A Study to Evaluate Glofitamab as a Single Agent vs. Investigator's Choice in Participants With Relapsed/Refractory Mantle Cell Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of glofitamab monotherapy compared with an investigator's choice of either rituximab plus bendamustine (BR), or lenalidomide with rituximab (R-Len) in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL).

Official Title
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A Phase III, Open-Label, Multicenter Randomized Study Evaluating Glofitamab as a Single Agent Versus Investigator's Choice in Patients With Relapsed/Refractory Mantle Cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Glofitamab
* Drug: Rituximab
* Drug: Bendamustine
* Drug: Lenalidomide
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Life expectancy at least 12 weeks Histologically-confirmed MCL, with documentation of either overexpression of cyclin D1 or the presence of t(11:14) Relapsed (disease progression after the last treatment regimen) or refractory (failure to achieve a partial or complete response from the last treatment regimen) disease At least 1 line of prior systemic therapy including a BTK inhibitor and additional systemic therapy option Confirmed availability of tumor tissue, unless deemed unsafe per investigator assessment At least one bi-dimensionally measurable (defined as at least 1.5 cm) nodal lesion, or one bi-dimensionally measurable (at least 1 cm) extranodal lesion, as measured on CT scan Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Negative HIV test at screening Adequate hematological function Exclusion Criteria: Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 3 months after the final dose of tocilizumab, 2 months after the final dose of glofitamab, whichever is longer Leukemic, non-nodal MCL History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products Contraindication to obinutuzumab or rituximab, and either bendamustine or lenalidomide Prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3 Prior treatment with CAR-T cell therapy Treatment with systemic therapy or BTK inhibitors, or any investigational agent for the purposes of treating cancer within 2 weeks or 5 half-lives (whichever is shorter) prior to first study treatment Primary or secondary CNS lymphoma at the time of recruitment or history of CNS lymphoma Current or history of CNS disease, such as stroke, epilepisy, CNS vasculitis, or neurodegenerative disease History of other malignancy that could affect compliance with the protocol or interpretation of results Significant or extensive cardiovascular disease Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment or any major episode of infection within 4 weeks prior to the first study treatment Suspected or latent tuberculosis Positive test for hepatitis B virus (HBV) or hepatitis C virus (HCV) Known or suspected chronic active Epstein-Barr viral infection (EBV) Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) Known history of progressive multifocal leukoencephalopathy (PML) Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better Administration of a live, attenuated vaccine within 4 weeks before first study treatment administration or anticipation that such a live, attenuated vaccine will be required during the study Prior solid organ transplantation or allogenic stem cell transplant Eligibility for stem cell transplantation (SCT) Active autoimmune disease requiring treatment Prior treatment with systemic immunosuppressive medications within 2 weeks or five half-lives (whichever is shorter) prior to the first dose of study treatment Corticosteroid therapy within 2 weeks prior to first dose of study treatment Recent major surgery (within 4 weeks before the first study treatment) other than for diagnosis Clinically significant history of cirrhotic liver disease

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: Glofitamab monotherapy<br>Participants will receive two intravenous (IV) obinutuzumab pretreatments prior to receiving IV glofitamab for 12 cycles (cycle length = 21 days). | Drug: Obinutuzumab<br>* Participants will receive two 1000 mg pretreatments of intravenous (IV) obinutuzumab from Cycle 1 Day 1<br>Drug: Glofitamab<br>* Participants will receive IV glofitamab beginning Cycle 1 Day 8 for 12 cycles (cycle length = 21 days).<br>Drug: Tocilizumab<br>* Participants will receive IV tocilizumab as required to manage cytokine release syndrome (CRS) events.<br>|
| Active Comparator: BR or R-Len<br>Participants will receive bendamustine + rituximab for up to 6 cycles (cycle length = 28 days), or rituximab + lenalidomide (cycle length = 28 days) until disease progression. | Drug: Rituximab<br>* Participants will receive IV rituximab every 28 days for up to 6 cycles (when in combination with bendamustine), or until disease progression (when in combination with lenalidomide).<br>Drug: Bendamustine<br>* Participants will receive IV bendamustine on Days 1 and 2 Q4W for 6 cycles (cycle length = 28 days).<br>Drug: Lenalidomide<br>* Participants will receive oral lenalidomide once daily on Days 1-21 Q4W until disease progression.<br>Drug: Tocilizumab<br>* Participants will receive IV tocilizumab as required to manage cytokine release syndrome (CRS) events.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) |  | From randomization to the first occurrence of disease progression or death from any cause (up to approximately 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate |  | Up to approximately 24 months | 
| Objective response rate (ORR) |  | Up to approximately 24 months | 
| Overall survival (OS) |  | From randomization to death from any cause (up to approximately 24 months) | 
| Time to deterioration in physical functioning/fatigue |  | From randomization to a 10-point decrease in physical functioning/10-point increase in fatigue compared to baseline (up to approximately 24 months) | 
| Investigator-assessed PFS |  | From randomization to disease progression or death from any cause (up to approximately 24 months) | 
| Investigator-assessed CR rate |  | Up to approximately 24 months | 
| Investigator-assessed ORR |  | Up to approximately 24 months | 
| Duration of Complete Response (DOCR) |  | From the initial occurrence of a documented CR until documented disease progression or death due to any cause, whichever occurs first (up to approximately 24 months) | 
| Duration of Response (DOR) |  | From the initial occurrence of a documented CR until documented disease progression or death due to any cause, whichever occurs first (up to approximately 24 months) | 
| Proportion of participants reporting each response option for item GP5 from the Functional Assessment of Cancer Therapy - General (FACT-G) subscale |  | Up to approximately 24 months | 
| Time to deterioration in lymphoma symptoms |  | From randomization to the first documentation of a 3-point or more decrease in score as assessed by the FACT-Lym lymphoma subscale (LymS) questionnaire (up to approximately 24 months) | 
| Proportion of participants experiencing a clinically meaningful improvement (3-point or more increase) in lymphoma symptoms as assessed through use of the FACT-Lym LymS |  | Up to approximately 24 months | 
| Change from baseline in physical functioning and fatigue at each cycle as assessed by the European Organization for Research and Treatment (EORTC) core Quality of Life Questionnaire (QLQ-C30) | The EORTC QLQ-C30 consists of 30 questions assessing five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), global health status and quality of life (QoL), and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functioning and symptoms items are scored on a 4-point scale that ranges from not at all to very much, and the global health status and QoL items are scored on a 7-point scale that ranges from very poor to excellent. | Up to approximately 24 months | 
| Change from baseline in lymphoma symptoms at each cycle as assessed by the FACT-Lym LymS |  | Up to approximately 24 months | 
| Serum concentration of glofitamab |  | Up to approximately 24 months | 
| Incidence of anti-drug antibodies (ADAs) |  | Up to approximately 24 months |