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3269 Phase 1 Study of CD19 Targeted 4-1BBL Costimulatory Agonist to Enhance T Cell (Glofitamab Combination) or NK Cell Effector Function (Obinutuzumab Combination) in Relapsed/Refractory B Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 704. Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
Biological, antibodies, Diseases, Therapies, Combinations, B-Cell Lymphoma, immunotherapy, Lymphoid Malignancies
Monday, December 7, 2020, 7:00 AM-3:30 PM

Martin Hutchings, MD, PhD1*, Fritz Offner, MD, PhD2, Francesc Bosch, MD, PhD3, Giuseppe Gritti, MD, PhD4*, Carmelo Carlo-Stella, MD5, Harriet Walter6*, William Townsend, MRCP, MD, FRCPath7*, Franck Morschhauser, MD, PhD8*, Guillaume Cartron, MD, PhD9*, Hervé Ghesquieres, MD, PhD10*, Sophie de Guibert, MD11*, Sylvia Herter, PhD12*, Koorosh Korfi, PhD13*, Veronica Craine14*, Sarah Louise Mycroft15*, Matt Whayman15*, Claudia Mueller16*, Natalie Dimier, PhD15*, Tom Moore, MBChB17*, Sara Belli18*, Martin Kornacker, MD18, Katharina Lechner16* and Michael Dickinson, MBBS, FRACP, FRCPA19

1Department of Hematology; Finsen Centre, National Hospital, Copenhagen University Hospital, Copenhagen, Denmark
2University Hospital Ghent, Gent, Belgium
3Department of Hematology, University Hospital Vall d’Hebron, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
4ASST Papa Giovanni XXIII, Bergamo, Italy
5Humanitas Clinical and Research Center, and Humanitas University, Milan, Italy
66The HOPE Clinical Trials Unit, Leicester, United Kingdom
7King's College, London - Rayne Institute, London, United Kingdom
8Department of Hematology, Centre Hospitalier Régional Universitaire De Lille, Lille, France
9Centre Hospitalier Universitaire de Montpellier, Montpellier, France
10Department of Hematology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre Benite, France
11Centre Hospitalier Universitaire, Rennes, France
12Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland
13A4P Consulting Ltd, Sandwich, United Kingdom
14Hoffmann-La Roche Limited, Mississauga, Canada
15Roche Innovation Center Welwyn, Roche Ltd, Welwyn, United Kingdom
16Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany
17Roche Innovation Center Munich, Roche Pharma Research and Early Development, Munich, Germany
18Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland
19Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Background: Up to 50% of patients suffering from Non-Hodgkin`s lymphoma (NHL) become refractory to or relapse after treatment (M. Crump, Blood 2017). With this, the lack of curative outcomes for patients with both indolent and aggressive NHL subtypes remains an unmet medical need. The CD20 CD3 T cell bispecific antibody glofitamab induces specific T-cell activation and has demonstrated significant single agent activity in r/r NHL patients (NP30179 study, M. Dickinson, EHA 2020, Abstract S241).

RO7227166, a CD19 targeted 4-1BBL (CD137) costimulatory agonist has shown synergistic anti‑tumor activity when combined with glofitamab in preclinical models (fig 1). RO7227166 is a bispecific antibody-like fusion protein composed of a split trimeric 4‑1BB ligand, a tumor antigen-targeting moiety recognizing CD19, and a silent Fc part preventing Fc-mediated toxicity. 4-1BB is an inducible co-stimulatory molecule expressed by activated T-cells or NK cells. Through CD19-binding, the 4-1BB ligand moiety can deliver co-stimulatory signals to activated T- and NK-cell subsets in the tumor.

The expected mode of action (MoA) for this molecule is to deliver a costimulatory signal 2 to enhance the effector function of tumor-infiltrating T cells or NK cells upon their activation (signal 1) by a T-cell bispecific antibody (e.g. glofitamab, RO7082859) or a tumor-targeted ADCC antibody (e.g. obinutuzumab). By delivering direct T-cell-target cell engagement followed by costimulatory activation the aim is to offer a highly active off-the-shelf immunotherapy combination.

Methods: RO7227166 is being developed in combination with glofitamab and obinutuzumab in a phase I, open-label, dose-escalation study BP41072 (NCT04077723). The study is designed to evaluate the combination maximum tolerated dose (MTD), safety, tolerability, pharmacokinetic (PK), and/or pharmacodynamic (PD) profile of escalating doses of RO7227166, and to evaluate preliminary anti-tumor activity in participants with r/r NHL. The dose escalation stage is divided into Part I (combination with obinutuzumab) and Part II (combination with glofitamab) followed by an expansion stage (Part III). During Part I patients receive 1000mg obinutuzumab intravenously (IV) at a q3w schedule in combination with CD19 4-1BBL IV. During part II glofitamab is given in a q3w schedule with RO7227166 introduced at C2D8 and administered concomitantly from C3D1 onwards. A fixed dose of obinutuzumab (Gpt; pre-treatment) is administered seven days prior to the first administration of RO7227166 and seven days prior to the first administration of glofitamab (M. Bacac, Clin Cancer Res 2018; M. Dickinson, EHA 2020, Abstract S241).

Patients will initially be recruited into part I of the study only using single-participant cohorts, where a rule-based dose-escalation is implemented, with dosing initiated at 5 μg (flat dose). As doses of RO7227166 increase, multiple participant cohorts will be recruited and dose-escalation will be guided by the mCRM-EWOC design for overdose control. Commencement of Part II including decision on the RO7227166 starting dose will be guided by safety and PK data from Part I.

Patients with r/r NHL meeting standard organ function criteria and with adequate blood counts will be eligible. The maximum duration of the study for each participant will be up to 24 months in Part I (excluding survival follow-up) and up to 18 months in Part II and Part III. Tumor biopsies and peripheral blood biomarker analyses will be used to demonstrate MoA and proof of concept of an off the shelf flexible combination option providing signals 1 and 2.

Disclosures: Hutchings: Takeda: Honoraria; Takeda: Research Funding; Genmab: Honoraria; Roche: Honoraria; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sankyo: Research Funding; Roche: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sanofi: Research Funding. Bosch: Hoffmann-La Roche: Research Funding. Gritti: Italfarmaco: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria; Jannsen: Other: Travel Support; Autolus: Consultancy; IQVIA: Consultancy; Kite: Consultancy; Takeda: Honoraria; Amgen: Honoraria. Carlo-Stella: Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy. Townsend: Roche, Gilead: Consultancy, Honoraria. Morschhauser: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy; Janssen: Honoraria; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy. Cartron: Celgene: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Gilead: Honoraria. Ghesquieres: CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. de Guibert: Gilead Sciences: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Herter: Roche Glycart AG: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Korfi: Roche Diagnostics GmbH: Consultancy. Craine: Roche: Current Employment. Mycroft: Roche: Current Employment. Whayman: Roche: Current Employment. Mueller: Roche: Current Employment. Dimier: Roche: Current Employment. Moore: Roche: Current Employment. Belli: Roche Pharma: Current Employment. Kornacker: Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Lechner: Roche Diagnostics GmbH: Current Employment, Current equity holder in publicly-traded company. Dickinson: Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

*signifies non-member of ASH