MARSUN: Phase III, Multicenter, Open label, Randomized, Controlled Study Investigating Mosunetuzumab-Lenalidomide versus investigator choices in Patients with Relapsed or Refractory Marginal Zone Lymphoma
- Trial ID
- 2022-501810-77-00
- Protocol
- MARSUN
- Sponsor
- Lysarc
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of the combination of mosunetuzumab and lenalidomide compared to treatments chosen by the investigator in patients with **relapsed or refractory marginal zone lymphoma**. The primary efficacy endpoint is **Progression-Free Survival (PFS)** as determined by the investigator, following the Lugano criteria 2014. This is clinically relevant as PFS is a critical measure of how effectively a treatment can delay disease progression, which is vital for improving patient outcomes in this challenging condition.
Secondary objectives include:
- Comparison of complete response at 24 months (CR24) between mosunetuzumab-lenalidomide and investigator choices, as determined by the investigator and by blinded central review based on PET results, according to Lugano criteria 2014.
- Assessment of overall response rate (ORR) and complete response (CR) other than CR24, as determined by both the investigator and blinded central review.
- Evaluation of duration of response (DOR), event-free survival (EFS), and time to next anti-lymphoma treatment (TTNLT).
- Determination of histological transformation rate.
- Safety assessment, including incidence and severity of adverse events (AE), serious adverse events (SAE), cytokine release syndrome (CRS), and study-drug-related events, as well as treatment tolerability.
- Measurement of health-related quality of life using the EQ-5D-5L questionnaire.
Participants
The clinical trial focuses on participants diagnosed with **Relapsed or Refractory Marginal Zone Lymphoma** (MZL), including extranodal, splenic, and nodal subtypes. The study population comprises both male and female subjects, aged 18 years and older, who are capable of complying with the study protocol and procedures. Participants must have a symptomatic disease requiring systemic treatment and an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or less. The trial includes individuals who have been treated with at least one prior systemic treatment but not more than three prior lines, with previous treatments including a drug targeting CD20. The trial population selection criteria ensure that participants have measurable disease and adequate hematopoietic function, among other health parameters. The sponsor has not provided the total number of participants involved in the study. Participants' lifestyle considerations, such as diet and physical activity, are not specified. The trial includes a vulnerable population, and both genders are represented in the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled study to evaluate the efficacy of **mosunetuzumab** combined with **lenalidomide** compared to investigator-chosen treatments in patients with **relapsed or refractory marginal zone lymphoma**. The trial is open-label and multicenter, with a primary endpoint of progression-free survival as determined by the investigator using the Lugano criteria 2014. The study is expected to run from September 2023 to September 2032, with participant involvement lasting up to 140 days, depending on the treatment arm and individual response.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as measurable disease and adequate hematopoietic function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as imaging scans and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may occur due to disease progression, unacceptable toxicity, or withdrawal of consent.
The trial includes several secondary endpoints, such as complete response rate at 24 months, overall response rate, and overall survival. Participants will be monitored for these outcomes throughout the study duration. Conditions that may lead to early termination from the study include adverse events, non-compliance with the study protocol, or the investigator's decision based on the participant's best interest. The study aims to provide comprehensive data on the efficacy and safety of the treatment regimen, contributing to the understanding of therapeutic options for this patient population.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their efficacy in patients with **Marginal Zone Lymphoma**. The primary experimental medication is **Mosunetuzumab**, a cancer medicine classified as a CD20xCD3 T-cell engaging bispecific antibody. It is provided as a solution for injection and administered via subcutaneous injection. The maximum daily dose is 45 mg, with a total maximum dose of 585 mg over a treatment period of 12 weeks. Participant compliance is monitored through regular assessments and adherence checks.
Another experimental treatment is **Lenalidomide**, an anticancer medicine categorized as an antineoplastic agent. It is available in the form of hard capsules for oral use. The maximum daily dose is 20 mg, with a total maximum dose of 2800 mg over a treatment period of 140 days. The blisters are removed from the original packaging and labeled with Roche standard IMP labels to ensure proper identification and compliance monitoring.
