First-in-human Dose Escalation and Expansion Study With the SIRPα-directed Monoclonal Antibody BYON4228

Study Overview
=================
Brief Summary
-----------------
This is the first-in-human study with BYON4228, a humanized monoclonal antibody (mAb) directed against SIRPα.

Detailed Description
-----------------
This study includes a dose escalation part (Part 1) in which the MTD and dose regimen for expansion (RDE) will be determined, and an expansion part (Part 2) to evaluate efficacy and safety in specific patient cohorts. BYON4228 is a humanized IgG1 mAb directed against SIRPα. BYON4228 binds SIRPα expressed on innate immune cells, especially monocytes, macrophages and neutrophils. BYON4228 blocks binding of SIRPα to CD47 and inhibits signaling through the CD47-SIRPα axis.

Official Title
-----------------
First-in-human Dose Escalation and Expansion Study With the SIRPα-directed Monoclonal Antibody BYON4228 Alone and in Combination With Rituximab to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy in Patients With Relapsed/Refractory CD20 Positive B-cell Non-Hodgkin's Lymphoma (NHL)

Conditions
-----------------
Lymphoma

Intervention / Treatment
-----------------
* Drug: BYON4228 + Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part 1 (dose escalation): B-cell NHL expressing CD20 by immunohistochemistry (IHC) or flow cytometry, relapsed/refractory (R/R) to at least 2 prior lines of therapy. Part 2 (dose expansion): A. Histologically confirmed diffuse large B-cell lymphoma (DLBCL) or Mantle Cell Lymphoma (MCL) expressing CD20 by IHC or flow cytometry, R/R to frontline therapy. B. Histologically confirmed marginal zone or follicular lymphoma (Grade 1-3a) expressing CD20 by IHC or flow cytometry, R/R to at least 2 prior lines of therapy. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1; Adequate organ function; Laboratory measurements, blood counts (Growth Factor (GF) support and blood transfusions are not allowed within 2 weeks prior to this assessment): Hemoglobin ≥ 8.5 g/dL (> 5.28 mmol/L); Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/mL; Platelet counts ≥ 50 × 10^9/mL; Exclusion Criteria: Having been treated with CD47 or SIRPα targeting agents at any time or other anticancer therapy within 4 weeks or as defined in the protocol; History of hypersensitivity or allergic reaction to any of the excipients of BYON4228 or rituximab which led to permanent discontinuation of the treatment; Burkitt's lymphoma; Red blood cell (RBC) transfusion dependence; Patients with active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD; History of autoimmune hemolytic anemia or autoimmune thrombocytopenia; History of active autoimmune disorders (including but not limited to: Crohn's disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave's disease) or other conditions that compromise or impair the immune system (except for hypogammaglobulinemia); History (within 6 months prior to start IMP) or presence of clinically significant cardiovascular disease such as unstable angina, congestive heart failure, myocardial infarction, uncontrolled hypertension, or cardiac arrhythmia requiring medication; Currently diagnosed or suspected CNS involvement; Severe active infection or other severe uncontrolled systemic disease (e.g. advanced renal disease, pulmonary, uncontrolled diabetes mellitus, severely immunocompromised state, or metabolic disease)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BYON4228 + Rituximab<br>BYON4228 is a humanized monoclonal antibody (mAb) directed against SIRPα. BYON4228 IV infusion every four weeks. Number of cycles: until cancer progression or unacceptable toxicity develops. Different doses. Rituximab IV infusion (375 mg/m2) starts after first BYON4228 cycle. Weekly infusion during the first cycle and every four weeks in subsequent 5 cycles. | Drug: BYON4228 + Rituximab<br>* 20 mg/mL BYON4228 in 8 mL solution for infusion. Rituximab 500 mg concentrate for solution for infusion.<br>* Other names: Truxima;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities | Part 1 | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Part 2 | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
mAB, Monoclonal antibody, Lymphoma, Non-Hodgkin's Lymphoma, SIRPα, NHL, CD20, CD47, SIRP, MCL, FL, MZL, DLBCL