Testing the Combination of Anti-cancer Drugs Mosunetuzumab, Polatuzumab Vedotin, and Lenalidomide for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma

A Phase 1 Study of Mosunetuzumab With Polatuzumab Vedotin and Lenalidomide (M+Pola+Len) in Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

This phase I trial studies the side effects and best dose of mosunetuzumab when given together with polatuzumab vedotin and lenalidomide in treating patients with diffuse large B-cell lymphoma (DLBCL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Mosunetuzumab and polatuzumab vedotin are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. Polatuzumab, linked to a toxic agent called vedotin, attaches to CD79B positive cancer cells in a targeted way and delivers vedotin to kill them. Lenalidomide may stimulate or suppress the immune system in different ways and stop cancer cells from growing and by preventing the growth of new blood vessels that cancer cells need to grow. Giving mosunetuzumab with polatuzumab vedotin and lenalidomide may work better in treating patients with relapsed/refractory DLBCL.

Study Overview

• Status: Recruiting
• Conditions: High Grade B-Cell Lymphoma; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Transformed Indolent B-Cell Non-Hodgkin Lymphoma to Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Procedure: Biospecimen Collection; Drug: Lenalidomide; Procedure: Computed Tomography; Procedure: Positron Emission Tomography; Drug: Polatuzumab Vedotin; Biological: Mosunetuzumab

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the safety and tolerability of mosunetuzumab + polatuzumab vedotin + lenalidomide in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL).

SECONDARY OBJECTIVE:

I. To observe and record anti-tumor activity of the combination of mosunetuzumab, polatuzumab vedotin, and lenalidomide in R/R DLBCL.

EXPLORATORY OBJECTIVES:

I. To assess the efficacy in patients that have failed prior polatuzumab vedotin containing regimens (i.e., patients who progressed/relapsed after prior polatuzumab).

II. To assess anti-tumor activity in patients that a) have ≥ Deauville score of 3 within the first 90 days after standard of care chimeric antigen receptor (CAR) T-cell therapy; b) other patients who have failed prior treatment (e.g. relapse after Day 90 from CAR-T, or relapsed after other therapies and were not considered candidates for CAR-T).

III. To identify biomarkers that can predict the response to mosunetuzumab + polatuzumab vedotin + lenalidomide.

IV. To describe anti-tumor activity in patients whose tumors have previously failed to respond to polatuzumab (i.e., patients who progressed/relapsed after prior polatuzumab).

OUTLINE: This is a dose-escalation study of mosunetuzumab, followed by a dose-expansion study.

Patients receive mosunetuzumab intravenously (IV) over 2-4 hours on days 1, 8, and 15 of cycle 1 and then day 1 of each subsequent cycle. Cycles repeat every 28 days for 8 cycles in patients who achieve a complete response (CR) or up to 17 cycles for patients with a partial response (PR) or stable disease (SD) in the absence of disease progression or unacceptable toxicity. Patients also receive polatuzumab vedotin IV over 30-90 minutes on day 1 of each cycle and lenalidomide orally (PO) on days 1-21 of each cycle. Cycles of polatuzumab vedotin repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Cycles of lenalidomide repeat every 28 days for 8 cycles in patients who achieve CR, or up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo positron emission tomography (PET)/ computed tomography (CT) and blood sample collection throughout the study.

