A Study to Evaluate the Safety and Efficacy of Glofitamab in Combination With Rituximab (R) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Circulating Tumor (ct)DNA High-Risk Patients With Untreated Diffuse Large B-Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
This Phase II, open-label, multicenter study will evaluate the safety, efficacy, and pharmacokinetics of glofitamab in combination with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in individuals with circulating tumor DNA (ctDNA) high-risk diffuse large B-cell lymphoma (DLBCL), as the first line of treatment.

Official Title
-----------------
A Phase II Study Evaluating the Safety and Efficacy of Glofitamab in Combination With Rituximab (R) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Circulating Tumor (ct)DNA High-Risk Patients With Untreated Diffuse Large B-Cell Lymphoma

Conditions
-----------------
Lymphoma

Intervention / Treatment
-----------------
* Drug: Glofitamab
* Drug: Tocilizumab
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone
* Drug: Rituximab
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Previously untreated patients with CD20-positive DLBCL, including one of the following diagnoses made according to the 2016 World Health Organization (WHO) classification of lymphoid neoplasms DLBCL, not otherwise specified, including GCB and ABC/non-GCB types as well as double-expressor lymphoma (coexpression of MYC and BCL2) High-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 translocations Patients with de novo transformed follicular lymphoma (patients with discordant bone marrow involvement, i.e., evidence of low-grade histology in bone marrow) may be considered after discussion with the Medical Monitor Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 International Prognostic Index (IPI): 2-5 Life expectancy of at least 6 months Adequate biomarker blood samples prior to initiation of R-CHOP on Day 1 of Cycle 1 and on Day 1 of Cycle 2 submitted for screening for determination of ctDNA status At least one bi-dimensionally fluorodeoxyglucose (FDG)-avid measurable lymphoma lesion on positron emission tomography/computed tomography (PET/CT) scan Left ventricular ejection fraction (LVEF) >=50%, as determined on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO) Adequate hematopoietic function Contraception use Additional Inclusion Criterion for ctDNA High-Risk Participants: Plasma sample evaluated to be ctDNA high risk Exclusion Criteria: Current diagnosis of B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma (gray-zone lymphoma), primary mediastinal (thymic) large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, Burkitt lymphoma, central nervous system (CNS) lymphoma (primary or secondary involvement), primary effusion DLBCL, and primary cutaneous DLBCL Contraindication to any of the individual components of R-CHOP, including prior receipt of anthracyclines, history of severe allergic or anaphylactic reactions to murine monoclonal antibodies, or known sensitivity or allergy to murine products Prior treatment for indolent lymphoma Prior solid organ or allogeneic stem cell transplant Prior therapy for DLBCL and high-grade B-cell lymphoma (HGBCL) with the exception of palliative, short-term treatment with corticosteroids Pregnant or breastfeeding, or intending to become pregnant during the study or within 12 months after the final dose of R-CHOP, 3 months after the final dose of tocilizumab (if applicable), or 2 months after the final dose of glofitamab

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glofitamab + R-CHOP Immunochemotherapy<br>Participants will receive step-up doses of glofitamab, starting on Day 8 of Cycle 3 (2.5 mg), Day 15 of Cycle 3 (10 mg), then 30 mg glofitamab will be given every three weeks (Q3W) onwards, on Day 8 of Cycles 4-6 and on Day 1 of Cycles 7-10. (cycle length = 21 days) Participants will receive rituximab, cyclophosphamide, doxorubicin, and vincristine Q3W on Day 1 of Cycles 1-6. Prednisone or prednisolone will be administered daily (QD) on Days 1-5 of Cycles 1-6. (cycle length = 21 days) | Drug: Glofitamab<br>* Participants will receive intravenous (IV) glofitamab as per schedule specified in the treatment arm.<br>Drug: Tocilizumab<br>* Participants will receive tocilizumab as needed to manage cytokine release syndrome (CRS).<br>Drug: Doxorubicin<br>* Participants will receive 50 mg/m2 body surface area of doxorubicin IV as per schedule specified in the treatment arm.<br>Drug: Vincristine<br>* Participants will receive 1.4 mg/m2 body surface area of vincristine IV as per schedule specified in the treatment arm.<br>Drug: Prednisone<br>* Participants will receive 100 mg of prednisone or prednisolone as per schedule specified in the treatment arm.<br>Drug: Rituximab<br>* Participants will receive 375 mg/m2 body surface area of rituximab IV as per schedule specified in the treatment arm.<br>Drug: Cyclophosphamide<br>* Participants will receive 750 mg/m2 body surface area of cyclophosphamide IV as per schedule specified in the treatment arm.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| End of Treatment Complete Response (EOT CR) Rate |  | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) at the EOT |  | Up to approximately 24 months | 
| Progression-free Survival (PFS) |  | Up to approximately 24 months | 
| Overall Survival (OS) |  | Up to approximately 24 months | 
| Percentage of Participants with Adverse Events (AEs) |  | Up to 90 days after the final dose of study treatment | 
| Serum Concentration of Glofitamab |  | At pre-defined intervals up to approximately 10 months | 
| Maximum Concentration (Cmax) of Glofitamab |  | At pre-defined intervals up to approximately 10 months | 
| Total Exposure (AUC) of Glofitamab |  | At pre-defined intervals up to approximately 10 months |