A Study to Compare How Well Odronextamab Combined With Chemotherapy Works and How Safe it is Against Rituximab Combined With Chemotherapy, in Patients With Previously Untreated Diffuse Large B-cell Lymphoma

Study Overview
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Brief Summary
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This study is researching an experimental drug called odronextamab, referred to as study drug, when used in combination with chemotherapy. The study is focused on patients with diffuse large B-cell lymphoma (DLBCL) that have not been treated before (called previously untreated), have come back after treatment (called relapsed), or have not responded to treatment (called refractory). This study will be made up of Part 1a, Part 1b, and Part 2.The aim of Part 1a and Part 1b of the study is to see how safe and tolerable the study drug in combination with chemotherapy is and to determine the dose and schedule of the study drug to be combined with chemotherapy in Part 2 of the study. The aim of Part 2 of the study is to see how effective the combination of the study drug with chemotherapy is in comparison with the combination of rituximab and chemotherapy, the current standard of care treatment approved for Non-Hodgkin's lymphoma (NHL). Standard of care means the usual medication expected and used when receiving treatment for a condition. The study is looking at several other research questions, including: What side effects may happen from taking the study drug when combined with chemotherapy How much study drug is in your blood at different times Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects) The impact from the study drug on your quality of life and ability to complete routine daily activities

Official Title
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A Phase 3, Open Label, Randomized Study Comparing the Efficacy and Safety of Odronextamab (REGN1979), an Anti-CD20 × Anti-CD3 Bispecific Antibody, in Combination With CHOP (O-CHOP) Versus Rituximab in Combination With CHOP (R-CHOP) in Previously Untreated Participants With Diffuse Large B-cell Lymphoma (DLBCL) (OLYMPIA-3)

Conditions
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Diffuse Large B-cell Lymphoma (DLBCL)

Intervention / Treatment
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* Drug: Odronextamab
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone/Prednisolone