After completion of study treatment, patients are followed up every 3-6 months for 2 years.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Comprehensive Cancer Center
      • Contact: Site Public Contact; Phone Number: 800-826-4673; Email: becomingapatient@coh.org
      • Principal Investigator: Geoffrey Shouse
    • Sacramento, California, United States, 95817
      • Recruiting
      • University of California Davis Comprehensive Cancer Center
      • Contact: Site Public Contact; Phone Number: 916-734-3089
      • Principal Investigator: Joseph M. Tuscano
  • Florida
    • Tampa, Florida, United States, 33612
      • Suspended
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
      • Contact: Site Public Contact; Phone Number: 312-695-1301; Email: cancer@northwestern.edu
      • Principal Investigator: Reem Karmali
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Wake Forest University Health Sciences
      • Principal Investigator: Rakhee Vaidya
      • Contact: Site Public Contact; Phone Number: 336-713-6771
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Case Western Reserve University
      • Contact: Site Public Contact; Phone Number: 800-641-2422; Email: CTUReferral@UHhospitals.org
      • Principal Investigator: Changchun Deng
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma Health Sciences Center
      • Principal Investigator: Sami Ibrahimi
      • Contact: Site Public Contact; Phone Number: 405-271-8777; Email: ou-clinical-trials@ouhsc.edu
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Recruiting
      • University of Virginia Cancer Center
      • Principal Investigator: Emily Ayers
      • Contact: Site Public Contact; Phone Number: 434-243-6303; Email: uvacancertrials@hscmail.mcc.virginia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically confirmed DLBCL NOS, high-grade B-cell lymphoma, or transformed indolent lymphoma as per the World Health Organization 2022 criteria
• All patients will have relapsed/refractory DLBCL after 1 or more prior lines of therapy with the exception of patients receiving CAR T in second line that have a D score of 3 at day (D)+ 30 through D+ 90
• Patients who progressed/relapsed after prior polatuzumab vedotin are allowed
• For the expansion cohorts only: cohort A must have Deauville score of ≥ 3 with the first 90 days) after standard of care chimeric antigen receptor (CAR) T-cell therapy; cohort B- other patients with relapsed/refractory after 1 or more prior lines of therapy (e.g. relapse after Day 90 from CAR-T, or relapsed after other therapies and were not considered candidates for CAR-T)
• All patients that have failed 1 line of therapy will be eligible with the exception of a 12 patient cohort (A) that will require prior CAR T therapy
• Measurable disease by CT or PET scan, with one or more sites of disease >= 1.5 cm in longest dimension

• Age >= 18 years

  • Because no dosing or adverse event data are currently available on the use of mosunetuzumab in combination with polatuzumab vedotin, and lenalidomide in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy >= 12 weeks
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 50,000/mcL without transfusion for 2 weeks prior to cycle 1 day 1 (C1D1)
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 × institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 × ULN may be enrolled)
• Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 3 × ULN (AST and/or ALT =< 5 × ULN for patients with liver involvement)
• Alkaline phosphatase =< 2.5 × ULN (=< 5 × ULN for patients with documented liver involvement or bone metastases)
• Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault: (140- age) × (weight in kg) × (0.85 if female) 72 × (serum creatinine in mg/dL)
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 × ULN (This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose.)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible if follow-up brain imaging 6-8 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression or CNS lymphoma
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs, as defined below:

  • 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, 3 months after the final dose of polatuzumab vedotin, and 1 month after the last dose of lenalidomide
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
  • With female partners of childbearing potential, men must remain abstinent or use a condom during the treatment period, 5 months after the final dose of polatuzumab vedotin, and 1 month after the last dose of lenalidomide
• Some concurrent cancer therapeutics (e.g., prostate, breast hormonal-based therapy) are allowed
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
• Agree to comply with all local requirements of the lenalidomide risk minimization plan

Exclusion Criteria:

• Plasmablastic lymphoma, primary mediastinal B-cell lymphoma, gray zone lymphoma
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Patients who are receiving any other investigational agents or treatments
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to mosunetuzumab or other agents used in study
• Patients with uncontrolled intercurrent illness
• Uncontrolled or known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to first study treatment administration
• Active CNS involvement or detectable disease by lymphoma, including leptomeningeal involvement
• Pregnant women are excluded from this study because mosunetuzumab is bispecific antibody with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with mosunetuzumab, breastfeeding should be discontinued if the mother is treated with mosunetuzumab. These potential risks may also apply to other agents used in this study. Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of mosunetuzumab, 3 months after the final dose of polatuzumab vedotin, and 1 month after the final dose of lenalidomide
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2 or better
• Known or suspected chronic active Epstein-Barr virus (EBV) infection

• Patients with any other significant condition(s) that would make this protocol unreasonably hazardous

