A Phase 1 Study Evaluating BI 765063, a First in Class Selective Myeloid Sirpa Inhibitor, As Stand-Alone and in Combination with BI 754091, a Programmed Death-1 (PD-1) Inhibitor, in Patients with Advanced Solid Tumours
Authors: Delord Jean-Pierre , Kotecki Nuria , Marabelle Aurelien , Vinceneux Armelle , Korakis Iphigenie , Jungels Christiane , Champiat Stéphane , Huhn Richard D. , Poirier Nicolas , Costantini Dominique , Vasseur Bérangère , Cassier Philippe A. 
Published: November 2019

Introduction: Signal Regulatory Protein α [SIRPα] is a polymorphic protein, strongly expressed on myeloid suppressive cells. BI 765063 (OSE172), a humanized IgG4 monoclonal antibody (mAb), is a selective antagonist of SIRPα/CD47 interaction, it does not bind to SIRP ɣ, known to assist T cell co-stimulation and migration. BI 765063 strongly binds V1 allele, one of the 2 major functional allele of SIRPα expressed in more than 80% of general population and Asian (in 60%).
Anti-tumor effect was shown in various in vivo cancer models using the validated anti-mouse SIRPα mAbs surrogate, as single agent. The effect was more pronounced in combination with T checkpoint inhibitors (Gauttier V et al, 2018). BI 765063 mechanism of action includes promotion of tumor-antigen-presentation while preserving T-cell activation and increase tumor phagocytosis.
This first in human (FIH) study is aiming at evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BI 765063 as monotherapy and in combination a mAb antagonist to PD-1 receptor (with BI 754091), in patients with advanced solid tumours.
Methods: This study comprises a dose escalation (step 1) to determine the Dose-Limiting Toxicities, Maximum Tolerated Dose (MTD), and Recommended Phase 2 Dose (RP2Ds) of BI 765063 monotherapy and with BI 754091, and dose-confirmation expansion cohorts (step 2).
In Step 1, ascending dose of BI 763063 once every 3 weeks intravenously (iv) using a Bayesian approach with overdose control are tested. When MTD determined, BI 763063 will be tested with BI 754091, a PD1 mAb inhibitor. In step 2, 2 parallel randomized, non-comparative mono and combination cohorts will further confirm the RP2Ds and assess the safety and preliminary efficacy (RECIST 1.1 and iRECIST).
Patients ≥ 18 years, PS:0-1, with advanced solid tumor who failed or are not eligible to standard therapy will be included. V1/V1 and V1/V2 patients (central testing) are evaluated in separate cohorts in step 1. In step 2 selected population of V1/V1 patients with advanced-stage cancers (e.g. non-small cell lung cancer, triple negative breast cancer, or gastro-intestinal cancers) will be included.
Pharmacokinetics (PK), SIRPα receptor occupancy (RO) and a comprehensive translational program (in blood and tumour) will assess PK/PD profile and biomarkers of activity.
A total of 116 (56 in step 1 and 60 in step 2) patients will be enrolled.
Results: This trial is currently in progress.
Conclusions: The trial is currently active and plans to assess the safety profile and preliminary efficacy of BI 765063, a first in class myeloid check point inhibitor antagonist of SIRPα on myeloid cells.

Disclosures
Marabelle: Merck Serono: Honoraria, Speakers Bureau; Merus: Research Funding; Sotio: Honoraria; Imcheck: Honoraria; Bayer: Honoraria; GSK: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding; Deerfield: Honoraria; Amgen: Honoraria, Speakers Bureau; Astra Zeneca/Medimmune: Honoraria, Other: Travel expenses, Speakers Bureau; Transgene: Honoraria, Research Funding; Corus: Honoraria; Imaxio: Honoraria; Bioncotech: Honoraria; Roche/Genentech: Honoraria, Other, Speakers Bureau; Servier: Honoraria; Daichii: Honoraria; BMS: Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; T3 Pharma: Honoraria; OSE Immunotherapeutics: Honoraria; MSD: Honoraria, Other, Research Funding, Speakers Bureau; Oncovir: Honoraria; Molecular Partners: Honoraria; Novartis: Honoraria; Genticel: Honoraria; System Analytics: Honoraria; Eisei: Honoraria; GLG: Honoraria; Pillar Partners: Honoraria; Sanofi: Honoraria, Speakers Bureau; Rigontel: Honoraria; BioNtech: Honoraria; Pierre Fabre: Honoraria; Innate Pharma: Honoraria; Edimark: Honoraria; Onxeo: Honoraria; Guide Point Global: Honoraria. Vinceneux:UBS: Consultancy. Champiat:Astra Zeneca: Honoraria, Research Funding; BMS: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Sanofi: Research Funding; Boehringer Ingelheim: Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Research Funding. Huhn:Boehringer Ingelheim Pharmaceuticals: Employment. Poirier:OSE Immunotherapeutics: Employment. Costantini:OSE Immunotherapeutics: Employment, Membership on an entity's Board of Directors or advisory committees. Vasseur:OSE Immunotherapeutics: Employment. Cassier:Blueprint Medecine: Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Roche/Genentech: Honoraria, Other, Research Funding; Astra Zeneca: Research Funding; BMS: Other: Travel expenses, Research Funding; Innate Pharma: Research Funding; Plexxikon: Research Funding; Merck Sereno: Research Funding; Taiho Pharmaceuticals: Research Funding; Transgene: Research Funding; Toray industries: Honoraria; Janssen: Research Funding; MSD: Other: Travel expenses, Research Funding; Novartis: Honoraria, Other: travel expenses, Research Funding; Amgen: Honoraria, Other: travel expenses; Lilly: Research Funding; Bayer: Research Funding; Loxo: Research Funding; GSK: Research Funding.