rationale and protocol of the phase i/ii trial of
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NCIC Clinical Trials Group
Lesley Seymour MD PhDDirector, Investigational New Drug ProgramNCIC Clinical Trials Group, KingstonProfessor of Oncology, Queens University
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NCIC Clinical Trials Group
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NCIC Clinical Trials Group
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NCIC Clinical Trials Group
CD94/NKG2A is a heterodimer complex between CD94 and NKG2A (natural killer group 2 member A)
Peripheral and tumour infiltrating NK cells Cytotoxic T cells
NK cells - major ligands are MHC 1Always at least one inhibitory receptor
CD94/NKG2A - ligand HLA-EKIR2DL – HLA-C KIR3DL – HLA-B or A3
Activating CD94/NKG2C – HLA-EKIR2DS – HLA-CKIR3DS – HLA-Bw4
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NCIC Clinical Trials Group
• Non classical major histocompatibility complex class I molecule• Expressed on cell surface of most leukocytes and large variety of
transformed cells
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NCIC Clinical Trials GroupGooden et al
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IPH2201: First in Class MAb targeting NKG2A
NK and T cell inhibition by NKG2A
HLA-E
NK cell
Activating ligand
Activating receptor
Tumor cell
+ +
Anti-NKG2A
Activation through NKG2A blockade
T cell
NKG2A
TCR
MHCNKG2A
HLA-E
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NCIC Clinical Trials Group
Data Kindly Provided by:L Favre-Kontula, Novo Nordisk A/S, Søborg, DenmarkN Wagtmann and P. Dodion, Innate Pharma, France
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Dose dependent increase in NK cell activation Restricted to CD94/NKG2A+ effector cells
In ex-vivo studies increases killing of autologous blasts“IPH2201” pretreated NGK2A+ NK cells prevent tumour engraftment in in-vivo mouse models “IPH2201” has anti-tumour activity in established xenograft models
IPH2201 does not bind to CD94/NKG2A in mice, so a surrogate rat anti-mouse NKG2A-blocking monoclonal antibody and a mousified version of this mAb, were used for in vivo efficacy studies. These antibodies increase mouse NK-cell cytolytic activity in vitro.
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NCIC Clinical Trials Group
Patients with rheumatoid arthritisRandomized, double-blind, placebo-controlled3 cohorts
Single dose ivSingle dose scMultiple dose sc
92 patients68 IPH220124 placebo
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NCIC Clinical Trials Group
Preferred TermSingle dose IV Multiple dose SC
Placebo(N=9)
IPH2201 (N=27)
Placebo(N=9)
IPH2201 (N=23)
Nasopharyngitis 22% 48% 56% 43%
Headache 22% 7% 0 26%
Dizziness 11% 7% 11% 4%
Rhinitis 11% 7% 0% 0%
Inject. site erythema 0% 0% 0 22%
Oral Herpes 0% 0% 0 13%
Diarrhoea 0% 0% 11% 9%
* Most frequent: defined as occurring in >5% of the IPH2201 treatment groupssorted by decreasing frequency in the IPH2201 SD IV group
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No DLT identified up to the highest tested dosage (10 mg/kg SD IV, 4 mg/kg SD SC and MD SC)No AE leading to treatment discontinuationOnly 7 ‘severe’ – all unrelated
3 placebo 4 IPH2201
2 episodes of transient tooth ache, one tooth extraction and one injury of meniscus.
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NCIC Clinical Trials Group
None were considered related to either placebo or IPH2201 and all occurred after off-treatmentPlacebo
Headache: 1 patient (SD IV) Amnesia: 1 patient in (SD SC)
IPH2201 Meniscus injury: 1 patient (SD IV) Abdominal pain, night sweats, dyspnea: 3 events in 1 patient (MD SC)
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NCIC Clinical Trials Group
NN
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0.001
0.010
0.100
1.000
10.000
100.000
1000.000
Planned Time (Weeks)0 7 14 21 28 35 42
W
Dose mg/kg: 0.0000 0.0002 0.0010 0.00500.0250 0.1000 0.4000 1.10003.5000 10.0000O O O O O O I I I I I IO O O H H H
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• Approximately dose-proportional for dose levels between 1 and 10 mg/kg• The apparent half-life is concentration dependent with longer half-life at higher concentrations• For the highest dose levels, the apparent t½ approaches the general half-life for IgG
mAbs (~ 3 weeks)• 3-6 fold accumulation after administration of 4 doses
at dose levels from 0.05 to 4 mg/kg
Single dose IV Multiple dose SC
NN
C01
41-0
100
(ug/
mL)
0.001
0.010
0.100
1.000
10.000
100.000
Planned Time (Weeks)0 7 14 21 28 35 42 49
W
Dose mg/kg: 0.000 0.005 0.0500.250 1.000 4.000O O O I I I H H H
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NCIC Clinical Trials Group
NK
G2A
Occupancy (%
)
0
20
40
60
80
100
120
140
Planned Time (Weeks)0 7 14 21 28 35 42
Dose mg/kg: 0.0000 0.0002 0.0010 0.00500.0250 0.1000 0.4000 1.10003.5000 10.0000O O O O O O I I I I I IO O O H H H
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G2A
Occ
upan
cy (%
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20
40
60
80
100
120
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Planned Time (Weeks)0 7 14 21 28 35 42 49
Dose mg/kg: 0.000 0.005 0.0500.250 1.000 4.000O O O I I I H H H
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Full occupancy at end-of-infusion for doses above 0.005 mg/kg
Single dose, IV Multiple dose, SC
Full occupancy maintained within the 8 week dosing period for 0.05-4 mg/kg
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NCIC Clinical Trials Group
At least 12 week safety data available for all patients
No DLT - benign profile Nasopharyngitis and headache most frequently reported AEsInjection site reaction in ~ 22% of patients in MD SC cohort
PK similar to other mAbs binding a membrane receptorExcellent NKG2A receptor occupancy
Dose-effect relationshipDose dependent duration
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NCIC Clinical Trials Group
A DOSE-RANGING STUDY OF IPH2201 IN PATIENTS WITH HIGH GRADE SEROUS
CARCINOMA OF OVARIAN, FALLOPIAN TUBE OR PERITONEAL ORIGIN
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NCIC Clinical Trials Group
High Grade Serous OVCA
1mg/kgN=6
4mg/kgN=6
10mg/kgN=6
Randomization
High Grade Serous OVCA
Platinum SensitiveN=10
Platinum ResistantN=10
Part one
Part two
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NCIC Clinical Trials Group
Primary: confirm RP2D in cancer patients
Secondary: safety, toxicity and pharmacokinetics pharmacodynamic effects (pre & post Rx)
TIL, HLA-E and CD94/NKG2A expression (FFPE, biopsy, ascites)Receptor occupancy studies (flow cytometry)ctDNA, cytokines
anti-drug antibodiesexplore the efficacy of IPH2201 as a single agent in platinum resistant or sensitive HGSC
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NCIC Clinical Trials Group
Protocol and CTA being finalized Starting soon…………
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NCIC Clinical Trials Group
“Efficacy Study of Pre-operative IPH2201 in Patients With Squamous Cell Carcinoma of the
Oral Cavity”
Patients: Treatment-naïve pre-operative patients with resectable intermediate or high risk SCC
Sponsor: Innate PharmaSite: Charité University Medicine Berlin
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NCIC Clinical Trials Group
Exciting and active area of investigationIPH2201 is first-in-class monoclonal antibody
Non-clinical evidence of activityGood PK profileBenign toxicity profilePD effects at achievable exposure
Clinical trials in cancer have just startedConfirm PK/PDExplore evidence clinical effects