Participation Criteria
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Eligibility Criteria
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KEY Inclusion Criteria: Previously untreated participants for lymphoma with documented cluster of differentiation 20+ (CD20+) DLBCL, as described in the protocol OR relapsed or refractory DLBCL (Part 1A only) Measurable disease with at least one nodal lesion or at least one extranodal lesion, as described in the protocol Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Life expectancy ≥ 12 months International Prognostic Index (IPI) of 3 to 5 (part 1 only) and ≥2 (part 2) for untreated DLBCL only; Adequate hematologic and organ function, as defined in the protocol. KEY Exclusion Criteria: Primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS NHL and history or current relevant CNS pathology Another active malignancy, significant active disease or medical condition, as described in the protocol Peripheral neuropathy Grade ≥3 Treatment with any systemic anti-lymphoma therapy Any investigational therapy within 28 days or 5 half-lives of the drug, whichever is shorter, prior to the start of study treatment Recent major surgery, prior organ transplantation, or standard radiotherapy, as described in the protocol Allergy/hypersensitivity to study drugs, as described in the protocol Infections such as any active infection (bacterial, viral, fungal, mycobacterial, parasitic or other), active Coronavirus disease (COVID-19) infection, uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV), Cytomegalovirus (CMV) infection, as described in the protocol. Note: Other protocol-defined Inclusion/ Exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Odronextamab + CHOP<br>Part 1, includes dose escalation (Part 1A), and randomized exploration of 2 regimens of odronextamab -cyclophosphamide, doxorubicin, vincristine, prednisone (O-CHOP) dose optimization, (Part 1B). | Drug: Odronextamab<br>* Odronextamab will be administered by intravenous (IV) infusion<br>* Other names: REGN1979;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered IV as part of chemotherapy<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Doxorubicin will be administered IV as part of chemotherapy<br>* Other names: Adriamycin;Drug: Vincristine<br>* Vincristine will be administered IV as part of chemotherapy<br>* Other names: Oncovin;Drug: Prednisone/Prednisolone<br>* Prednisone or prednisolone will be administered orally (PO) as part of chemotherapy<br>* Other names: Deltasone/Omnipred;|
| Active Comparator: Rituximab + CHOP<br>Part 2 is the randomized controlled portion, participants will receive either O-CHOP or R-CHOP. | Drug: Rituximab<br>* Rituximab will be administered IV, or subcutaneously (SC)<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered IV as part of chemotherapy<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Doxorubicin will be administered IV as part of chemotherapy<br>* Other names: Adriamycin;Drug: Vincristine<br>* Vincristine will be administered IV as part of chemotherapy<br>* Other names: Oncovin;Drug: Prednisone/Prednisolone<br>* Prednisone or prednisolone will be administered orally (PO) as part of chemotherapy<br>* Other names: Deltasone/Omnipred;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) | Part 1 | Up to 35 days | 
| Incidence of treatment emergent adverse events (TEAEs) | Part 1 | Up to 2 years | 
| Severity of TEAEs | Part 1 | Up to 2 years | 
| Progression free survival (PFS), assessed by independent central review (ICR) | Part 2 | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) assessed by ICR | Part 2 | Up to 5 years | 
| Complete response (CR) assessed by ICR | Part 2 | Up to 22 weeks | 
| Overall survival (OS) | Part 2 | Up to 5 years | 
| Best Overall response (BOR) as assessed by local investigators | Part 1 and Part 2 | Up to 22 weeks | 
| CR as assessed by local investigators | Part 1 and Part 2 | Up to 22 weeks | 
| Duration of response (DOR) as assessed by local investigators | Part 1 and Part 2 | Up to 5 years | 
| Odronextamab concentrations in serum when administered with CHOP | Part 1 and Part 2 | Up to 22 weeks | 
| Incidence of anti-drug antibodies (ADA) to odronextamab when administered with CHOP | Part 1 and Part 2 | Up to 22 weeks | 
| Titer of ADA to odronextamab when administered with CHOP | Part 1 and Part 2 | Up to 22 weeks | 
| Incidence of neutralizing antibodies (NAb) to odronextamab when administered with CHOP | Part 1 and Part 2 | Up to 22 weeks | 
| PFS assessed by local investigator review | Part 2 | Up to 5 years | 
| EFS assessed by local investigator review | Part 2 | Up to 5 years | 
| BOR assessed by ICR | Part 2 | Up to 22 weeks | 
| DOR assessed by ICR | Part 2 | Up to 5 years | 
| Incidence of TEAEs | Part 2 | Up to 2 years | 
| Severity of TEAEs | Part 2 | Up to 2 years | 
| Measurable Residual Disease (MRD) status | Part 2 | Up to 22 weeks | 
| Duration of MRD-negativity | Part 2 | Up to 5 years | 
| Change in physical functioning as measured by EORTC QLQ C30 | Part 2 The EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/QoL scale, and six single items (constipation, diarrhea, insomnia, shortness of breath, appetite loss and financial difficulties). For the functioning scales and global health status / QoL, scores range from 1 = very poor to 7 = excellent with higher scores indicate better functioning; for the symptom scales, scores range from 1 = not at all to 4 = very much higher scores indicate higher symptom burden. | Up to 5 years | 
| Change from baseline of patient reported outcomes, as measured by European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C) 30 | Part 2 The EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/QoL scale, and six single items (constipation, diarrhea, insomnia, shortness of breath, appetite loss and financial difficulties). For the functioning scales and global health status / QoL, scores range from 1 = very poor to 7 = excellent with higher scores indicate better functioning; for the symptom scales, scores range from 1 = not at all to 4 = very much higher scores indicate higher symptom burden. | Up to 5 years | 
| Change from baseline of patient reported outcomes, as measured by Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) | Part 2 The FACT-Lym lymphoma subscale (LymS) includes 15 items to assess NHL-related symptoms and concerns. All questions are answered on a 5-point scale ranging from not at all (0) to very much (4). Higher scores are associated with a worse quality of life. | Up to 5 years | 
| Change from baseline of patient reported outcomes, as measured by Patient Global Impression of Severity (PGIS) | Part 2 The PGIS includes a single-item to assess how a patient perceives the overall severity of cancer symptoms over the past 7 days. Patients will choose the response that best describes the severity of their overall cancer symptoms with options on a 5-point scale ranging from 1 (No symptoms) to 4 (Very Severe). | Up to 5 years | 
| Change from baseline of patient reported outcomes, as measured by Patient Global Impression of Change (PGIC) | Part 2 The PGIC item includes a single-item to assess how a patient perceives their overall change in health status since the start of study treatment. Patients will choose from response options on a 7-point scale ranging from 1 (Much Better) to 7 (Much worse); 1- Much Better, 2-Moderately Better, 3-A Little Better, 4-About the Same, 5-A Little Worse, 6-Moderately Worse, 7-Much Worse. | Up to 5 years | 
| Change from baseline of patient reported outcomes, as measured by EuroQol-5 Dimension-5 Level Scale (EQ-5D-5L) | Part 2 The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ VAS records the participant's self-rated health on a vertical visual analogue scale where the endpoints are labeled Best imaginable health state and Worst imaginable health state. | Up to 5 years | 
| Change in score of the Functional Assessment of Cancer Therapy-General (FACT-G ) GP5 item | Part 2 A single item (GP5) of the validated FACT-G questionnaire will be used to assess from the participant perspective the overall impact of treatment side-effect. The question item is on a 5-point scale ranging from not at all (0) to very much (4). | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkin lymphomas (NHL), B-cell non-Hodgkin lymphomas (B-NHL), Diffuse Large B-cell Lymphoma, Odronextamab, Anti-CD20 × anti-CD3 bispecific antibody