Mosunetuzumab Consolidation Therapy After autoSCT in r/r Aggressive B Cell Lymphoma

Study Overview
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Brief Summary
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This phase 1 pilot study examines the feasibility and safety of mosunetuzumab after autologous stem cell transplant for patients with aggressive B cell lymphomas. Mosunetuzumab is an antibody that has been engineered to attach to two target cells in the immune system: T cells that normally perform tasks like killing virus-infected cells, and cancerous B cells. Mosunetuzumab has been designed to direct these T cells to kill the cancerous B cells instead.

Official Title
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A Pilot Study Evaluating the Safety and Efficacy of Mosunetuzumab Consolidation Therapy After Autologous Stem Cell Transplantation in Patients With Relapsed/Refractory Aggressive B Cell Lymphoma

Conditions
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B Cell Lymphoma, Aggressive Lymphoma, Diffuse Large B Cell Lymphoma, High-grade B-cell Lymphoma, Transformed Lymphoma, Follicular Lymphoma Grade 3

Intervention / Treatment
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* Drug: Mosunetuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Initial Screening (pre-autoSCT): Diagnosis of rCD20+ diffuse large B cell lymphoma, high-grade B cell lymphoma, transformed B cell lymphoma, or follicular lymphoma grade 3B. Planning to undergo autologous stem cell transplantation after two or more prior lines of therapy for lymphoma, including treatment for prior/underlying indolent B-NHL. At least 18 years of age. ECOG performance status ≤ 2 Adequate hematologic function (unless attributed to underlying lymphoma per the investigator; see below), defined as follows: Absolute neutrophil count ≥ 1,000/mcL without G-CSF use in past 7 days Platelets ≥ 75,000/mcL without TPO mimetic use in past 7 days Hemoglobin ≥ 8 g/dL without red blood cell transfusion in past 7 days Patients with extensive bone marrow involvement by lymphoma and/or disease-related cytopenias (e.g., immune thrombocytopenia) may be enrolled if the following criteria are met: Absolute neutrophil count ≥ 500/mcL and without G-CSF use in past 7 days Platelet count ≥ 50,000/mcL without transfusion in past 14 days and without TPO mimetic use in past 7 days No red blood cell transfusion in past 7 days Normal laboratory values: Serum total bilirubin ≤ 1.5 x IULN (or ≤ 3 x IULN for patients with Gilbert syndrome) AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN Measured or estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault The effects of mosunetuzumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study treatment, and for 3 months following the final dose of mosunetuzumab. Specifically, women must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the treatment period and for 3 months after the final dose of mosunetuzumab as applicable. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol with a female partner of childbearing potential or pregnant female partner must also agree to use adequate contraception prior to the study, for the duration of study treatment, and for 3 months following the final dose of mosunetuzumab. Ability to understand and willingness to sign an IRB approved written informed consent document. Exclusion Criteria for Initial Screening (pre-autoSCT): Chemotherapy-resistant (stable or progressive disease) lymphoma at pre-autoSCT response assessment to salvage therapy. Known history of grade 3+ treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents. Known history of macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH). Current or recent history (within the last 6 months) of clinically relevant CNS disease or pathology, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Prior allogeneic stem cell transplant. History of solid organ transplantation. History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine monoclonal antibodies (mAbs). Known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of the mosunetuzumab, including mannitol. History of erythema multiforme, grade ≥ 3 rash, or blistering following prior treatment with immunomodulatory derivatives. Known or suspected chronic active Epstein-Barr virus (EBV) infection. Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis. Active hepatitis B infection: Patients who are hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (Anti-HBc) positive, must be negative for hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible for study participation. Active hepatitis C infection: Patients who are positive for hepatitis C virus (HCV) antibody must be negative for HCV by PCR to be eligible for study participation. Known history of human immunodeficiency virus (HIV) positive status. History of progressive multifocal leukoencephalopathy (PML). Other malignancy that could affect compliance with the protocol or interpretation of results, with the exception of the following: Any of the following malignancies previously curatively treated: carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the breast, basal, or squamous cell skin cancer. Stage I melanoma, low grade, early stage localized prostate cancer, or any other previously treated malignancy that has been in remission without treatment for ≥ 2 years prior to enrollment. Active autoimmune disease requiring treatment. History of autoimmune disease, including, but not limited to: myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis: Patients with a remote history of, or well-controlled autoimmune disease, with a treatment free interval from immunosuppressive therapy for 12 months may be eligible to enroll if judged to be safe by the investigator. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. Patients with a history of disease-related immune thrombocytopenic purpura or autoimmune hemolytic anemia may be eligible. Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including but not limited to, significant cardiovascular disease (e.g., New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) or significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm). Pregnant or lactating or intending to become pregnant during the study: Women of childbearing potential must have one negative serum pregnancy test result (minimum sensitivity, 25 mIU/mL) within seven days of enrollment. Exclusion Criteria for Rescreening (post-autoSCT): At time of rescreening, the patient must continue to fulfill the above criteria. Additionally, if any of the additional criteria below are met, the patient will be considered ineligible and will not be able to participate in the study. Clinical evidence of progressive lymphoma. Clinically significant toxicity (other than alopecia) from prior treatment that has not resolved to grade ≤ 1 per NCI CTCAE v 5.0 prior to Day 1 of Cycle 1. Treatment with systemic immunosuppressive medications, including but not limited to prednisone (>20 mg), azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents within 2 weeks prior to Day 1 of Cycle 1. Note: The use of inhaled corticosteroids, mineralocorticoids for management of orthostatic hypotension, and single-dose dexamethasone for nausea or B symptoms is permitted. Known active bacterial, viral, fungal, or other infection, or any major episode of infection requiring treatment with IV antibiotics within 1 week of Day 1 of Cycle 1. Administration of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study. Patients must not receive live, attenuated vaccines (e.g., FluMist®) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges. Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1 Day 1 or anticipation of a major surgical procedure during the course of the study. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results.

