A Phase III Study Evaluating Glofitamab in Combination With Gemcitabine + Oxaliplatin vs Rituximab in Combination With Gemcitabine + Oxaliplatin in Participants With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of glofitamab in combination with gemcitabine plus oxaliplatin (Glofit-GemOx) compared with rituximab in combination with gemcitabine plus oxaliplatin (R-GemOx) in patients with R/R DLBCL.

Official Title
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A Phase III, Open-Label, Multicenter, Randomized Study Evaluating the Efficacy and Safety of Glofitamab in Combination With Gemcitabine Plus Oxaliplatin Versus Rituximab in Combination With Gemcitabine and Oxaliplatin in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Glofitamab
* Drug: Rituxumab
* Drug: Tocilizumab
* Drug: Gemcitabine
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically confirmed diffuse large B-cell lymphoma (DLBCL), not otherwise specified Relapsed/refractory (R/R) disease, defined as follows: Relapsed = disease that has recurred ≥6 months after completion of the last line of therapy; Refractory = disease that either progressed during the last line of therapy or progressed within 6 months (<6 months) of the last line of prior therapy At least one (≥1) line of prior systemic therapy Participants who have failed only one prior line of therapy must not be a candidate for high-dose chemotherapy followed by autologous stem cell transplant, as defined by the study protocol Confirmed availability of tumor tissue, unless unobtainable per investigator assessment. Freshly collected biopsy is preferred. Archival tissue is acceptable At least one bi-dimensionally measurable (≥1.5 cm) nodal lesion, or one bi-dimensionally measurable (≥1 cm) extranodal lesion, as measured on computed tomography (CT) scan Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Adequate hematologic function (unless attributable to the underlying disease, as established by extensive bone marrow involvement or associated with hypersplenism secondary to the involvement of the spleen by DLBCL per the investigator), as defined by the study protocol Negative SARS-CoV-2 antigen or PCR test within 7 days prior to enrollment Adequate renal function, defined as an estimated creatinine clearance ≥30 mL/min Exclusion Criteria Patient has failed only one prior line of therapy and is a candidate for stem cell transplantation History of transformation of indolent disease to DLBCL High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphoma not otherwise specified, as defined by 2016 WHO guidelines Primary mediastinal B-cell lymphoma 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, rituximab, gemcitabine or oxaliplatin, or tocilizumab Prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3 Peripheral neuropathy assessed to be Grade >1 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 at enrollment Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to first study treatment Treatment with monoclonal antibodies for the purposes of treating cancer within 4 weeks prior to first study treatment Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment or history of CNS lymphoma Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection (as evaluated by the investigator) within 4 weeks prior to the first study treatment Positive SARS-CoV-2 infection within 30 days prior to the first study treatment, including asymptomatic SARS-CoV-2 infection Documented SARS-CoV-2 infection within 6 months of first study treatment Suspected or latent tuberculosis Positive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) Known or suspected chronic active Epstein-Barr viral infection Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) Known history of progressive multifocal leukoencephalopathy Adverse events from prior anti-cancer therapy not resolved to Grade 1 or better (with the exception of alopecia and anorexia) 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 Prior allogeneic stem cell transplant Active autoimmune disease requiring treatment Prior treatment with systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents), within 4 weeks prior to first dose of study treatment Corticosteroid therapy within 2 weeks prior to first dose of study treatment (exceptions defined by study protocol) 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: Glofit-GemOx<br>Participants will receive up to 8 cycles of glofitamab (Glofit) in combination with gemcitabine and oxaliplatin (GemOx), followed by up to 4 cycles of glofitamab monotherapy. A single dose of obinutuzumab will be administered 7 days prior to the first dose of glofitamab. Treatment is administered in 21-day cycles. | Drug: Obinutuzumab<br>* Participants will receive a single dose of intravenous (IV) obinutuzumab pre-treatment 7 days prior to the first dose of glofitamab.<br>Drug: Glofitamab<br>* Participants will receive IV glofitamab for up to 12 cycles.<br>Drug: Tocilizumab<br>* Participants will receive IV tocilizumab as needed for treatment of cytokine-release syndrome (CRS).<br>Drug: Gemcitabine<br>* Participants will receive IV gemcitabine prior to oxaliplatin administration for up to 8 cycles.<br>Drug: Oxaliplatin<br>* Participants will receive IV oxaliplatin after gemcitabine administration for up to 8 cycles.<br>|
| Experimental: R-GemOx<br>Participants will receive rituxumab (R) in combination with gemcitabine and oxaliplatin (GemOx) for up to 8 cycles. Treatment is administered in 21-day cycles. | Drug: Rituxumab<br>* Participants will receive IV rituxumab on Day 1 of each cycle for up to 8 cycles.<br>Drug: Gemcitabine<br>* Participants will receive IV gemcitabine prior to oxaliplatin administration for up to 8 cycles.<br>Drug: Oxaliplatin<br>* Participants will receive IV oxaliplatin after gemcitabine administration for up to 8 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS), defined as the time from randomization to date of death from any cause |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS), defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the Independent Review Committee (IRC) |  | Up to 5 years | 
| PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the investigator |  | Up to 5 years | 
| Complete response (CR) rate, defined as the proportion of patients whose best overall response is a CR on positron emission tomography/computed tomography (PET/CT) during the study, as determined by the IRC |  | Up to 5 years | 
| CR rate, defined as the proportion of patients whose best overall response is a CR on positron emission tomography/computed tomography (PET/CT) during the study, as determined by the investigator |  | Up to 5 years | 
| Objective response rate (ORR), defined as the proportion of patients whose best overall response is a partial response (PR) or a CR during the study, as determined by the IRC |  | Up to 5 years | 
| ORR, defined as the proportion of patients whose best overall response is a partial response (PR) or a CR during the study, as determined by the investigator |  | Up to 5 years | 
| Duration of objective response (DOR), defined as the time from the first occurrence of a documented objective response (CR or PR) to disease progression, or death from any cause, whichever occurs first |  | Up to 5 years | 
| Duration of CR, defined as the time from the first occurrence of a documented CR to disease progression, or death from any cause, whichever occurs first |  | Up to 5 years | 
| Time to deterioration in physical functioning and fatigue, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) |  | Up to 5 years | 
| Time to deterioration in lymphoma symptoms, as measured by the Functional Assessment of Cancer Therapy-Lymphoma subscale (FACT-Lym LymS) |  | Up to 5 years | 
| Percentage of Participants with Adverse Events |  | Up to 5 years | 
| Tolerability, as assessed by dose interruptions, dose reductions, and dose intensity, and study treatment discontinuation because of adverse events |  | Up to 5 years |