A Trial to Learn if Odronextamab is Safe and Well-tolerated and How Well it Works Compared to Rituximab Combined With Different Types of Chemotherapy for Participants With Follicular Lymphoma

Study Overview
=================
Brief Summary
-----------------
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 (a type of non-Hodgkin lymphoma or NHL). This study will be made up of two parts: Part 1 (non-randomized) and Part 2 (randomized - controlled). The aim of Part 1 of the study is to see how safe and tolerable the study drug is. The aim of Part 2 of the study is to see how the study drug works compared to 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 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
-----------------
A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Odronextamab (REGN1979), an Anti-CD20 X Anti-CD3 Bispecific Antibody Versus Investigator's Choice in Previously Untreated Participants With Follicular Lymphoma (OLYMPIA-1)

Conditions
-----------------
Follicular Lymphoma (FL)

Intervention / Treatment
-----------------
* Drug: Odronextamab
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone/prednisolone
* Drug: Bendamustine


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Diagnosis of cluster of differentiation 20^+ (CD20^+) FL Grade 1-3a, stage II bulky or stage III / IV Need for treatment as described in the protocol Have measurable disease on cross-sectional imaging documented by diagnostic imaging Computed tomography (CT) or Magnetic resonance imaging (MRI) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Adequate bone marrow function and hepatic function Key Exclusion Criteria: Central nervous system (CNS) lymphoma or leptomeningeal lymphoma Histological evidence of transformation to a high-grade or diffuse large B-cell lymphoma Waldenström macroglobulinemia (WM, lymphoplasmacytic lymphoma), Grade 3b follicular lymphoma, chronic lymphocytic leukemia, or small lymphocytic lymphoma Treatment with any systemic anti-lymphoma therapy Infections and allergy/hypersensitivity to study drug or excipient 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Odronextamab<br>Part 1 is a safety run-in. All participants will receive odronextamab. In part 2 participants will be randomly assigned in a 1:1 ratio to receive odronextamab followed by odronextamab maintenance. | Drug: Odronextamab<br>* Administered by intravenous infusion (IV)<br>* Other names: REGN1979;|
| Active Comparator: Rituximab + Investigator's Choice Chemotherapy<br>Part 2 only, participants will be randomized 1:1 to receive rituximab in combination with chemotherapy followed by rituximab maintenance. | Drug: Rituximab<br>* Rituximab will be administered by IV, or subcutaneously (SC)<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Administered by IV as part of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) chemotherapy, or Cyclophosphamide, Vincristine, Prednisone (CVP) chemotherapy<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Administered by IV as part of CHOP chemotherapy<br>* Other names: Adriamycin;Drug: Vincristine<br>* Administered by IV as part of CHOP, and CVP chemotherapy<br>* Other names: Oncovin;Drug: Prednisone/prednisolone<br>* Administered orally (PO) as part of CVP chemotherapy<br>* Other names: Deltasone/Omnipred;Drug: Bendamustine<br>* Administered by IV as part of chemotherapy (Rituximab-Bendamustine)<br>* Other names: Treanda;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) for odronextamab | Part 1 | Up to 35 days | 
| Incidence of treatment-emergent adverse events (TEAEs) of odronextamab | Part 1 | Up to 2 years | 
| Severity of TEAEs of odronextamab | Part 1 | Up to 2 years | 
| Complete Response at 30 months (CR30) as assessed by independent central review | Part 2 | Up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of odronextamab in serum | Part 1 | Up to 30 months | 
| Incidence of anti-odronextamab antibodies (ADAs) | Part 1 | Up to 30 months | 
| Titer of ADAs | Part 1 | Up to 30 months | 
| Incidence of neutralizing antibodies (NAbs) to odronextamab | Part 1 | Up to 30 months | 
| Objective response as assessed by the investigator | Part 1 | Up to 30 months | 
| Progression-free survival (PFS) as assessed by independent central review | Part 2 | Up to 5 years | 
| Event-free survival (EFS) as assessed by independent central review | Part 2 | Up to 5 years | 
| CR30 as assessed by local investigator | Part 2 | Up to 30 months | 
| Overall mean change from baseline in physical function [European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 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 | 
| Overall survival (OS) | Part 2 | Up to 5 years | 
| PFS as assessed by the local investigator | Part 2 | Up to 5 years | 
| EFS as assessed by the local investigator | Part 2 | Up to 5 years | 
| Objective response assessed by local investigator | Part 2 | Up to 30 months | 
| Objective response assessed by independent central review | Part 2 | Up to 30 months | 
| Duration of response (DOR) assessed by independent central review | Part 2 | Up to 5 years | 
| DOR 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 | 
| Odronextamab concentrations in serum during the induction period | Part 2 | Up to 30 months | 
| Odronextamab concentrations in serum during the maintenance period | Part 2 | Up to 30 months | 
| Incidence of ADAs to odronextamab over time | Part 2 | Up to 30 months | 
| Titer of ADAs to odronextamab over time | Part 2 | Up to 30 months | 
| Incidence of NAbs to odronextamab over time | Part 2 | Up to 30 months | 
| Overall mean changes in scores of patient reported outcomes (PROs), as measured by the validated instruments EORTCQLQ- 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 | 
| Overall mean changes in scores of PROs, as measured by the validated instruments Functional Assessment of Cancer Therapy-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 | 
| Overall mean changes in scores of PROs, as measured by the validated instruments 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 | 
| Overall mean changes in scores of PROs, as measured by the validated instruments 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 | 
| Overall mean changes in scores of PROs, as measured by the validated instruments 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 | 
| Overall mean changes in scores PROs, as measured by the validated Functional Assessment of Cancer - General (FACT-G) global population 5 (GP5) question | 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 in score of the GP5 item in the participant 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
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-Hodgkin lymphomas (NHLs), Indolent NHL, B-cells NHL (B-NHL), Follicular lymphoma, Odronextamab