A Study Evaluating the Efficacy, Safety, and Pharmacokinetics of Glofitamab in Combination With Rituximab Plus Ifosfamide, Carboplatin Etoposide Phosphate in Participants With Relapsed/Refractory Transplant or CAR-T Therapy Eligible Diffuse B-Cell Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the preliminary efficacy, safety, and pharmacokinetics of glofitamab (glofit) in combination with rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE) in participants with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), who have failed one prior line of therapy incorporating an anti-cluster of differentiation (CD) 20 antibody (i.e., rituximab) and an anthracycline, and who are transplant or chimeric antigen receptor T-cell (CAR-T) therapy eligible, defined as being medically eligible for intensive platinum-based salvage therapy followed by autologous stem cell transplantation (ASCT) or for CAR-T therapy.

Official Title
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A Phase IB, Open-Label, Multicenter, Single Arm Study Evaluating the Preliminary Efficacy, Safety, and Pharmacokinetics of Glofitamab in Combination With Rituximab Plus Ifosfamide, Carboplatin Etoposide Phosphate in Patients With Relapsed/Refractory Transplant or CAR-T Therapy Eligible Diffuse B-Cell Lymphoma

Conditions
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Diffuse Large B-Cell Lymphoma (DLBCL)

Intervention / Treatment
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* Drug: Glofitamab
* Drug: Obinutuzumab
* Drug: Tocilizumab
* Drug: Rituximab
* Drug: Ifosfamide
* Drug: Carboplatin
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Life expectancy ≥ 12 weeks Histologically confirmed B-cell lymphoma One line of prior systemic therapy including an anti-CD20 monoclonal antibody (i.e. rituximab) and an anthracycline Relapsed or refractory disease after first-line chemoimmunotherapy Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Participant must be a candidate for high-dose chemotherapy followed by ASCT or CAR-T therapy Exclusion Criteria: Treatment with more than one prior line of therapy for DLBCL Primary mediastinal B-cell lymphoma 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 CNS lymphoma at the time of enrollment or history of CNS lymphoma Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) Known history of progressive multifocal leukoencephalopathy Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better (with the exception of alopecia and anorexia, or as otherwise permitted by inclusion criteria) Prior solid organ transplantation Prior allogeneic stem cell transplant Prior ASCT for lymphoma Prior autologous stem cell transplant for any indication other than lymphoma, within 5 years from the start of study treatment 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 Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent. Participants who received corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks' duration prior to Cycle 1 Day 1. Participants may have received a brief (≤ 7 days) course of systemic steroids (≤ 100 mg prednisone equivalent per day) prior to initiation of study therapy for control of lymphoma-related symptoms 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R/R DLBCL<br>Participants will receive up to 3 21-day cycles of glofitamab, rituximab, ifosfamide, carboplatin, and etoposide (glofit-R-ICE). | Drug: Glofitamab<br>* Participants will receive intravenous (IV) glofitamab for up to 3 cycles.<br>Drug: Obinutuzumab<br>* Participants will receive IV obinutuzumab on Cycle 1 Day 1.<br>Drug: Tocilizumab<br>* Participants will receive IV tocilizumab as necessary to manage cytokine release syndrome (CRS) events.<br>Drug: Rituximab<br>* Participants will receive up to 2 doses of IV rituximab.<br>Drug: Ifosfamide<br>* Participants will receive IV ifosfamide for up to 3 cycles.<br>Drug: Carboplatin<br>* Participants will receive IV carboplatin for up to 3 cycles.<br>Drug: Etoposide<br>* Participants will receive IV etoposide for up to 3 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR), defined as the proportion of participants that achieves a CR or PR within three cycles of glofit-R-ICE, as determined by the investigator according to Lugano criteria |  | Up to 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) after enrollment |  | From enrollment to the first occurrence of disease progression, initiation of new anti-lymphoma therapy (not including planned ASCT or CAR-T therapy), or death from any cause (whichever occurs first) (up to 2.5 years) | 
| Progression-free survival (PFS) after enrollment |  | From enrollment to the first occurrence of disease progression or death from any cause (whichever occurs first) as determined by the investigator according to Lugano criteria (up to 2.5 years) | 
| Mobilization-adjusted response rate (MARR) | The proportion of participants treated with intent to proceed to ASCT that achieves a CR or PR within three cycles of glofit-R-ICE, as determined by the investigator according to Lugano criteria, and additionally achieves mobilization of a minimum of 2,000,000 CD34+ hematopoietic stem cells/kg for ASCT | Up to 2.5 years | 
| Overall survival (OS) after enrollment |  | From enrollment to death from any cause (up to 2.5 years) | 
| CR rate after enrollment, defined as the proportion of participants that achieves a CR within three cycles of glofit-R-ICE, as determined by the investigator according to Lugano criteria |  | Up to 2.5 years | 
| Duration of Response (DOR) |  | From the first occurrence of a documented objective response (CR or PR) to disease progression or death from any cause (whichever occurs first) as determined by the investigator according to Lugano criteria (up to 2.5 years) | 
| Duration of complete response (DOCR) |  | From the first occurrence of a documented complete response to disease progression or death from any cause (whichever occurs first) as determined by the investigator according to Lugano criteria (up to 2.5 years) | 
| Percentage of participants with adverse events (AEs) |  | Up to 2.5 years | 
| Percentage of participants with cytokine release syndrome (CRS) |  | Up to 2.5 years | 
| Maximum serum concentration (Cmax) of glofitamab |  | Up to 2.5 years | 
| Minimum serum concentration (Cmin) of glofitamab |  | Up to 2.5 years | 
| Percentage of participants with anti-drug antibodies (ADAs) |  | From baseline up to 2.5 years |