Slide 1: Lesley Seymour MD PhD, NCIC Clinical Trials Group
Lesley Seymour MD PhD Director, Investigational New Drug Program NCIC Clinical Trials Group, Kingston Professor of Oncology, Queens University NCIC Clinical Trials Group
Slide 2: NCIC Clinical Trials Group conflict disclosure
NCIC CTG : drug and some funding to support a planned study | have no other conflicts to declare ————
Slide 3: New frontiers in immunotherapy plenary sessions
10:45 - 12:45 Plenary session 2 New frontiers in immunotherapy (1): Checkpoint targets Chairs: Alexander Eggermont, Villejuif, France & Alex A. Adjei, Buffalo, NY, USA 10:45 - 11:05 (02.1) Educational overview and recent CTLA4, PD1, and PD-L1 data Alexander Eggermont, Cancer Institute Gustave Roussy
Slide 4: CD94/NKG2A is a heterodimer complex between CD94 and NKG2A
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 1 Always at least one inhibitory receptor CD94/NKG2A - ligand HLA-E KIR2DL – HLA-C KIR3DL – HLA-B or A3 Activati
Slide 5: HLA-E: non classical MHC class I molecule
• Non classical major histocompatibility complex class I molecule • Expressed on cell surface of most leukocytes and large variety of transformed cells NCIC Clinical Trials Group
Slide 6: Gooden et al
NCIC Clinical Trials Group Gooden et al
Slide 7: IPH2201: First in Class MAb targeting NKG2A
IPH2201: First in Class MAb targeting NKG2A NKG2A HLA-E NK cell Tumor cell + Activating Activating ligand + receptor HLA-E MHC NKG2A TCR T cell Anti-NKG2A NK and T cell inhibition by NKG2A Activation through NKG2A blockade
Slide 8: Data kindly provided by Novo Nordisk and Innate Pharma
Data Kindly Provided by: L Favre-Kontula, Novo Nordisk A/S, Søborg, Denmark N Wagtmann and P. Dodion, Innate Pharma, France NCIC Clinical Trials Group
Slide 9: Preclinical activity of IPH2201
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
Slide 10: Phase I study design in rheumatoid arthritis patients
Patients with rheumatoid arthritis Randomized, double-blind, placebo-controlled 3 cohorts Single dose iv Single dose sc Multiple dose sc 92 patients 68 IPH2201 24 placebo NCIC Clinical Trials Group
Slide 11: Most frequent adverse events
Single dose IV Multiple dose SC Preferred Term Placebo IPH2201 Placebo IPH2201 (N=9) (N=27) (N=9) (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 frequen
Slide 12: No DLT identified; severe adverse events
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 discontinuation Only 7 ‘severe’ – all unrelated 3 placebo 4 IPH2201 2 episodes of transient tooth ache, one tooth extraction and one injury of meniscus.
Slide 13: Severe adverse events unrelated to treatment
None were considered related to either placebo or IPH2201 and all occurred after off-treatment Placebo 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) NCIC Clinical Trials Group
Slide 14: Pharmacokinetics: single dose IV and multiple dose SC
Single dose IV Multiple dose SC 1000.000 100.000 100.000 10.000 NNC0141-0100 (ug/mL) NNC0141-0100 (ug/mL) 10.000 H 1.000 1.000 H HH H O HH HH HHHHH HHH HO O HH H O OOOO H HHH H 0.100 I O H 0.100 H H I O H IIIII O H H I H 0.010 I I I 0.010 HII I I I I I I I I I H O I II O O H H I 0.001 O OI H I I I I
Slide 15: NKG2A receptor occupancy
140 140 Single dose, IV Multiple dose, SC 120 120 O O HIIH NKG2A Occupancy (%) O NKG2A Occupancy (%) 100 O H O H HO HO HIO HO 100 HH O O HHO II O HH HH HHHHI H HHH 80 II H H HHII HH I I O 80 I I I H OIII I I I 60 OII I 60 I H OI O O H 40 O I I 40 HI I I 20 OOOI I I I H H O I O H 20 I H O OO I OI O H
Slide 16: Phase I safety, PK and occupancy summary
At least 12 week safety data available for all patients No DLT - benign profile Nasopharyngitis and headache most frequently reported AEs Injection site reaction in ~ 22% of patients in MD SC cohort PK similar to other mAbs binding a membrane receptor Excellent NKG2A receptor occupancy Dose-effect r
Slide 17: Dose-ranging study of IPH2201 in high grade serous ovarian carcinoma
A DOSE-RANGING STUDY OF IPH2201 IN PATIENTS WITH HIGH GRADE SEROUS CARCINOMA OF OVARIAN, FALLOPIAN TUBE OR PERITONEAL ORIGIN NCIC Clinical Trials Group
Slide 18: Trial design: Part one and Part two
High Grade Serous OVCA Part one Randomization 1mg/kg 4mg/kg 10mg/kg N=6 N=6 N=6 High Grade Serous OVCA Part two Platinum Sensitive Platinum Resistant N=10 N=10 NCIC Clinical Trials Group
Slide 19: Primary and secondary objectives
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 antibodies explore the efficacy of IPH
Slide 20: Protocol and CTA being finalized
Protocol and CTA being finalized Starting soon………… NCIC Clinical Trials Group
Slide 21: Pre-operative IPH2201 in oral cavity squamous cell carcinoma
“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 Pharma Site: Charité University Medicine Berlin NCIC Clinical Trials Group
Slide 22: Summary: IPH2201 first-in-class monoclonal antibody
Exciting and active area of investigation IPH2201 is first-in-class monoclonal antibody Non-clinical evidence of activity Good PK profile Benign toxicity profile PD effects at achievable exposure Clinical trials in cancer have just started Confirm PK/PD Explore evidence clinical effects NCIC Clinica