**Cyclophosphamide** is used as a comparator treatment in the study. It is an anticancer medicine classified as an alkylant agent, provided as a solution for injection. The administration route is intravenous, with a maximum daily dose of 750 mg/m² and a total maximum dose of 4500 mg/m² over a 6-week treatment period.
**Bendamustine Hydrochloride** is another comparator treatment, categorized as an alkylant antineoplastic agent. It is supplied as a powder for concentrate for solution for infusion and administered via intravenous infusion. The maximum daily dose is 90 mg/m², with a total maximum dose of 1080 mg/m² over a 6-week treatment period.
**Vincristine Sulfate** is included as a chemotherapeutic treatment, provided as a solution for injection. It is administered intravenously, with a maximum daily dose of 2 mg and a total maximum dose of 12 mg over a 6-week treatment period.
**Tocilizumab** is used as an auxiliary treatment, classified as a recombinant humanized, anti-human monoclonal antibody for the treatment of cytokine release syndrome (CRS). It is provided as a solution for infusion and administered via intravenous infusion. The maximum daily dose is 800 mg, with a total maximum dose of 2400 mg over a 1-day treatment period.
**Prednisone** is used as a glucocorticoid anti-inflammatory treatment, provided in tablet form for oral administration. The maximum daily dose is 40 mg/m², with a total maximum dose of 1200 mg/m² over a 6-week treatment period.
**Rituximab** is included as an antineoplastic monoclonal antibody, provided as a solution for injection and administered via subcutaneous injection. The maximum daily dose is 1400 mg, with a total maximum dose of 15400 mg over a 10-week treatment period.
**Doxorubicin Hydrochloride** is used as an anticancer medicine, provided as a solution for infusion and administered intravenously. The maximum daily dose is 50 mg/m², with a total maximum dose of 300 mg/m² over a 6-week treatment period.
Participant compliance is monitored through regular assessments, and adherence to dosing schedules is ensured through detailed tracking and documentation. The study aims to compare the efficacy of these treatments, with the primary endpoint being progression-free survival as determined by the investigator using the Lugano criteria 2014.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**, as determined by the investigator using the Lugano criteria 2014. This primary endpoint will evaluate the time from randomization to disease progression or death from any cause. Secondary efficacy endpoints include the Complete Response Rate at 24 months (CR24), Overall Response Rate (ORR), Overall Survival (OS), Duration of Response (DOR), Event-Free Survival (EFS), Time to Next Anti-Lymphoma Treatment (TTNLT), and Histological Transformation Rate. These endpoints will be analyzed on the Intent-to-Treat (ITT) set.
The CR24 is defined as the percentage of complete responses among all patients, with non-responders being those without a response assessment. The ORR includes both complete and partial responses. OS is measured from the date of randomization to death from any cause, with living patients censored at their last contact. DOR is the time from the first documented objective response to progression, relapse, or death, with censoring at the last visit for patients without progression or death. EFS considers the time to death, disease progression, relapse, early treatment discontinuation, or new anti-lymphoma treatment, with censoring at the last visit for patients without events. TTNLT measures the time to the first new anti-lymphoma treatment, with censoring for patients alive without such treatment. The Histological Transformation Rate is the percentage of transformation to diffuse large B-cell lymphoma among all patients.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Have a biopsy proven diagnosis of MZL, extranodal (EMZL) or nodal (NMZL) Or have a diagnosis of splenic MZL (SMZL) based on mandatory 13 flow cytometry markers: surface immunoglobulins (SmIg), CD5, CD23, FMC7, CD22 or CD79b, CD200, CD180, CD20, CD43, CD11c, CD10, CD103 and CD123 and validated by a centralized review). In case of large dissemination, disseminated MZL (as evaluated by investigator; please contact the Sponsor to discuss any doubt) will be included as DMZL and included in NMZL subtype. Participants with high tumor burden criteria are eligible. Patients with borderline or related entities, such as splenic diffuse red pulp lymphoma (SDRPL), typical hairy cell leukemia (HCL), and HCL variant (HCLv), are not eligible.”
