Trial in Progress: First Report of the Phase 1/2 Study of the Safety and Efficacy of CPO107, a Bispecific Agent Targeting CD20/CD47 in CD20 Expressing Non-Hodgkin Lymphoma (NHL)

Background: CD47 is a myeloid checkpoint that is overexpressed by cancer cells to evade the host's immune response [Jaiswal et al. 2009]. It is a cell surface protein of the immunoglobulin superfamily, and expressed by virtually all cells [Oldenborg et al. 2013]. CD47 binds thrombospondin-1 and signal-regulatory protein alpha. Blocking CD47/SIRPα interaction may be useful to treat cancers without inducing clearance of host cells [Eladl et al. 2020]. CD47 is variably expressed in many subsets of B-cell NHL including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukaemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) [Zhang et al. 2018; Yang et al. 2019]. CD47 expression is an independent predictor of disease progression in multivariate analysis with the international prognostic index for DLBCL. [Chao et al. 2010]

CPO107 is a bispecific fusion protein based off the anti-CD20 ofatumumab antibody with one Fab fragment being replaced with a SIRPα domain, which natively binds CD47. The CD20/CD47 dual targets is a single bispecific antibody and its "Left-Right asymmetrical" structure makes the CD47-binding capacity being CD20-binding dependent. CPO107 has no binding capacity with human and monkey platelets or red blood cells in vitro. The product's specific target binding to CD20+ cancer cells with low possibility of CD47 binding to non-CD20 expressing cells can result in promising efficacy with potentially no concern for off-target risks such as hematologic toxicities that are typical of non-tumor specific CD47-targeting agents. When administered in vivo, CPO107 demonstrated potent anti-tumor activities in various lymphoma tumor models, both as a single agent and in combination with other agents. In addition, CPO107 at 3.3 mg/kg had comparable activities as rituximab at 30 mg/kg and CPO107 was active in a rituximab-resistant DLBCL model [CSPC, internal data].

The combination of CD20 and CD47 targeted therapy provides a novel approach to the treatment of CD20+ malignancies. In theory, the efficacy seen from the effective inhibition of the CD20 target may be enhanced by abrogating the "don't eat me" signal associated with over expression of CD47 at a cellular level. The monoclonal antibody Magrolimab (Hu5F9-G4) in combination with rituximab induced a high rate of tolerable and durable complete responses in heavily pretreated patients (pts) with rituximab-refractory DLBCL and FL [Chao et al. 2010]. However, it is expected that in contrast to Magroimab and other CD47 directed agents, CPO107 is expected to have a reduction in off target toxicity. In addition, due to its CD20 targeting, CPO107 has the potential for bridging therapy of CD19 driven CAR-T therapy, or to offer a potential regimen for the relapsed/refractory CD20+ disease after CAR-T therapy, a current unmet medical need. There is also potential for it to be added in combination with other agents.

Study Design and Methods:

This is a multicenter, open-label, dose-escalation/dose-expansion study in patients with relapsed or refractory CD20+ NHL. The primary objective is to determine the MTD and RP2D of CPO107. The secondary objective is to evaluate safety, tolerability, PK, and early efficacy as assessed by the Lugano criteria. All CD20+ B cell NHL histologies with disease progression or relapse after at least two prior lines of conventional chemoimmunotherapy with a CD20 therapy are eligible.

Patients with CLL/SLL must have received, or not be eligible for, BTK and BCL-2 inhibitor therapy.

In Study Part A (dose escalation), two dosing schedules (once a week and once every 3 weeks; in a 21-day cycle) will be explored to determine optimal dosing to explored in Study Part B (dose expansion). Between 1 and 6 patients will be enrolled in each dose escalation step which will proceed according to a modified 3 + 3 dose-escalation design. The number of pts in Part A of the study could potentially range from as few as 4 patients (assuming unacceptable toxicity at the first dose level) to up to 60 patients (assuming a total of 5 dose levels with 6 pts per group on both schedules).

At the end of dose escalation, one of the schedules will be further explored in 6 pts to collect further PK and safety data. Upon reaching the MTD or RP2D, Part B of the study will enroll approximately 15 pts with CD20+ NHL to explore preliminary efficacy. The study has been registered on ClinicalTrials.gov (NCT04853329).

Skarbnik:Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Lilly: Consultancy, Honoraria. Chen:Abbvie: Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Speakers Bureau. Novick:Conjupro: Current Employment. Su:Conjupro Biotherapeutics: Current Employment. Advani:ADC Therapeutics, Cyteir, Daiichi Sankyo, Gilead, Merck, Regeneron, Roche, Seattle Genetics: Research Funding; ADC Therapeutics, BMS, Daiichi Sankyo, Epizyme, Gilead, Incyte, Merck, Roche, Sanofi: Consultancy.