An Open-Label Study Comparing Glofitamab and Polatuzumab Vedotin + Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone Versus Pola-R-CHP in Previously Untreated Patients With Large B-Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare the efficacy and safety of glofitamab in combination with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs Pola-R-CHP in participants with previously untreated CD20-positive large B-cell lymphoma (LBCL).

Official Title
-----------------
A Phase III, Multicenter, Randomized, Open-Label Study Comparing the Efficacy and Safety of Glofitamab (RO7082859) in Combination With Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) Versus Pola-R-CHP in Previously Untreated Patients With Large B-Cell Lymphoma

Conditions
-----------------
Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: Glofitamab
* Drug: Polatuzumab vedotin
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Prednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Previously untreated participants with CD20-positive LBCL Confirmed availability of tumor tissue International prognostic index (IPI) score 2-5 Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2 At least one bi-dimensionally measurable lesion, defined as > 1.5 cm in its longest dimension as measured by CT or MRI Left ventricular ejection fraction (LVEF) >/=50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO) Adequate hematologic function Negative HIV test at screening with exceptions as defined by the protocol Negative SARS-CoV-2 antigen or PCR test Exclusion Criteria: Contraindication to any of the individual components of Pola-R-CHP or glofitamab, including prior receipt of anthracyclines, or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, or known sensitivity or allergy to murine products Prior solid organ transplantation Current Grade > 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease History of indolent lymphoma Current diagnosis of the following: Follicular lymphoma grade 3B; transformations of indolent B-cell lymphomas (e.g., de novo transformed follicular lymphoma); mediastinal grey zone lymphoma; primary mediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma; primary large B-cell lymphoma of immune-privileged sites; primary effusion DLBCL; and primary cutaneous DLBCL Prior treatment with systemic immunotherapeutic agents Prior use of any monoclonal antibody for the purposes of treating cancer within 3 months of the start of Cycle 1 Any investigational therapy for the purposes of treating cancer within 28 days prior to the start of Cycle 1 Prior radiotherapy to the mediastinal/pericardial region Prior therapy for LBCL, with the exception of corticosteriods Corticosteroid use > 50 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control History of other malignancy that could affect compliance with the protocol or interpretation of results Significant or extensive history of cardiovascular disease Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease History of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents Active autoimmune disease which is not well controlled by therapy Clinically significant liver disease Live, attenuated vaccine within 4 weeks before study treatment infusion on Day 1 of Cycle 1 or anticipation that such a live, attenuated vaccine will be required during the study. Live vaccines during the study and until participants B cells recover are prohibited Any active infection within 7 days prior to Cycle 1 Day 1 that would impact participant safety Suspected active or latent tuberculosis Positive test results for chronic hepatitis B infection, hepatitis C, or the human T-lymphotropic virus type 1 (HTLV-1) History of progressive multifocal leukoencephalopathy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 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: Glofitamab + Pola-R-CHP<br>Participants will receive glofitamab in combination with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP). | Drug: Glofitamab<br>* Participants will receive intravenous (IV) glofitamab<br>Drug: Polatuzumab vedotin<br>* Participants will receive IV polatuzumab vedotin in combination with R-CHP<br>Drug: Rituximab<br>* Participants will receive IV rituximab<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide as part of CHP chemotherapy<br>Drug: Doxorubicin<br>* Participants will receive IV doxorubicin<br>Drug: Prednisone<br>* Participants will receive oral prednisone as part of CHP chemotherapy<br>|
| Active Comparator: Pola-R-CHP<br>Participants will receive Pola-R-CHP. | Drug: Polatuzumab vedotin<br>* Participants will receive IV polatuzumab vedotin in combination with R-CHP<br>Drug: Rituximab<br>* Participants will receive IV rituximab<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide as part of CHP chemotherapy<br>Drug: Doxorubicin<br>* Participants will receive IV doxorubicin<br>Drug: Prednisone<br>* Participants will receive oral prednisone as part of CHP chemotherapy<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) as determined by Independent Review Facility (IRF) |  | From randomization to the first occurrence of disease progression or relapse, or death due to any cause, whichever occurs first (up to approximately 65 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS as determined by the investigator |  | From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 65 months) | 
| PFS as determined by the investigator and IRF for participants with international prognostic index (IPI) 3-5 |  | From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to 65 months) | 
| Event-free survival efficacy causes (EFSeff) |  | From randomization to the earliest occurrence of disease progression or relapse; death due to any cause; initiation of new anti-lymphoma treatment; or positive biopsy for residual disease after treatment completion (up to approximately 65 months) | 
| Complete response (CR) rate |  | At the end of treatment (up to approximately 65 months) | 
| Objective response rate (ORR) |  | At treatment completion or discontinuation (up to approximately 65 months) | 
| Overall survival (OS) |  | From randomization to death from any cause (up to approximately 65 months) | 
| Duration of response (DOR) |  | From the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 65 months) | 
| Duration of complete response (DOCR) |  | From the first occurrence of a documented complete response (CR) to disease progression or death, whichever occurs first (up to approximately 65 months) | 
| Disease-free survival (DFS) |  | From a documented CR at the end of treatment to disease progression or death, whichever occurs first (up to approximately 65 months) | 
| Serum concentration of glofitamab |  | Up to approximately 65 months | 
| Incidence of anti-drug antibodies (ADAs) |  | Baseline up to approximately 65 months | 
| Proportion of participants experiencing a clinically meaningful improvement in physical functioning and fatigue (EORTC QLQ-C30) and lymphoma symptoms (FACT-Lym LymS) |  | Up to approximately 65 months | 
| Time to deterioration in physical functioning and fatigue (EORTC QLQ-C30) and lymphoma symptoms (FACT-Lym LymS) |  | Up to approximately 65 months | 
| Percentage of Participants with Adverse Events (AEs) |  | From randomization to the end of study (up to approximately 65 months) |