followed until the cut off date
(3 first patients of dose level 7 - 3 mg/kg) – (unvalidated data).
• Safety and tolerability (NCI-CTC) of IPH
2101 (1-7F9)
• PK
3/ NK and tumor cells from patient
KIR
blockade
Assessements
60
20
> 146 AEs reported, 25 considered as possibly or probably related to the trial product
MHC from transplanted
patient is not recognized by
KIR of NK cells from donor
due to genetic difference
between donor and recipient
=> NK cell is activated
80
3 mg/kg
Safety results
1
Pharmadynamics
KIR occupancy (0 to 28 days)
% KIR Occupancy
Rationale for Clinical development of IPH 2101
Study design
and assessments
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
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.
IPH2101 Conc (ng/mL)
Scientific & medical rationales
1 Division
• KIR full occupancy (> 90%) for at
least 3 weeks is reached at 1mg
/kg. In accordance with the preclinical PK/PD model there is a
clear relationship between
exposure (Cmax) and KIR
occupancy.
• No deleterious effect on NK cell
maturation has been seen.
• In two heavily pre-treated
patients, both with high-risk
cytogenetics, protein M follow-up
suggested transient disease
stabilization while receiving
IPH 2101.
VASCULAR DISORDERS
FLUSHING
Grade 1
0
* 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