- Measurable disease in at least two perpendicular dimensions on an imaging scan is defined as: lymph node or nodal mass bi-dimensional measurement with ≥ 15 mm in longest transverse diameter or the short diameter must measure ≥ 10 mm regardless of the longest transverse diameter. Spleen is considered as a measurable disease if vertical axis is higher than 13 cm.
- Adequate hematopoietic function at screening as follows unless cytopenia is clearly due to marrow involvement of MZL or hypersplenism or autoimmune thrombocytopenia: 11.1. Platelet count ≥ 75 G/L; in cases of thrombocytopenia clearly due to marrow involvement of MZL or hypersplenism or auto-immune thrombocytopenia, platelet count should be ≥ 30 G/L Washout platelet transfusion is 7 days between transfusion and D1 of starting treatment 11.2. ANC ≥ 1 G/L unless neutropenia is clearly due to marrow involvement of MZL or hypersplenism. G-CSF is not allowed within 7 days before screening 11.3. Total hemoglobin ≥ 8 g/dL unless anemia is clearly due to marrow involvement of MZL or hypersplenism or autoimmune hemolytic anemia. Washout erythrocyte transfusion is 7 days between transfusion and D1 of starting treatment
- Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN) (or ≤3 x ULN for patients with Gilbert syndrome),
- AST or ALT ≤ 2.5 x ULN, unless directly attributable to the patient’s MZL
- Measured or estimated creatinine clearance ≥ 40 mL/min by institutional standard method
- Patients who are hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (HBcAb) positive, must be negative for hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible for study participation. Patients who are hepatitis B surface antigen (HBsAg) negative, hepatitis B surface antibody (anti-HBsAb) positive and hepatitis B core antibody (HBcAb) negative are eligible.
- Contraception: 16.1 For women of childbearing potential (WOCBP) (refer to section 14.6.1): LYSARC MARSUN EUCT#: 2022-501810-77-00 Confidential, do not disclose without prior agreement Protocol version 12.0 dated 15/07/2025 EN-SOP-PM-11-Temp-01-protocol template-v8.0 effective date: 24/06/2019 Page 17/180 - must have a negative result for pregnancy test (highly sensitive serum) within 7 days before randomization and within 7 days before initiation of study treatment. - must agree to abstain from becoming pregnant or breastfeeding, and agree to use highly effective contraceptive methods during study participation, and for at least 28 days after the final dose of Lenalidomide (if applicable), 3 months after the final dose of mosunetuzumab and tocilizumab (if applicable), 12 months after the final dose of CHOP (if applicable), 6 months after the final dose of bendamustine (if applicable) and 12 months after the final dose of rituximab (if applicable). 16.2 For men: with a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period (including periods of treatment interruption), and for at least 28 days after the final dose of lenalidomide (if applicable), 2 months after the final dose of tocilizumab (if applicable), 6 months after the final dose of CHOP (if applicable), 3 months after the final dose of bendamustine (if applicable) and 12 months after the final dose of rituximab) (if applicable). Men must also agree to refrain from donating sperm from the first day of treatment until at least 7 days after the final dose of lenalidomide (if applicable), 2 months after the final dose of tocilizumab (if applicable), 6 months after the final dose of CHOP (if applicable), 3 months after the final dose of bendamustine (if applicable), 12 months after the final dose of rituximab (if applicable),
- Patient covered by any social security system (France)
- Patient who understands and speak one of the country official languages
- Have been treated with at least one prior systemic treatment and not more than three prior lines. Previous line must include at least one systemic line with a drug targeting CD20 (monoclonal antibody at least 2 cycles; participants treated with monoclonal antibody monotherapy should have received at least 4 weekly injections) with or without chemotherapy (RCHOP, R-Bendamustine, R-CVP, R-Chlorambucil at least 2 cycles) or targeted treatment such as BTK inhibitors (at least 1 month). Participants previously treated by lenalidomide are eligible if the last administration of lenalidomide is superior to 12 months before C1D1. When randomized in comparator arm, those participants should require R-chemo. Prior local therapy (including surgery, radiotherapy antibiotics for H. pylori-positive gastric lymphoma, and antiviral for hepatitis C virus) is not considered as one line of treatment.