  • Current > grade 1 peripheral neuropathy
  • Prior solid organ transplantation
  • Patients with known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
  • Patients with history of confirmed progressive multifocal leukoencephalopathy (PML)

  • Currently active or uncontrolled autoimmune disease

    • Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be 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, autoimmune hemolytic anemia, or other stable autoimmune diseases may be eligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (mosunetuzumab, polatuzumab vedotin, lenalidomide); Patients receive mosunetuzumab IV over 2-4 hours on days 1, 8, and 15 of cycle 1 and then day 1 of each subsequent cycle. Cycles repeat every 28 days for 8 cycles in patients who achieve a CR or up to 17 cycles for patients with a PR or SD in the absence of disease progression or unacceptable toxicity. Patients also receive polatuzumab vedotin IV over 30-90 minutes on day 1 of each cycle and lenalidomide PO on days 1-21 of each cycle. Cycles of polatuzumab vedotin repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Cycles of lenalidomide repeat every 28 days for 8 cycles in patients who achieve CR, or up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET/CT and blood sample collection throughout the study.

Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Drug: Lenalidomide; Given PO; Other Names: CC-5013; Revlimid; CC5013; CDC 501; CC 5013; Procedure: Computed Tomography; Undergo PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Polatuzumab Vedotin; Given IV; Other Names: DCDS4501A; ADC DCDS4501A; Antibody-Drug Conjugate DCDS4501A; FCU 2711; polatuzumab vedotin-piiq; Polivy; RG7596; Ro 5541077-000; FCU-2711; FCU2711; RG 7596; RG-7596; Biological: Mosunetuzumab; Given IV; Other Names: RO7030816; BTCT4465A; Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody BTCT4465A; BTCT 4465A; BTCT-4465A; CD20/CD3 BiMAb BTCT4465A; RG 7828; RG-7828; RG7828; Lunsumio; Mosunetuzumab-axgb

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of monsunetuzumab+polatuzumab vedotin+lenalidomide for determination of recommended phase 2 dose	Dose limiting toxicity will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.	During cycle 1 (cycle=28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Will be assessed per the Lugano 2014 criteria.	Up to 2 years
Complete response rate	Will be assessed per the Lugano 2014 criteria.	Up to 2 years
Progression free survival	Will be assessed per the Lugano 2014 criteria.	Up to 2 years
Duration of response	Will be assessed per the Lugano 2014 criteria.	From time of initial response assessment demonstrating at least partial response until disease response assessment that demonstrates progressive disease, assessed up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD79b expression levels	Will be assessed via ribonucleic acid and immunohistochemistry assessment and correlation with response.	At baseline
Frequency of CD4 T-cells and IFN-gamma+ producing CD4 T-cells	Will be assessed via intracellular flow cytometry.	At baseline and up to 2 years
Ultrasensitive determination of cytokine profile	Will be assessed with Luminex assay to identify biomarkers that might predict a response.	At baseline and up to 2 years
Efficacy in relapsed/refractory double-expresser lymphoma and double-hit lymphoma		Up to 2 years
Efficacy post chimeric antigen receptor (CAR) T-cell therapy		Up to 2 years
Efficacy post polatuzumab vedotin		Up to 2 years
Percent of patients able to start the triplet therapy		At cycle 2 (cycle=28 days)
CAR T-cell immunophenotypes		Up to 2 years
Chimeric antigen receptor (CAR) T-cell expansion and persistence		Up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Joseph M Tuscano, City of Hope Comprehensive Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: August 26, 2023
• First Submitted That Met QC Criteria: August 26, 2023
• First Posted (Actual): August 29, 2023

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, Large B-Cell, Diffuse; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Carboxylic Acids; Piperidines; Chemistry Techniques, Analytical; Spectrum Analysis; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Isoindoles; Lenalidomide; Specimen Handling; Magnetic Resonance Spectroscopy; polatuzumab vedotin
• Other Study ID Numbers: NCI-2023-06477 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10601 (Other Identifier: CTEP); UM1CA186717 (U.S. NIH Grant/Contract); PHI-141

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No