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: Consolidation Mosunetuzumab<br>Mosunetuzumab is a CD3xCD20 bispecific antibody administered intravenously in the consolidation setting after autologous stem cell transplant (autoSCT). Mosunetuzumab will be given in a step-up dosing schedule beginning on Day 49 after autoSCT on C1D1, C1D8, C1D15, and then Day 1 of all cycles thereafter. Patients will undergo PET-CT restaging around Day 100 post-autoSCT (approximately Cycle 3) and patients in complete response will continue mosunetuzumab for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients not in complete response will discontinue treatment and enter follow-up. All cycles are planned to be 21 days. | Drug: Mosunetuzumab<br>* Mosunetuzumab is administered intravenously in a step-up dosing strategy. The doses will be 1 mg on C1D1, 2 mg on C1D8, 60 mg on C1D15, 60 mg on C2D1, and 30 mg for all doses following.<br>* Other names: BTCT4465A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequencies and grades of treatment-emergent adverse events (TEAEs) | Treatment-emergent adverse events (TEAE) are defined as adverse events possibly, probably, or definitely related to mosunetuzumab that occur on or after first dose of study treatment. | Evaluated from start of study treatment through 30 days after last dose of mosunetuzumab, study discontinuation/termination, or until initiation of alternate treatment for lymphoma, whichever occurs earlier (estimated to be 1 year and 30 days). | 
| Rate of treatment discontinuation due to treatment-emergent adverse events (TEAEs) | Treatment-emergent adverse events (TEAE) are defined as adverse events possibly, probably, or definitely related to mosunetuzumab that occur on or after first dose of study treatment. | Evaluated from start of study treatment through 30 days after last dose of mosunetuzumab, study discontinuation/termination, or until initiation of alternate treatment for lymphoma, whichever occurs earlier (estimated to be 1 year and 30 days). | 
| Percentage of consented and enrolled patients completing at least 2 cycles of mosunetuzumab consolidation | Patients are consented and enrolled prior to autoSCT, and given the long delay from consent to treatment, this will allow evaluation of feasibility of this approach. | Evaluated from time of consent to completion of cycle 2 (each cycle is 21 days) of mosunetuzumab (estimated to be 13 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Progression-free survival (PFS) is defined as the time from day zero of autologous stem cell transplantation to the first occurrence of disease progression as determined by the investigator with use of the Lugano Response Criteria or death from any cause. | At 1 year post-autoSCT (estimated to be 1 year and 7 weeks). | 
| Progression-free survival (PFS) | Progression-free survival (PFS) is defined as the time from day zero of autologous stem cell transplantation to the first occurrence of disease progression as determined by the investigator with use of the Lugano Response Criteria or death from any cause. | At 2 years post-autoSCT (estimated to be 2 years and 7 weeks). | 
| Progression-free survival (PFS) | Progression-free survival (PFS) is defined as the time from day zero of autologous stem cell transplantation to the first occurrence of disease progression as determined by the investigator with use of the Lugano Response Criteria or death from any cause. | At 3 years post-autoSCT (estimated to be 3 years and 7 weeks). | 
| Overall survival (OS) | Overall survival (OS) is defined as the time from day zero of autologous stem cell transplantation to death from any cause. | At 1 year post-autoSCT (estimated to be 1 year and 7 weeks). | 
| Overall survival (OS) | Overall survival (OS) is defined as the time from day zero of autologous stem cell transplantation to death from any cause. | At 2 years post-autoSCT (estimated to be 2 years and 7 weeks). | 
| Overall survival (OS) | Overall survival (OS) is defined as the time from day zero of autologous stem cell transplantation to death from any cause. | At 3 years post-autoSCT (estimated to be 3 years and 7 weeks). | 
| Percentage of patients requiring any tocilizumab doses for management of cytokine release syndrome (CRS) | Tocilizumab is recommended for treatment of grade 2 CRS and required for grade 3 or 4 CRS. Tocilizumab should be administered by IV infusion for a maximum of 4 doses. | Up to approximately 58 weeks and 3 days | 
| Number of tocilizumab doses per patient for management of cytokine release syndrome (CRS) | Tocilizumab is recommended for treatment of grade 2 CRS and required for grade 3 or 4 CRS. Tocilizumab should be administered by IV infusion for a maximum of 4 doses. | Up to approximately 58 weeks and 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aggressive B cell lymphoma, consolidation post stem cell transplant, DLBCL, transformed B cell lymphoma, follicular lymphoma grade 3B