A Phase Ib/II Study Investigating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Mosunetuzumab (BTCT4465A) in Combination With CHOP or CHP-Polatuzumab Vedotin in Participants With B-Cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This study will evaluate the safety, pharmacokinetics, and preliminary efficacy of mosunetuzumab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (M-CHOP) and, subsequently, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) plus polatuzumab vedotin (CHP-pola) in participants with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL), and in previously untreated participants with diffuse large B-cell lymphoma (DLBCL).

Official Title
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A Phase Ib/II, Open-Label, Multicenter, Randomized, Controlled Study Investigating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Mosunetuzumab (BTCT4465A) in Combination With CHOP or CHP-Polatuzumab Vedotin in Patients With B-Cell Non-Hodgkin Lymphoma

Conditions
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B-cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Mosunetuzumab
* Drug: Polatuzumab Vedotin
* Drug: Rituxumab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Phase Ib and Phase II Portions At least one bi-dimensionally measurable nodal lesion, defined as > 1.5 cm in its longest dimension, or one bi-dimensionally measurable extranodal lesion, defined as > 1.0 cm in its longest diameter Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2 Adequate hematologic function Inclusion Criteria for Phase Ib Portion Participants must also meet the following criteria for study entry into the Phase Ib portion: Histologically confirmed B-cell NHL according to the World Health Organization (WHO) 2016 classification expected to express the cluster of differentiation-20 (CD20) antigen Relapsed or refractory (R/R) B-cell NHL after at least one prior systemic lymphoma therapy Treatment with at least one prior CD20-directed therapy Group B only: no prior treatment with polatuzumab vedotin Inclusion Criteria for Phase II Portion Participants must also meet the following criteria for study entry in the Phase II portion: Previously untreated, histologically confirmed DLBCL according to WHO 2016 classification International Prognostic Index (IPI) score of 2-5 Exclusion Criteria Prior treatment with mosunetuzumab Prior allogenic stem-cell transplant Current Grade >1 peripheral neuropathy Participants with history of confirmed progressive multifocal leukoencephalopathy (PML) Known or suspected chronic active Epstein Barr virus (CAEBV), hepatitis B, hepatitis C (HCV), or Human Immunodeficiency Virus (HIV) Prior solid organ transplantation History of autoimmune disease Current or past history of central nervous system (CNS) lymphoma Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease Significant cardiovascular disease or pulmonary disease Clinically significant history of liver disease Recent major surgery within 4 weeks before the start of C1D1, other than superficial lymph node biopsies for diagnosis Exclusion Criteria for Phase Ib Portion Participants who also meet any of the following criteria will be excluded from study entry in the Phase Ib portion: Prior treatment with chemotherapy, immunotherapy, and biologic therapy 4 weeks prior to C1D1 Prior treatment with radiotherapy within 2 weeks prior to C1D1 Adverse events from prior anti-cancer therapy resolved to ≤Grade 1 (with the exception of alopecia and anorexia) Prior treatment with >250 mg/m^2 doxorubicin (or equivalent anthracycline dose) Exclusion Criteria for Phase II Portion Participants who also meet any of the following criteria will be excluded from study entry in the Phase II portion: Participants with transformed lymphoma Prior therapy for B-cell NHL

