A first-in-human study of monoclonal antibody GM102 in patients with anti- Mullerian-hormone-receptor II (AMHRII) positive gynecological cancers.

Abstract # 5542_Presented Monday, June 4, 2018

Authors:
Alexandra Leary, Philippe Georges Aftimos, Jean-Pierre Delord, Christophe Le Tourneau, Isabelle Laure Ray-Coquard, Christiane Jungels, Andrea I. Varga, Francesco Ricci, Carlos Alberto Gomez-Roca, Guillaume Bataillon, Nathalie Van Acker, Grégory Noël, Olivier Lantz, Lydie Cassard, Agnès Coste, Bérengère Jean, Isabelle Marie Tabah-Fisch, Anne Vincent- Salomon, Jean-François Prost, Ahmad Awada; Gustave Roussy Cancer Campus, Villejuif, France; Institut Jules Bordet – Université Libre de Bruxelles, Brussels, Belgium; Institut Universitaire du Cancer de Toulouse, Toulouse, France; Institut Curie, Paris, France; GINECO Group and Centre Léon Bérard, Lyon, France; Department of Medical Oncology, Institut Curie, Paris, France; Institut Universitaire du Cancer de Toulouse – Oncopole, Toulouse, France; Laboratory of Immunomonitoring in Oncology, Gustave Roussy, Villejuif, France; UMR152 UPS-IRD, Toulouse, France; GamaMabs Pharma, Toulouse, France

Background:
AMH and its membrane receptor AMHRII induce regression of Müllerian ducts in the male embryo. AMHRII is constitutively expressed in ovarian granulosa tumors (GCT) and re-expressed in ~70% of gynecological tumors. GM102, a low-fucose IgG1 antibody, binds AMHRII and acts through macrophage engagement via CD16 high anity binding, resulting in enhanced tumor phagocytosis.

Methods:
In the completed escalation part, AMHRII-positive ovarian, cervical and endometrial cancer patients (pts), with measurable disease, Performance Status ≤1 and adequate organ function, received GM102 1 to 20mg/kg every 2 weeks (q2w) then 7 and 10mg/kg weekly (qw) in 8 successive cohorts. Expansion phase will include granulosa, epithelial ovarian and cervical cancers. The objective was to determine a recommended dose (RP2D) from safety, pharmacokinetics, pharmacodynamics (PD) and GM102 antitumor activity (RECIST) and change in tumor growth rate (TGR = % change in tumor volume/month pretreatment vs. after 2 cycles). PD included circulating immune cells (CIC) (ICOS, CD14, CD16, CD64, CD69) and in paired biopsies, macrophage (CD68, CD163, CD16) and T cell (CD3, CD4, CD8, FoxP3, Granzyme B) markers.

Results:
27 pts with AMHRII+ gynecological tumors (including 4 GCTs) received 1 to 21 GM102 infusions.
Terminal half-life was 130-200hrs. No dose limiting toxicity was observed. Treatment-emergent toxicities were mostly grade 1-2 (including rash, inuenza-like symptom, 1 pt each). One pt had grade 3 anorexia and weight loss. 8/17 (47%) evaluable pts exhibited a decrease in TGR [45%-169%] under GM102. Among 4 GCT pts, 2 had a partial response and inhibin B decreased in 3. In CIC, T cell, monocyte and neutrophil activation was observed, and circulating CD16+ monocytes decreased suggesting possible recruitment to tumor site. In paired biopsies, CD16 expression increased in macrophages as well as Granzyme B suggesting GM102-induced cellular cytotoxicity.

Conclusions:
GM102 was well tolerated at all doses and schedules. RP2D includes 7mg/kg qw and 15mg/kg q2w. The encouraging PD and anti-tumor activity warrants further development of GM102, especially in the rare subtype of GCT. Clinical trial information: NCT02978755

 

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