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This is an open label, multi-center, international, randomized phase III trial to compare the efficacy of Mosunetuzumab-Lenalidomide with investigator choices exclusively in R/R MZL patients. Patients with a proven diagnosis of EMZL, SMZL or NMZL subtypes and previously treated with at least one prior systemic treatment and not more than three prior lines are eligible. Previous treatment line must include at least one systemic line with a drug targeting CD20 (monoclonal antibody at least 2 cycles) with or without chemotherapy (R-CHOP, R-Bendamustine, R-CVP, R-Chlorambucil at least 2 cycles) or targeted treatment such as Ibrutinib.
The patients will be Randomized as follows:
Arm A - Experimental arm:
• Mosunetuzumab-Lenalidomide
Arm B - Comparator arms ( Investigator Choices):
Full description
This is an open label, multi-center, international, randomized phase III trial to compare the efficacy of Mosunetuzumab-Lenalidomide with investigator choices exclusively in R/R MZL patients. Patients with a proven diagnosis of EMZL, SMZL or NMZL subtypes and previously treated with at least one prior systemic treatment and not more than three prior lines are eligible. Previous treatment line must include at least one systemic line with a drug targeting CD20 (monoclonal antibody at least 2 cycles) with or without chemotherapy (R-CHOP, R-Bendamustine, R-CVP, R-Chlorambucil at least 2 cycles) or targeted treatment such as Ibrutinib.
Patients are stratified according to MZL subtypes and time to progression of disease after first-line within 2 years (POD24) < 2 years or > 2 years.
Mosunetuzumab will be administered sub-cutaneously (SC) (21 days first cycle, then 28 days next cycles) and Lenalidomide will be given PO 20 mg/day from Day 1 to Day 21 from cycles C2 to C6. For each patient, investigator choice had to be decided before randomization between Rituximab-Lenalidomide and Rituximab-chemotherapy (R-Bendamustine or R-CHOP).
The primary efficacy endpoint for comparison is the Progression-free survival (PFS) as determined by investigator (Lugano criteria 2014). Secondary objectives include CR24 as determined by investigator (at 24 months) according to Lugano criteria 2014 and by central review based on PET result, Overall response rate (ORR) and CR other than CR24 as determined by investigator, or by central review based on PET result according to Lugano Criteria 2014. 260 patients are planned to be enrolled in France, Belgium, Germany, Italy and Portugal
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Have a diagnosis of MZL, of extranodal (EMZL) or splenic (SMZL based on the Matutes score and CD20 + CD11c + CD180 + CD43 + CD200 expression and validated by a centralized review) or nodals (NMZL) subtypes. 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.
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; patient treated with monoclonal antibody monotherapy should have received at least 4 weekly injections) with or without chemotherapy (R-CHOP, R-Bendamustine, R-CVP, R-Chlorambucil at least 2 cycles) or targeted treatment such as Ibrutinib (at least 1 month). Patients 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 patients 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).
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 starting treatment
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): Serum test pregnancy at screening and Day 1 before first dose. And then monthly until end of chemotherapy or end of lenalidomide. Efficient contraceptive method is required during the treatment period (including periods of treatment interruption), 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: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: 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 and 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.
Exclusion criteria
MZL with histologic transformation to high-grade lymphoma
Participants who have received any of the following treatments prior to study entry:
Participants who have received any of the following treatments, whether investigational or approved, within the respective time periods prior to initiation of study treatment:
Administration of acute, low-dose, systemic immunosuppressant medications (e.g., single dose of 4 mg/day of dexamethasone for nausea or B-symptoms) is permitted during 4 days without washout.
- Any other anti-cancer investigational therapy within 4 weeks prior to initiation of study treatment.
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). Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.
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
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
Patients unable to receive adequate prophylaxis and/or therapy for thromboembolic events (aspirin or low molecular weight heparin)
History of prior malignancy, except for conditions as listed below if patients have recovered from the acute side effects incurred as a result of previous therapy:
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),
Evidence of any significant, concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to:
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
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
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:
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
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
Suspicion or clinical evidence of transformed lymphoma at enrollment by investigator assessment (e.g. very high SUV (regarding 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 Sponsor to discuss any possible inclusion in borderline cases or any doubt).
Uncontrolled symptomatic pleural or serous effusion requiring urgent treatment within 48 hours (patients with controlled disease after adequate pleural/serous drainage and/or effective pleurX™ or similar system are eligible).
Uncontrolled symptomatic ureterohydronephrosis resulting in renal failure (patients with adequate management i.e. ureteral catheter or double J stent allowing renal failure control are eligible).
MZL with high tumor burden defined as:
Primary purpose
Allocation
Interventional model
Masking
260 participants in 4 patient groups
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Central trial contact
Christine STEPHAN
Data sourced from clinicaltrials.gov
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