a first-in-human study of monoclonal antibody …...a first-in-human study of monoclonal antibody...

# 5542A First-In-Human study of monoclonal antibody GM102 in patients with Anti-Müllerian-Hormone-Receptor II (AMHRII) positive gynecological cancers

Alexandra Leary1, Philippe Aftimos2, Jean-Pierre Delord3, Christophe Le Tourneau4, Isabelle Ray-Coquard5, Christiane Jungels2, Andrea Varga1, Francesco Ricci4, Carlos Gomez-Roca3, Guillaume Bataillon4, Nathalie Van Acker3, Grégory Noël2, Olivier Lantz4, Lydie Cassard1,Agnès Coste6, Bérengère Jean7, Isabelle Tabah-Fisch7, Anne Vincent-Salomon4, Jean-François Prost7 and Ahmad Awada2

1Institut Gustave Roussy, Villejuif, France; 2Institut Jules Bordet-Université Libre de Bruxelles, Brussels, Belgium; 3IUCT, Toulouse, France; 4Institut Curie, Paris, France; 5Centre Léon Bérard, Lyon, GINECO, France; 6UMR152 UPS-IRD, Toulouse, France; 7GamaMabs Pharma, Toulouse, France

C101 FIH STUDY DESIGN

INTRODUCTION

Colorectal cancer

AMHRII- Anti-Müllerian Hormone and its membrane

Receptor II (AMHRII), induce regression of Müllerian ducts in the male embryo

- In normal adults, AMHRII expression is restricted to Sertoli cells (testis) and Granulosa cells (ovary)

- AMHRII is re-expressed in approx. 70% of gynecological tumors

- AMHRII is constitutively expressed in ovarian granulosa cell tumors (GCT)

GM102- Low-fucose IgG1 antibody- Binds AMHRII (tumor cells, approx. 1 nM)- Acts through macrophage engagement via

CD16 high affinity binding (3,4 nM)- Resulting in enhanced tumor phagocytosis- Toxicology data (male and female monkeys):

no off-target toxicity, especially testis and ovary

Tumor MicroEnvironment

STUDY OBJECTIVE - ENDPOINTS

Primary Objective

Determine GM102 recommended dose(s) for phase 2 (RP2D) from safety, pharmacokinetics, pharmacodynamics and anti-tumor activity

Endpoints

Primary - Determine RP2D (DLT during first 28-day cycle)

Secondary - Safety- Pharmacokinetics (PK)- Antitumor activity (RECIST1.1 and biomarkers)- Immunogenicity

Exploratory - Tumor Growth Rate (TGR) kinetics- Cytokine release in peripheral blood (TNF, IFN, IL6, IL2, IL8 and IL10)- Circulating immune cells changes in peripheral blood- Immunological changes (lymphocytes T, macrophages, NK cells) in the TumorMicroEnvironnment

REFERENCESBakkum-Gamez et al., Gynecological Oncology, 108: 141–148, 2008.Bougherara, H. et al., Oncotarget, 8: 99950-65, 2017.Estupina, P. et al., Oncotarget, 8: 37061-79, 2017.Ferté, C. et al., Clinical Cancer Research, 20: 246-252, 2014.

TREATMENT-EMERGENT ADVERSE EVENTS OVERVIEW (IA)

Cohort 1mg/kg

q2w

Cohort 3mg/kg

q2w

Cohort 7mg/kg

q2w

Cohort 10mg/kg

q2w

Cohort 15mg/kg

q2w

Cohort 20mg/kg

q2w

Cohort 7mg/kg

q1w

Cohort 10mg/kg

q1wALL DOSES

Events

(n = 10 cyclesa)

Patients(n = 3b)

Events

(n = 13 cyclesa)

Patients(n = 3b)

Events

(n = 9 cyclesa)

Patients(n = 4b)

Events

(n = 8 cyclesa)

Patients(n = 3b)

Events

(n = 15 cyclesa)

Patients(n = 4b)

Events

(n = 8 cyclesa)

Patients(n = 3b)

Events

(n = 10 cyclesa)

Patients(n = 3b)

Events

(n = 7 cyclesa)

Patients(n = 4b)

EventsPatients

(n = 27)

Treatment-emergent adverse

events (TEAE) [1]21 3 25 3 33 4 27 3 24 4 23 3 40 3 23 4 216 27

TEAE related to GM102 [1] 8 2 6 2 5 2 4 3 8 3 1 1 6 2 5 3 43 18

TEAE of CTCAE grade ≥ 3

related to GM102 [1]0 0 0 0 0 0 0 0 2 1 0 0 0 0 0 0 2 1

Serious TEAE related to GM102 1 1 0 0 0 0 0 0 2 2 0 0 0 0 0 0 3 3

TEAE leading to permanent

GM102 treatment discontinuation0 0 0 0 1 1 0 0 2 2 1 1 0 0 1 1 5 5

Dose Limiting Toxicity 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

[1] Treatment-emergent adverse events (TEAE) include TEAE and serious TEAE.; Safety population = all patients included in phase I for whom at least one infusion of GM102 has been administered

N = total number of patients included in the safety population ; a Total number of cycles initiated by the patients in the dose level cohort ; b Total number of patients included in the dose level cohort

Patients = total number of patients with at least one adverse event ; Events = total number of adverse events reported in the dose level cohort

Adverse Events related to GM102 treatment- 43 adverse reactions in 18 out of 27 treated patients, including:

- 9 G1-2 fatigue / asthenia- 2 G3: decrease of appetite and weight loss in the same patient- 3 Suspected Unexpected Serious Adverse Reactions (SUSAR): one G1 influenza-like illness, one G2 atrial fibrillationand one G3 decrease appetite

GM102 PK RESULTS (IA)Dosing

FrequencyUnit Dose

(mg/kg)

AUC0-2wk,ss

(h.µg/mL)Cmax,ss

(µg/mL)Cmin,ss

(µg/mL)

q1w7 36691 194 55.5

10 43379 296 104

q2w

10 20694 192 30.9

15 42891 342 53.3

20 32187 337 31.9

In tumor-bearing mice, GM102 efficacy was achieved at 10 mg/kg GM102 q2w, Steady-state exposure was: 2-week AUC = 26,616 μg.h/mL, Ctrough 47.7 μg/mL and Cmax 213.4 μg/mL

- Both q1w and q2w dosing regimens achieved the target efficacy exposures at Steady-State with doses ≥ 7 mg/kg for q1w and ≥ 15 mg/kg for q2w.

- The average half-life estimated for q2w and q1w dosing regimens ranged from 96.6 to 140 h (approx. 4 - 6 days).

ANTI-TUMOR ACTIVITY (IA)

Objective responses (n = 26 evaluable patients)

2 GCT patients achieved partial response with transient inhibin B decrease:- patient 02-01, 7 mg/kg q1w at 2 cycles (confirmed, per investigator)- patient 05-07, 15 mg/kg q2w at 6 cycles (not confirmed, per central review)

Tumor Growth Rate (n = 17 evaluable patients)

TGR decreased under GM102 for 8/17 patients (47%):

- mean pretreatment TGR = 40 % [8 ; 89]

- mean under-GM102 TGR = 13 % [-17 ; 48]

- % of TGR variation ranged from -45% to -169%

CONCLUSIONS

• GM102 was well tolerated at all doses tested

- No Dose Limiting Toxicities for the 27 patients treated with GM102 in 8 successive dose and regimencohorts (1-20 mg/kg every 2 weeks and 7-10 mg/kg once a week),

- The most commonly reported adverse reaction was grade 1-2 fatigue/asthenia,

- 3 Serious Adverse Events possibly related to GM102: one grade 1 influenza-like illness, one grade 2asymptomatic atrial fibrillation and one grade 3 decreased appetite leading to a significant weightloss.

• Partial Responses were observed in 2 patients with Granulosa Cell Tumors.

• Based on the safety profile, the PK data and the first signs of activity, GM102 recommendeddoses for phase 2 are 7 mg/kg every week and 15 mg/kg every 2 weeks.

• Both doses and regimens are being further evaluated in the expansion phase Ib part of theC101 study.

ACKNOWLEDGEMENTS

Tumor MicroEnvironnment (TME) evolution under GM102, paired biopsies, IF (n = 2 evaluable patients)- CD16+ cells are abundantly present in the TME- Under GM102: CD16 expression increase and Granzyme B expression increase in CD16+ cells, reflecting TME cell activation

DOSE ESCALATION MONOTHERAPY STATUS, n = 29 (16-May-2018)

PATIENT BASELINE CHARACTERISTICS (Interim Analysis - IA for RP2D determination, n = 27, 13-Feb-2018)

Percentage of CD16 + stained area evaluated

using the HALO HighPlex Immunofluorescence

module of Indica Labs, at baseline and cycle 2

on tumor biopsies (patients 04-01 and 01-01).

Combination of markers: CD8-CD16-GZB-PanCK

CD16 (pink), CD8 (red) and Granzyme B (blue)expression at baseline and cycle 2 on tumorbiopsies (patients 04-01 and 01-01).Pan-cytokeratin (green) is used as a tumor cellmarker.

PHARMACODYNAMICS (IA)

Cellular based cell count (number/mm2) of

cells expressing Granzyme B and CD16 in

tumor biopsies from patients 04-01 and

01-01 at baseline and cycle 2.

EudraCT: 2015-004252-22NCT02978755

q2w: every two weeks ; q1w: every week

Patient 05-07

Baseline (15-Mar-2017) End Cycle 6 (28-Aug-2017)

Circulating immune cells evolution under GM102, FACS (n = 21 evaluable patients) - High interpatient variability in immune cell numbers at baseline- Minor changes observed under GM102:

• Neutrophil activation (CD64) • T cell activation (ICOS & CD69) • Monocyte activation (CD69 & CD64)• Classical monocyte increase and intermediate monocyte decrease (CD16 decrease)

- Age, median, [range] - years 63 [23 - 79]

- Time since primary diagnosis, 6 [0.9 - 24]median, [range] - years

- Number of previous lines of 5 [2 - 13] chemotherapy, median, [range]

- Time to progression of last 4.2 [0.4 - 47]treatment line, median, [range]- months

- Tumor types and histologies:

17 epithelial ovarian cancers:15 serous, 1 mixed tumor, 1 undifferentiated

5 sex-cord stromal tumors: 4 granulosa cell tumors, 1 Sertoli Leydig

2 cervical cancers:1 squamous, 1 clear cell

2 endometrial cancers: 1 endometrioid, 1 undifferentiated

1 vulva cancer:1 squamous

GM102 EXPOSURE (IA)

- Total number of infusions

- Number of infusions per patient, median, [range]

- Duration of treatment, median, [range] - months

- Number of patients with ≥ 6 cycles of GM102

173

5 [1 - 24]

1.4 [0 - 6]

2 (6 and 7 cycles)

No DLT observed at all doses tested