A Trial to Learn if Odronextamab Combined With Lenalidomide is Safe and Works Better Than Rituximab Combined With Lenalidomide in Participants With Follicular Lymphoma and Marginal Zone 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 patients who have one of two types of cancer: follicular lymphoma (FL) or marginal zone lymphoma (MZL) that has come back after treatment (called relapsed), or did not respond to treatment (called refractory). FL and MZL are subtypes of Non-Hodgkin 's lymphoma (NHL). This study will be made up of two parts (Part 1 not randomized, Part 2 randomized - controlled). The aim of Part 1 of the study is to see how safe and tolerable the study drug is when used in combination with lenalidomide, in participants with FL or MZL, and to determine the dose of the study drug to be used in Part 2 of this study. This combination is considered first-in-human as it has not been tested as a combination treatment in humans before. The aim of Part 2, of the study is to assess how the combination of odronextamab and lenalidomide works compared to the combination of rituximab and lenalidomide, (the current standard-of-care treatment for FL and/or MZL). 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 in combination with lenalidomide 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-CD20 x Anti-CD3 Bispecific Antibody, in Combination With Lenalidomide Versus Rituximab in Combination With Lenalidomide Therapy in Relapsed/Refractory Participants With Follicular Lymphoma and Marginal Zone Lymphoma (OLYMPIA-5)

Conditions
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Relapsed/Refractory Follicular Lymphoma, Marginal Zone Lymphoma (MZL)

Intervention / Treatment
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* Drug: Odronextamab
* Drug: Lenalidomide
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Local histologic confirmation of FL grade 1-3a or MZL (nodal, splenic, or extra nodal MZL) as assessed by the investigator. Must have refractory disease or relapsed after at least 2 cycles of prior systemic chemo-immunotherapy or immunotherapy. Prior systemic therapy should have included at least one anti-cluster of differentiation 20 (CD20) monoclonal antibody and patient should meet indication for treatment. 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 to 2. Adequate hematologic and organ function. Key Exclusion Criteria: Primary central nervous system (CNS) lymphoma or known involvement (either current or prior history of CNS involvement) by non-primary CNS NHL. Participants with histological evidence of transformation to a high-grade or diffuse large B-cell lymphoma, or any histology other than FL grade 1-3a or MZL. History of or current relevant CNS pathology, as described in the protocol. A malignancy other than NHL unless the participant is adequately and definitively treated and is cancer free for at least 3 years, with the exception of localized prostate cancer treated with hormone therapy or local radiotherapy (ie, pellets), cervical carcinoma in situ, breast cancer in situ, or nonmelanoma skin cancer that was definitively treated. 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. Allergy/hypersensitivity to study drugs or excipients. Active infection as defined 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+Lenalidomide<br>In part 1 (safety run-in), participants with R/R indolent lymphoma (FL and ML), will receive odronextamab in combination with lenalidomide. In part 2, 1:1 randomized participants with indolent lymphoma (FL/MZL), will receive odronextamab in combination with lenalidomide. | Drug: Odronextamab<br>* Administered by intravenous (IV) infusion<br>* Other names: REGN1979;Drug: Lenalidomide<br>* Administered orally (PO)<br>* Other names: REVLIMID;|
| Experimental: Rituximab+Lenalidomide<br>In part 2 only, 1:1 randomized participants with R/R lymphoma (FL and ML), will receive rituximab in combination with lenalidomide (R2) followed by lenalidomide monotherapy. | Drug: Lenalidomide<br>* Administered orally (PO)<br>* Other names: REVLIMID;Drug: Rituximab<br>* Administered by IV infusion<br>* Other names: Rituxan;|

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 lenalidomide | Part 1 | Up to 35 days | 
| Incidence of treatment emergent adverse events (TEAEs) for odronextamab in combination with lenalidomide | Part 1 | Up to 2 years | 
| Severity of TEAEs for odronextamab in combination with lenalidomide | Part 1 | Up to 2 years | 
| Progression-free survival (PFS) as assessed by independent central review (ICR) in participants with R/R FL and participants with indolent lymphoma | Part 2 | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Odronextamab concentrations in serum | Part 1 and Part 2 | Up to 30 months | 
| Incidence of anti-odronextamab antibodies (ADA) to odronextamab over time | Part 1 and Part 2 | Up to 30 months | 
| Titer of ADAs to odronextamab over time | Part 1 and Part 2 | Up to 30 months | 
| Incidence of neutralizing antibodies (NAbs) to odronextamab over time | Part 1 and Part 2 | Up to 30 months | 
| Best overall response (BOR) as assessed by investigator review | Part 1 and Part 2 | Up to 30 months | 
| Duration of response (DOR) as assessed by investigator review | Part 1 and Part 2 | Up to 5 years | 
| PFS as assessed by investigator review | Part 1 and Part 2 | Up to 5 years | 
| Complete response (CR) as assessed by ICR | Part 2 | Up to 30 months | 
| BOR as assessed by ICR | Part 2 | Up to 30 months | 
| Overall survival (OS) | 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 review | Part 2 | Up to 5 years | 
| DOR as assessed by ICR | Part 2 | Up to 5 years | 
| Time to next anti-lymphoma treatment (TTNT) | Part 2 | Up to 5 years | 
| Incidence of TEAEs for odronextamab in combination with lenalidomide versus R2 | Part 2 | Up to 2 years | 
| Severity of TEAEs for odronextamab in combination with lenalidomide versus R2 | Part 2 | Up to 2 years | 
| Overall change from baseline in patient reported outcomes (PROs) as measured by scores of European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQC30) | 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 | 
| Overall change from baseline in PROs as measured by scores of 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 | 
| Overall change from baseline in PROs as measured by scores of Patient Global Impression on 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 | 
| Overall change from baseline in PROs as measured by scores of Patient Global Impression on 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 | 
| Overall change from baseline in PROs as measured by scores of 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 | 
| Overall change from first assessment to end of treatment in score of the global population item 5 (GP5) items of the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire | 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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Relapsed/Refractory Follicular Lymphoma, Marginal Zone Lymphoma, Non-Hodgkin lymphomas, Indolent lymphomas, Odronextamab