- Signed Informed Consent Form
- Age ≥ 18 years at the time of signing the informed consent form
- Ability to comply with the study protocol and procedures and required hospitalizations, in the investigator’s judgement
- Eastern Cooperative Oncology Group (ECOG) performance score (PS) of ≤ 2
- Have a symptomatic disease requiring a systemic treatment
- Not eligible for a local treatment including radiotherapy or surgery
- Stage I disease of EMZL, SMZL or NMZL may be eligible only if not candidate to local therapy (surgery or radiotherapy).
- LVEF within normal range (i.e. > 50% as evaluated by Transthoracic Echocardiography or > 45% as evaluated by isotopic method (MUGA scan).
Exclusion Criteria
- MZL with histologic transformation to high-grade lymphoma
- History of erythema multiforme, Grade ≥3 rash, or blistering following prior treatment with immunomodulatory derivatives
- History of interstitial lung disease (ILD), drug-induced pneumonitis, and autoimmune pneumonitis
- Participants who have received any of the following treatments prior to study entry: - Treatment with mosunetuzumab or other CD20/CD3-directed bispecific antibodies - Allogeneic stem cell transplant
- Active autoimmune disease requiring treatment
- History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis; except: - 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 or autoimmune hemolytic anemia may be eligible. - 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 after review and discussion with the Medical Monitor.
- Recent major surgery with risk of bleeding within 4 weeks prior to first study treatment administration (C1D1)
- History of solid organ transplantation
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study
- Person deprived of his/her liberty by a judicial or administrative decision
- Person hospitalized without consent
- History of prior malignancy, except for conditions as listed below if participants have recovered from the acute side effects incurred as a result of previous therapy and only with a single occurrence of the following conditions: - Malignancies treated with curative intent and with no known active disease present for ≥2 years before enrollment - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated cervical carcinoma in-situ without evidence of disease - Surgically/adequately treated low grade, early stage I, localized prostate in-situ carcinoma
- Adult person under legal protection
- Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness
- patient unable to receive at least one of the three regimens of the comparator arm (ICT). As in usual practice, physician has to verify the absence of contraindication to the use of the drugs, hypersensitivity, and to take into account the lymphoma history and previous treatment scheme used
- Participants who have received any of the following treatments, whether investigational or approved, within the respective time periods prior to initiation of study treatment: - Radiotherapy within 2 weeks prior to the first dose of study treatment - Autologous stem cell transplant within 100 days prior to first study treatment - Use of monoclonal antibodies within 4 weeks prior to first study treatment - Systemic immunosuppressive medications (including, but not limited to, Cyclophosphamide, Azathioprine, Methotrexate, Thalidomide, and antitumor necrosis factor agents) and corticosteroids on the long run with the following exceptions: inhaled steroids for asthma, topical steroids, or replacement or stress corticosteroids during the study at any time. Participants who require lymphoma symptom control during screening may receive corticosteroid < or = 1mg/kg/day prednisone or equivalent for a maximum of 10 days prior to first dose of study treatment. - Any other anti-cancer investigational therapy within 4 weeks prior to initiation of study treatment.
- Suspicion or clinical evidence of transformed lymphoma at enrollment by investigator assessment (e.g. very high SUV (SUV > 20 or double compared to SUV of other lesions) in at least one lesion that was not biopsied, and discordant with SUV of biopsied lesion, LDH > 2.5 ULN in a context of rapidly progressive disease, etc). Please contact the Coordinating Investigators / Sponsor to discuss such cases or if there is any doubt before considering enrollment.