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: Phase Ib: Mosunetuzumab (M)-CHOP Dose Finding<br>Participants will receive M-CHOP up to the phase II recommended dose (RP2D). | Drug: Mosunetuzumab<br>* Participants will receive intravenous (IV) mosunetuzumab.<br>Drug: Polatuzumab Vedotin<br>* Participants will receive polatuzumab vedotin via IV.<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide via IV.<br>Drug: Doxorubicin<br>* Participants will receive doxorubicin via IV.<br>Drug: Vincristine<br>* Participants will receive vincristine via IV.<br>Drug: Prednisone<br>* Participants will receive oral prednisone.<br>Drug: Tocilizumab<br>* Participants will receive tocilizumab via IV.<br>|
| Experimental: Phase Ib: M-CHP-Pola Dose-Finding<br>Participants will receive M-CHP-Pola up to the RP2D. | Drug: Mosunetuzumab<br>* Participants will receive intravenous (IV) mosunetuzumab.<br>Drug: Polatuzumab Vedotin<br>* Participants will receive polatuzumab vedotin via IV.<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide via IV.<br>Drug: Doxorubicin<br>* Participants will receive doxorubicin via IV.<br>Drug: Prednisone<br>* Participants will receive oral prednisone.<br>Drug: Tocilizumab<br>* Participants will receive tocilizumab via IV.<br>|
| Experimental: Phase II: M-CHOP Previously Untreated (1L) DLBCL Safety Cohort<br>Participants with 1L DLBCL will receive mosunetuzumab at the RP2D in combination with CHOP. | Drug: Mosunetuzumab<br>* Participants will receive intravenous (IV) mosunetuzumab.<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide via IV.<br>Drug: Doxorubicin<br>* Participants will receive doxorubicin via IV.<br>Drug: Vincristine<br>* Participants will receive vincristine via IV.<br>Drug: Prednisone<br>* Participants will receive oral prednisone.<br>Drug: Tocilizumab<br>* Participants will receive tocilizumab via IV.<br>|
| Experimental: Phase II: M-CHP-Pola 1L DLBCL<br>Participants with 1L DLBCL will receive M-CHP-Pola at a dose determined in the dose finding stage. | Drug: Mosunetuzumab<br>* Participants will receive intravenous (IV) mosunetuzumab.<br>Drug: Polatuzumab Vedotin<br>* Participants will receive polatuzumab vedotin via IV.<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide via IV.<br>Drug: Doxorubicin<br>* Participants will receive doxorubicin via IV.<br>Drug: Prednisone<br>* Participants will receive oral prednisone.<br>Drug: Tocilizumab<br>* Participants will receive tocilizumab via IV.<br>|
| Active Comparator: Phase II: Rituxumab (R)-CHP-Pola 1L DLBCL<br>Participants with 1L DLBCL will receive R-CHP-Pola at a dose determined in the dose finding stage. | Drug: Polatuzumab Vedotin<br>* Participants will receive polatuzumab vedotin via IV.<br>Drug: Rituxumab<br>* Participants will receive rituxumab via IV.<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide via IV.<br>Drug: Doxorubicin<br>* Participants will receive doxorubicin via IV.<br>Drug: Prednisone<br>* Participants will receive oral prednisone.<br>|
| Experimental: Phase II: M-CHOP 1L DLBCL<br>Participants with 1L DLBCL will receive M-CHOP at a dose determined in the dose finding stage. | Drug: Mosunetuzumab<br>* Participants will receive intravenous (IV) mosunetuzumab.<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide via IV.<br>Drug: Doxorubicin<br>* Participants will receive doxorubicin via IV.<br>Drug: Vincristine<br>* Participants will receive vincristine via IV.<br>Drug: Prednisone<br>* Participants will receive oral prednisone.<br>Drug: Tocilizumab<br>* Participants will receive tocilizumab via IV.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Adverse Events (AE) |  | Baseline through approximately 90 days after the last study treatment | 
| Complete Response (CR) Rate at the Time of Primary Response Assessment Based on Positron Emission Tomography - Computed Tomography (PET-CT) as Assessed According to Lugano 2014 Response Criteria |  | Approximately 6-8 weeks after Cycle 6 (cycle = 21 days), or at early treatment discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Serum Concentration (Cmax) of Mosunetuzumab |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Minimum Serum Concentration (Cmin) of Mosunetuzumab |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Area Under the Curve (AUC) of Mosunetuzumab |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Clearance (CL) of Mosunetuzumab |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Volume of Distribution at Steady State (Vss) of Mosunetuzumab |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Maximum Plasma Concentration (Cmax) of Polatuzumab Vedotin |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Minimum Plasma Concentration (Cmin) of Polatuzumab Vedotin |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| AUC of Polatuzumab Vedotin |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| CL of Polatuzumab Vedotin |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Vss of Polatuzumab Vedotin |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Best Objective Response Rate (ORR), Defined as Complete Response (CR) or Partial Response (PR) at any Time on Study Based on PET-CT and/or CT scan as Assessed According to Lugano 2014 Response Criteria |  | Baseline through 2 years after partial response assessment (PRA) (up to a total of approximately 2.5 years) | 
| Duration of Response (DOR) |  | From the first occurrence of a response to disease progression, relapse, or death, whichever comes first (up to approximately 2.5 years) | 
| Anti-Drug Antibodies (ADAs) to Mosunetuzumab |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| ADAs to Polatuzumab Vedotin |  | At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days) | 
| Progression-Free Survival (PFS) |  | From randomization to the first occurrence of disease progression, relapse, or death from any cause, whichever occurs first (up to approximately 2.5 years) | 
| PFS at 1 Year |  | Randomization to 1 Year | 
| Event-Free Survival (EFS) |  | From randomization to the first occurrence of disease progression or relapse, initiation of new anti-lymphoma therapy (NALT), or death from any cause, whichever occurs first (up to approximately 2.5 years) | 
| Time to Deterioration in the European Organization for Research and Treatment of Cancer Quality of Life - Core 30 Questionnaire (EORTC QLQ-C30) Physical Functioning and Fatigue |  | From baseline through follow-up (up to approximately 2.5 years) | 
| Time to Deterioration in the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale |  | From baseline through follow-up (up to approximately 2.5 years) |