MARSUN: Evaluation of the benefits of the combination of Mosunetuzumab-Lenalidomide versus a treatment chosen by the investigator in Patients with Relapsed or Refractory Marginal Zone Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Lysarc

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Sep 2023 → ongoing

Decision date (initial)

2023-07-10

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche Ltd

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Evaluate the efficacy of mosunetuzumab-lenalidomide compared with investigator choices. The primary efficacy endpoint for comparison is the Progression–Free Survival (PFS) as determined by investigator.

Secondary objectives 11

1. Compare between Mosunetuzumab-Lenalidomide and investigator choices in terms of: CR24: Complete Response rate as determined by investigator at 24 months from the C1D1
2. CR24 as determined by blinded central review based on PET result (at 24 months from the C1D1 (-0/+30 days)) according to Lugano Criteria 2014
3. Overall response rate (ORR) and complete response rate (CRR) (other than CR24) as determined by investigator
4. ORR and CRR (other than CR24) as determined by blinded central review
5. Duration of response (DOR)
6. Event-free survival (EFS)
7. Time to next anti-lymphoma treatment (TTNLT)
8. Histological transformation rate
9. Safety: incidence and severity of AE, incidence and severity of SAE, incidence and severity of CRS, iIncidence and severity of AE grade 3 or 4 of study-drug-related events, death and Secondary Primary Malignancies (SPM)
10. Health related quality of life as measured by the EQ-5D-5L (Appendix 11: EuroQol 5-Dimension Questionnaire, Five-Level Version (EQ-5D-5L)
11. Overall Survival (OS)

Conditions and MedDRA coding

Relapsed or Refractory Marginal Zone Lymphoma

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. 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.”
2. 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.
3. 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
4. Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN) (or ≤3 x ULN for patients with Gilbert syndrome),
5. AST or ALT ≤ 2.5 x ULN, unless directly attributable to the patient’s MZL
6. Measured or estimated creatinine clearance ≥ 40 mL/min by institutional standard method
7. 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.
8. 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),
9. Patient covered by any social security system (France)
10. Patient who understands and speak one of the country official languages
11. 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.
12. Signed Informed Consent Form
13. Age ≥ 18 years at the time of signing the informed consent form
14. Ability to comply with the study protocol and procedures and required hospitalizations, in the investigator’s judgement
15. Eastern Cooperative Oncology Group (ECOG) performance score (PS) of ≤ 2
16. Have a symptomatic disease requiring a systemic treatment
17. Not eligible for a local treatment including radiotherapy or surgery
18. Stage I disease of EMZL, SMZL or NMZL may be eligible only if not candidate to local therapy (surgery or radiotherapy).
19. LVEF within normal range (i.e. > 50% as evaluated by Transthoracic Echocardiography or > 45% as evaluated by isotopic method (MUGA scan).

Exclusion criteria 32

1. MZL with histologic transformation to high-grade lymphoma
2. History of erythema multiforme, Grade ≥3 rash, or blistering following prior treatment with immunomodulatory derivatives
3. History of interstitial lung disease (ILD), drug-induced pneumonitis, and autoimmune pneumonitis
4. 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
5. Active autoimmune disease requiring treatment
6. 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.
7. Recent major surgery with risk of bleeding within 4 weeks prior to first study treatment administration (C1D1)
8. History of solid organ transplantation
9. 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
10. Person deprived of his/her liberty by a judicial or administrative decision
11. Person hospitalized without consent
12. 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
13. Adult person under legal protection
14. Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness
15. 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
16. 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.
17. 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.
18. 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).
19. 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).
20. 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).
21. 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
22. Active or history of CNS lymphoma or leptomeningeal infiltration
23. 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),
24. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins) – grade 3 and 4
25. Known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of the mosunetuzumab, rituximab, tocilizumab, lenalidomide, or thalidomide formulation, including Mannitol
26. Participants unable to receive adequate prophylaxis and/or therapy for thromboembolic events (aspirin or low molecular weight heparin or direct oral anticoagulants)
27. 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.
28. History of confirmed progressive multifocal leukoencephalopathy (PML)
29. Known Positive serologic HIV test at screening
30. 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.
31. Known or suspected history of hemophagocytic lymphohistiocytosis
32. Known or suspected chronic active Epstein-Barr virus (EBV) infection within the last 4 weeks prior to inclusion

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-Free Survival (PFS) from randomization to progression or death from any cause.

Secondary endpoints 8

1. Complete response rate at 24 months (CR24). The CR24 is defined as the percentage of CR at 24 months from C1D1 among all participants. Participants without response assessment (due to whatever reason) will be considered as non-responder. The CR24 will be determined by blinded central review and by the investigator. This endpoint will be analyzed on the ITT Set.
2. Complete response rate (CRR) other than CR24. The CRR is defined as the percentage of CR among all patients. Patient without response assessment (due to whatever reason) will be considered as non-responder. The CRR will be determined by blinded central review and the investigator.
3. Overall Response Rate (ORR). The ORR is defined as the percentage of complete or partial response among all patients. Patient without response assessment (due to whatever reason) will be considered as non-responder. The ORR will be determined by central review and the investigator.
4. Overall Survival (OS). The overall survival is defined as the time from the date of randomization to the date of death from any cause. Alive patients will be censored at their last contact. This endpoint will be analyzed on the ITT Set.
5. Duration of Response (DOR). The DOR is defined as the time from the first occurrence of a documented objective response (complete or partial response) to progression/relapse or death from any cause. For patients who have not progressed or died at the time of analysis, DOR will be censored at the time of last visit with adequate assessment. This endpoint will be analyzed on the ITT Set.
6. Event-free survival (EFS). EFS is defined as the time from the date of randomization to the event of death from any cause, disease progression or relapse, early discontinuation of the treatment because of any reason or first documented administration of any new anti-lymphoma treatment. Consent withdrawal is not considered as an event for EFS analysis. For patients without event, EFS will be censored at the time of last visit with adequate assessment. This endpoint will be analyzed on ITT Set.
7. Time to next anti-lymphoma treatment (TTNLT). The TTNLT is defined as the time from the date of randomization to the date of first documented administration of any new anti-lymphoma treatment. Patients alive without next anti-lymphoma treatment will be censored at the last visit. Subjects who died (due to any cause) before having received a new anti-lymphoma treatment will be censored on their date of death. This endpoint will be analyzed on the ITT Set.
8. Histological transformation rate. The histological transformation (as determined by investigator) rate is defined as the percentage of transformation from MZL to diffuse large B-cell lymphoma (DLBCL) among all participants. This endpoint will be analyzed on the ITT Set.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Comparator 7

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Lysarc

Sponsor organisation

Lysarc

Address

2d Lyon Sud Batiment

City

Pierre Benite Cedex

Postcode

69495

Country

France

Scientific contact point

Organisation

Lysarc

Contact name

Coordinating Investigator

Public contact point

Organisation

Lysarc

Contact name

Project Management

Third parties 6

Locations

5 EU/EEA countries · 47 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 3 · Art. 54 CTR

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 109 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications