Tazemetostat and Mosunetuzumab in Untreated Follicular Lymphoma

Study Overview
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Brief Summary
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The goal of this study is to learn about the safety and effectiveness of the combination of tazemetostat pills in combination with mosunetuzumab injections for people with follicular lymphoma who haven't received treatment before. The investigators hypothesize that tazemetostat with mosunetuzumab has the potential to increase the efficacy of the product without compromising the safety. Tazemetostat is a drug that inhibits EZH2, an enzyme known to drive the development of B-cell lymphomas, and inhibiting it appears to have many effects that slow down lymphoma growth and enhance the immune system's ability to fight it. Tazemetostat is FDA-approved in previously treated follicular lymphoma and currently undergoing study in other lymphomas. Mosunetuzumab is a bispecific antibody therapy that is a therapeutic strategy that uses the immune system to fight lymphoma, called immunotherapy. Bispecific antibodies have two ends: one attaches to T cells in the immune system and the other attaches to lymphoma cells, helping guide our immune system to attack the cancer. Mosunetuzumab has been studied in follicular lymphoma that has previously been treated, with positive results. Mosunetuzumab is approved by the FDA to be given intravenously (directly into a vein) but is not yet approved by the FDA is not yet approved as an injection under the skin, which is how it is given in this study. They have not yet been studied in combination.

Detailed Description
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This is a phase II, open-label study. Fifty patients with previously untreated follicular lymphoma will be enrolled and treated with standard dosing of subcutaneous mosunetuzumab, and with oral tazemetostat by mouth twice daily at standard dosing (800 mg twice daily) beginning at the same time as mosunetuzumab initiation. Mosunetuzumab and tazemetostat will be given in 28-day cycles for up to 12 cycles. Response assessments by PET/CT will occur at 12 weeks post-mosunetuzumab and again at 30 and 48 weeks for those with an ongoing response to treatment. Treatment with steroids, tocilizumab, growth factors, tumor lysis prophylaxis, and antibiotics may be used as per standard of care at our institution. Dose modifications are permitted for toxicity. There will be a follow-up visit after 2 years from starting the study.

Official Title
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A Phase II Trial of Tazemetostat Plus Mosunetuzumab in Untreated Follicular Lymphoma

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Drug: Mosunetuzumab
* Drug: Tazemetostat Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to comply with the study protocol Willing to use highly effective contraception, if of childbearing potential Diagnosed with follicular lymphoma (FL; Grades 1-3a) Received no prior systemic lymphoma therapy (local radiotherapy is not considered systemic therapy) Exclusion Criteria: Inability to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat Grade 3b FL History of transformation of indolent disease to diffuse large B cell lymphoma Any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN) Any prior history of T cell lymphoblastic lymphoma (T-LBL)/ T cell lymphoblastic leukemia (T-ALL) Active or history of central nervous system lymphoma or leptomeningeal infiltration Prior standard or investigational systemic anti cancer therapy for lymphoma. Patients who have received prior XRT will not be excluded History of solid organ transplantation History of severe allergic or anaphylactic reaction to humanized, chimeric or murine monoclonal antibodies (MAbs) Known or suspected chronic active Epstein-Barr virus (EBV) infection Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis Active Hepatitis B or Hepatitis C infection HIV positive with CD4 count <200 and not currently taking antiretroviral therapy History of progressive multifocal leukoencephalopathy (PML) 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 Prior allogeneic stem cell transplant (SCT) 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) Major surgery 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 Active central nervous system disease or underlying neurologic disease such as stroke or intracranial hemorrhage within 3 months prior to enrollment, history of seizure disorder, or history of neurogenerative disease History of pneumonitis or interstitial lung disease Pregnant or breastfeeding or intending to become pregnant during the study

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: Subcutaneous Mosunetuzumab and Oral Tazemetostat<br>50 patients will be enrolled and treated with standard dosing of subcutaneous mosunetuzumab, and with oral tazemetostat by mouth twice daily at standard dosing (800 mg twice daily) beginning at the same time as mosunetuzumab initiation. | Drug: Mosunetuzumab<br>* Mosunetuzumab will be administered in weekly dose increments (step-up dosing) during Cycle 1 and then on Day 1 of each cycle. Mosunetuzumab will be given in 28-day cycles for up to 12 cycles. Mosunetuzumab will be administered SC at the dose of 5 mg on Day 1, 45 mg on Day 8, and 45 mg on Day 15 in Cycle 1. Beginning with Cycle 2, it will be administered SC at the dose of 45 mg on Day 1. Each cycle lasts 4 weeks.<br>Drug: Tazemetostat Pill<br>* Oral tazemetostat will be administered by mouth twice daily at standard dosing (800 mg twice daily) beginning at the same time as mosunetuzumab initiation until disease progression, unacceptable toxicity, or consent is withdrawn. Patients will remain on tazemetostat for up to twelve 28-day cycles from initiation of mosunetuzumab.<br>* Other names: Tazverik;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who achieve a complete response (CR) by completion of therapy, as determined by the Lugano Criteria | The proportion of patients who achieve complete response as per the Lugano criteria will be calculated and their 90% confidences will be computed with Clopper-Pearson method via exact binomial distribution. | Estimated day 336 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who experience cytokine release syndrome (CRS) | CRS will be assessed per American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading | Day 0 to Day 28 | 
| Number of participants who experience Immune effector cell-associated neurotoxicity syndrome (ICANS) | ICANS will be assessed per American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading | Day 0 to Day 28 | 
| Median Progression-Free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death from any cause. Patients will be followed for a maximum of approximately 10 years from the start of treatment. | For a maximum of approximately 10 years | 
| Median Overall Survival (OS) | OS is defined as the duration of time from start of treatment to death from any cause. Patients will be followed for a maximum of approximately 10 years from the start of treatment. | For a maximum of approximately 10 years | 
| Objective Response Rate (ORR) at the time of therapy completion, as defined by Lugano Criteria | ORR is defined as the proportion of patients who have a partial or complete response to therapy | Estimated to be day 336 | 
| Number of participants who achieve a Complete Response (CR) per Lugano's Criteria | Response and progression are evaluated according to the Lugano criteria for lymphoma response. | For a maximum of approximately 10 years | 
| Median Duration of Response | The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease or death due to any cause, whichever occurs first is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). | For a maximum of approximately 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mosunetuzumab, Follicular Lymphoma, Tazemetostat