A Study to Learn How Well Odronextamab Combined With Chemotherapy Works and How Safe it is Compared to Rituximab and Chemotherapy in Adult Participants With Previously Untreated Follicular 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. The study is focused on participants with previously untreated follicular lymphoma in Part 2, as well as participants with lymphoma that has come back after treatment (called relapsed) or did not respond to treatment (called refractory), in Part 1. Follicular lymphoma is a type of non-Hodgkin lymphoma or NHL. This study is made up of 3 parts: Part 1A (non-randomized), Part 1B and Part 2 (randomized - controlled). 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 to be used in Part 2 of the study. The aim of Part 2 of the study is to assess 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 for 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 How much study drug is in your blood at different times Whether the body makes antibodies against the study drug (which could make the study 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 to Compare the Efficacy and Safety of Odronextamab (REGN1979), an Anti-CD20x Anti-CD3 Bispecific Antibody, Combined With Chemotherapy Versus Rituximab Combined With Chemotherapy in Previously Untreated Participants With Follicular Lymphoma (OLYMPIA-2)

Conditions
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Follicular Lymphoma (FL)

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


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Have diagnosis of cluster of differentiation 20 positive (CD20+) FL grade 1-3a, stage II bulky or stage III / IV For Part 1A: previously untreated participants who have Follicular Lymphoma International Prognostic Index (FLIPI)-1 score of 3 to 5, or R/R FL who have not received R-CHOP or R-CVP. For Part 1B: previously untreated participants who have FLIPI-1 score of 3 to 5 For Part 2: previously untreated participants who have FLIPI-1 score of 0 to 5 Have measurable disease on cross sectional imaging documented by diagnostic computed tomography [CT], or magnetic resonance imaging [MRI] imaging, as described in the protocol Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Adequate bone marrow and hepatic function. Key Exclusion Criteria: Participants with central nervous system lymphoma or leptomeningeal lymphoma Participants with histological evidence of transformation to a high-grade or diffuse large B-cell lymphoma Participants with Waldenström macroglobulinemia (WM, lymphoplasmacytic lymphoma), grade 3b follicular lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma Recent major surgery and history or organ transplantation A malignancy other than NHL unless the participant is adequately and definitively treated and any other significant active disease or medical condition that could interfere with the conduct of the study or put the participant at significant risk, 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 + Chemotherapy<br>Part 1 of the study includes ordonextamab dose escalation for participants with previously untreated FL and relapsed/refractory FL (Part 1A only) followed by a randomized exploration of 2 regimens of odronextamab (O) and cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) with the objective of dose optimization (Part 1B) in previously untreated patients with FL. | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;Drug: Cyclophosphamide<br>* Administered by IV infusion<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Administered by IV infusion<br>* Other names: Adriamycin;Drug: Prednisone/Prenisolone<br>* Administered orally (PO)<br>* Other names: Deltasone/Omnipred;|
| Active Comparator: Rituximab + Chemotherapy<br>In Part 2 only, participants will be randomized 1:1:1 to receive rituximab (R) with chemotherapy (CHOP), followed by rituximab monotherapy maintenance. | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;Drug: Rituximab<br>* Administered by IV infusion, or subcutaneous (SC)<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Administered by IV infusion<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Administered by IV infusion<br>* Other names: Adriamycin;Drug: Vincristine<br>* Administered by IV infusion<br>* Other names: Oncovin;Drug: Prednisone/Prenisolone<br>* Administered orally (PO)<br>* Other names: Deltasone/Omnipred;|
| Experimental: Odronextamab + Chemotherapy + Maintenance<br>In Part 2, participants will be randomized 1:1:1 to receive odronextamab with chemotherapy [CHOP, or cyclophosphamide, vincristine, and prednisone (CVP)], followed by odronextamab monotherapy maintenance. | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;Drug: Vincristine<br>* Administered by IV infusion<br>* Other names: Oncovin;|
| Experimental: Odronextamab + Chemotherapy + No maintenance<br>In Part 2, participants will be randomized 1:1:1 to receive odronextamab with chemotherapy (CHOP, or CVP) without maintenance. | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;Drug: Vincristine<br>* Administered by IV infusion<br>* Other names: Oncovin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) for odronextamab in combination with chemotherapy | Part 1, DLT period | Up to 35 days | 
| Incidence of treatment-emergent adverse events (TEAEs) of odronextamab in combination with chemotherapy | Part 1, Treatment period | Up to 2 years | 
| Severity of TEAEs of odronextamab in combination with chemotherapy | Part 1, Treatment period | Up to 2 years | 
| Complete Response rate at 30 months (CR30) assessed by independent central review (ICR) | Part 2 | Up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Odronextamab concentrations in serum when administered with chemotherapy | Part 1, Maintenance period and Part 2, Induction period | Up to 30 months | 
| Odronextamab concentrations in serum when administered as monotherapy | Part 1 and Part 2, Maintenance period | Up to 30 months | 
| Incidence of anti-odronextamab antibodies (ADAs) | Part 1 and Part 2 | Up to 30 months | 
| Titers of ADAs to odronextamab | Part 1 and Part 2 | Up to 30 months | 
| Incidence of neutralizing antibodies (NAb) to odronextamab | Part 1 and Part 2 | Up to 30 months | 
| Best overall response (BOR) as assessed by the investigator | Part 1, end of Induction period and end of Maintenance period | Up to 30 months | 
| Progression free survival (PFS) as assessed by ICR | Part 2 | Up to 5 years | 
| CR30 as assessed by local investigator | Part 2 | Up to 30 months | 
| Change from baseline in patient reported physical functioning scale scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Cancer-30 (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 global health status (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 | 
| PFS as assessed by local investigator | Part 2 | Up to 5 years | 
| Event-free survival (EFS) as assessed by ICR | Part 2 | Up to 5 years | 
| EFS as assessed by local investigator | Part 2 | Up to 5 years | 
| Overall Survival (OS) | Part 2 | Up to 5 years | 
| BOR as assessed by local investigator | Part 2 | Up to 30 months | 
| BOR as assessed by ICR | Part 2 | Up to 30 months | 
| Duration of response (DOR) assessed by ICR | Part 2 | Up to 5 years | 
| DOR as assessed by local investigator | Part 2 | Up to 5 years | 
| Time to next anti-lymphoma treatment (TTNT) | Part 2 | Up to 5 years | 
| Incidence of TEAEs | Part 2 | Up to 2 years | 
| Severity of TEAEs | Part 2 | Up to 2 years | 
| Change from baseline of patient reported health related quality of life (HRQoL) 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 global health status (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 in cancer disease 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 global health status (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 in treatment related symptoms 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 global health status (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 in patient-reported lymphoma disease as measured by the Lymphoma Subscale of the Functional Assessment of Cancer Treatment-Lymphoma (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 in treatment-related symptoms as measured by the Lymphoma Subscale of the Functional Assessment of Cancer Treatment-Lymphoma (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 in patient-reported general health status per EuroQol-5 Dimensions-5 Levels (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 from baseline in patient-reported treatment side effects burden per FACT-Lym General Population 5 (GP5) Item Score | Part 2 A single item Global Population item 5 (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 | 
| Change from baseline in 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 in 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 in score of the FACT-G GP5 item in the patient population | Part 2 A single item Global Population item 5 (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), Relapsed or Refractory (R/R) FL, B-cells NHL (B-NHL), Untreated FL, Odronextamab