- Uncontrolled symptomatic pleural or serous effusion requiring urgent treatment within 48 hours (participants with controlled disease after adequate pleural/serous drainage and/or effective pleurX™ or similar system are eligible only if control system is in place before randomization).
- Uncontrolled symptomatic ureterohydronephrosis resulting in renal failure (participants with adequate management i.e. ureteral catheter or double J stent allowing renal failure control are eligible only if control system is in place before randomization).
- Pregnant or breastfeeding or intending to become pregnant during the study or within 28 days after the final dose of lenalidomide, 3 months after the final dose of mosunetuzumab and tocilizumab (if applicable), 12 months after the final dose of CHOP, 6 months after the final dose of bendamustine and 12 months after the final dose of rituximab (if applicable).
- Received a live, attenuated vaccine within 4 weeks before first dose of study treatment, or in whom it is anticipated that such a live attenuated vaccine will be required during the study period or within 5 months after the final dose of study treatment, except for acute pandemic situation such COVID19
- Active or history of CNS lymphoma or leptomeningeal infiltration
- Participants with infections requiring IV treatment with antibiotics or hospitalization (Grade 3 or 4) within the last 4 weeks prior to inclusion or known active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds),
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins) – grade 3 and 4
- Known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of the mosunetuzumab, rituximab, tocilizumab, lenalidomide, or thalidomide formulation, including Mannitol
- Participants unable to receive adequate prophylaxis and/or therapy for thromboembolic events (aspirin or low molecular weight heparin or direct oral anticoagulants)
- Evidence of any significant, concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to: - Significant cardiovascular disease [e.g., Objective Class C or D heart diseases (cf. Classes of Heart Failure | American Heart Association)], myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) - Significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm) - Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis - Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no residual neurologic deficits as judged by the investigator are allowed. Participants with a history of epilepsy who have had no seizures in the past 2 years with or without anti-epileptic medications can be eligible.
- History of confirmed progressive multifocal leukoencephalopathy (PML)
- Known Positive serologic HIV test at screening
- Acute or chronic hepatitis C virus (HCV) infection Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation.
- Known or suspected history of hemophagocytic lymphohistiocytosis
- Known or suspected chronic active Epstein-Barr virus (EBV) infection within the last 4 weeks prior to inclusion
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Sept 2023 | 30 |
 France | Recruiting | 01 Sept 2023 | 120 |
 Germany | Recruiting | 01 Sept 2023 | 50 |
 Italy | Recruiting | 01 Sept 2023 | 50 |
 Portugal | Recruiting | 01 Sept 2023 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PREDNISONE BIOGARAN 20 mg, comprimé sécable | Comparator | COMPRIMÉ SÉCABLE | ORAL | 40 | 6 | PRD3995184 |
Mosunetuzumab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 45 | 12 | PRD9581694 |
MabThera 1400 mg solution for subcutaneous injection | Comparator | SOLUTION FOR SUBCUTANEOUS INJECTION | SUBCUTANEOUS INJECTION | 1400 | 10 | PRD1182393 |
ENDOXAN 1000 mg, poudre pour solution injectable | Comparator | POUDRE POUR SOLUTION INJECTABLE | INTRAVENOUS | 750 | 6 | PRD350184 |
DOXORUBICINE ACCORD 2 mg/ml, solution pour perfusion | Comparator | SOLUTION POUR PERFUSION | INTRAVENOUS | 50 | 6 | PRD3590500 |
MabThera 500 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 375 | 1 | PRD2154043 |
Mosunetuzumab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 45 | 12 | PRD9581693 |
LENALIDOMIDE | Test | — | ORAL USE | 20 | 140 | SUB25389 |
LENALIDOMIDE | Test | — | ORAL USE | 20 | 140 | SUB25389 |
LENALIDOMIDE | Test | — | ORAL USE | 20 | 140 | SUB25389 |