A Study to Assess the Anti-Tumor Activity and Safety of Odronextamab in Patients With B-cell Non-Hodgkin Lymphoma That Have Been Previously Treated

Study Overview
=================
Brief Summary
-----------------
Primary objective is to assess the anti-tumor activity of single agent odronextamab as measured by the objective response rate (ORR) according to the Lugano Classification of response in malignant lymphoma (Cheson, 2014) and as assessed by independent central review in each of the following B-cell non-Hodgkin lymphoma (B-NHL) subgroups: In patients with follicular lymphoma (FL) grade 1-3a *1,2 In patients with diffuse large B-cell lymphoma (DLBCL) *1,2 In patients with mantle cell lymphoma (MCL) that has relapsed after or is refractory to a BTK inhibitor. This cohort will also include patients who have relapsed or have disease refractory to prior systemic therapy, or patients who have demonstrated intolerance to BTK inhibitor therapy, and who have progressed after other systemic therapy. In patients with marginal zone lymphoma (MZL) *1 In patients with other B-NHL subtypes *1 Secondary objectives are: To assess the anti-tumor activity of single agent odronextamab in each of 5 disease-specific cohorts, as measured by: ORR according to the Lugano Classification and as assessed by local investigator evaluation Complete response (CR) rate according to the Lugano Classification and as assessed local by local investigator evaluation and independent central review Progression-free survival (PFS)*3 Overall survival (OS) Duration of response (DOR)*3 Disease control rate (DCR)*3 To evaluate the safety and tolerability of odronextamab To assess the pharmacokinetics (PK) of odronextamab To assess the immunogenicity of odronextamab To assess the effect of odronextamab on patient reported outcomes, including health-related quality of life (HRQL), as measured by the validated instruments European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym), and EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) 1 that has relapsed after or is refractory to at least 2 prior lines of systemic therapy 2 including an anti-CD20 antibody and an alkylating agent 3 according to Lugano Classification and as assessed by independent central review and local investigator evaluation

Official Title
-----------------
An Open-Label Study to Assess the Anti-Tumor Activity and Safety of REGN1979, an Anti CD20 x Anti-CD3 Bispecific Antibody, in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Conditions
-----------------
B-cell Non-Hodgkin Lymphoma (NHL)

Intervention / Treatment
-----------------
* Drug: Odronextamab


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: For the FL grade 1-3a cohort only: Central histopathologic confirmation of the FL Grade 1 to 3a diagnosis must be obtained before study enrollment. Patients with FL grade 3b are ineligible for this cohort but may be included in the other B-NHL cohort. Follicular lymphoma subtyping is based on the World Health Organization (WHO) classification (Swerdlow, 2017). Disease-specific cohorts that has relapsed after or is refractory to at least 2 prior lines of systemic therapy as defined in the protocol DLBCL cohort: Patients with DLBCL that has relapsed after or is refractory to at least 2 prior lines of systemic therapy as defined in the protocol MCL after BTK inhibitor therapy cohort: New enrollment is paused until further notice MZL cohort: Patients with MZL that have relapsed or is refractory to at least 2 prior lines of systemic therapy. Other B-NHL cohort: Patients with B-NHL other than FL grade 1-3a, DLBCL, MCL, or MZL that has relapsed after or is refractory to at least 2 prior lines of systemic therapy as defined in the protocol. New enrollment stopped for patients with Burkitt lymphoma and Burkitt-like lymphoma. Patients should in the judgment of the investigator require systemic therapy for lymphoma at the time of study enrollment Measurable disease on cross sectional imaging as defined in the protocol documented by diagnostic imaging (computed tomography (CT), or magnetic resonance imaging (MRI) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Adequate bone marrow, hepatic, and renal function as defined in the protocol Key Exclusion Criteria: Primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS Non-Hodgkin Lymphoma (NHL) (suspected CNS lymphoma should be evaluated by lumbar puncture, as appropriate, in addition to the mandatory head CT or MRI). Treatment with any systemic anti-lymphoma therapy within 5 half-lives or within 28 days prior to first administration of study drug, whichever is shorter. History of allogeneic stem cell transplantation Prior treatment with any chimeric antigen receptor T-cell (CAR-T) therapy Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours of start of study drug History of neurodegenerative condition or CNS movement disorder. Patients with a history of seizure within 12 months prior to study enrollment are excluded Another malignancy except B-NHL in the past 5 years, with the exception of non-melanoma skin cancer that has undergone potentially curative therapy or in situ cervical carcinoma, or any other tumor that has been deemed to be effectively treated with definitive local control and with curative intent. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection; cytomegalovirus (CMV) infection as noted by detectable levels on a blood polymerase chain reaction (PCR) assay as defined in the protocol or other uncontrolled infections Known hypersensitivity to both allopurinol and rasburicase Prior treatment with an anti-CD20 x anti-CD3 bispecific therapy Note: Other protocol-defined Inclusion/Exclusion criteria apply

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 5 cohorts The first 68 patients in the DLBCL cohort will be randomized; the remaining patients will not be randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FL<br>Follicular lymphoma grade 1-3a cohort | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;|
| Experimental: DLBCL<br>Diffuse large B-cell lymphoma cohort | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;|
| Experimental: MCL<br>Mantle Cell Lymphoma cohort | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;|
| Experimental: MZL<br>Marginal Zone Lymphoma cohort | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;|
| Experimental: Other B-NHL<br>Other B-cell non-Hodgkin lymphoma cohort (excluding FL Grade 1-3a, DLBCL, MCL, MZL, Waldenström macroglobulinemia [WM]); Patients with a current diagnosis of mixed histology of B-NHL with an aggressive component (such as concurrent FL and DLBCL) will be allowed | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR (FL grade 1-3a/MZL) | For each of the 5 disease-specific cohorts according to the Lugano Classification of response in malignant lymphoma (Cheson, 2014) and as assessed by independent central review. | From first patient first dose until all patients have completed 52 weeks of study treatment or have withdrawn from the study | 
| ORR (DLBCL/MCL/Other B-NHL) | For each of the 5 disease-specific cohorts according to the Lugano Classification of response in malignant lymphoma (Cheson, 2014) and as assessed by independent central review. | From first patient first dose until all patients have completed 36 weeks of study treatment or have withdrawn from the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR (FL/MZL) | According to the Lugano Classification, as assessed by local investigator evaluation | First patient first dose until all patients have completed 52 weeks of study treatment or have withdrawn from the study. | 
| ORR (DLBCL/MCL/Other B-NHL) | According to the Lugano Classification, as assessed by local investigator evaluation | First patient first dose until all patients have completed 36 weeks of study treatment or have withdrawn from the study. | 
| CR rate (FL grade 1-3a/MZL) | According to the Lugano Classification and as assessed by local investigator evaluation and independent central review | First patient first dose until all patients have completed 52 weeks of study treatment or have withdrawn from the study. | 
| CR rate (DLBCL/MCL/Other B-NHL) | According to the Lugano Classification and as assessed by local investigator evaluation and independent central review | First patient first dose until all patients have completed 36 weeks of study treatment or have withdrawn from the study. | 
| PFS | According to the Lugano Classification and as assessed by independent central review and local investigator evaluation | First patient first dose to disease progression or death due to any cause, whichever comes first, approximately 194 weeks following the first dose | 
| OS |  | First patient first dose to disease progression or death due to any cause, whichever comes first, approximately 194 weeks following the first dose | 
| DOR | According to the Lugano Classification and as assessed by independent central review and local investigator evaluation | First patient first dose to disease progression or death due to any cause, whichever comes first, approximately 194 weeks following the first dose | 
| DCR (FL grade 1-3a/MZL) | According to the Lugano Classification and as assessed by independent central review and local investigator evaluation | First patient first dose until all patients have completed 52 weeks of study treatment or have withdrawn from the study. | 
| DCR (DLBCL/MCL/Other B-NHL) | According to the Lugano Classification and as assessed by independent central review and local investigator evaluation | First patient first dose until all patients have completed 36 weeks of study treatment or have withdrawn from the study. | 
| Incidence and severity of treatment emergent adverse events (TEAEs) |  | First patient first dose to disease progression or death due to any cause, whichever comes first, approximately 194 weeks following the first dose | 
| Pharmacokinetics: Concentration of odronextamab | End of infusion [EOI]; Concentration at a specified time t [Ct]) | 12 weeks following end of treatment | 
| Incidence of anti-drug antibodies (ADA) to odronextamab over time |  | 12 weeks following end of treatment | 
| Titer of anti-drug antibodies to odronextamab over time |  | 12 weeks following end of treatment | 
| Incidence of neutralizing antibodies (Nab) to odronextamab over time |  | 12 weeks following end of treatment | 
| Changes in scores of patient-reported outcomes as measured by EORTC QLQ-C30 | EORTC QLQ-C30 is a self-reported, 30-item generic questionnaire developed to assess 15 domains: global health status scale, five functional scales (physical, role, emotional, cognitive, and social functioning) and nine symptom scales (fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). | First patient first dose to disease progression or death due to any cause, whichever comes first, approximately 194 weeks following the first dose | 
| Changes in scores of patient-reported outcomes as measured by FACT-Lym | Composed of the FACT-G plus the 15-item Lymphoma Subscale (LymS). | First patient first dose to disease progression or death due to any cause, whichever comes first, approximately 194 weeks following the first dose | 
| Changes in scores of patient-reported outcomes as measured by EQ-5D-3L | The EQ-5D-3L is a standardized instrument for use as a measure of health outcome. It is a health questionnaire that consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. | First patient first dose to disease progression or death due to any cause, whichever comes first, approximately 194 weeks following the first dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Relapsed B-NHL, Refractory B-NHL, NHL, FL, DLBCL, MZL, MCL, bispecific antibody, CD20