2022-501810-77-00招募中3 期
MARSUN: Phase III, Multicenter, Open label, Randomized, Controlled Study Investigating Mosunetuzumab-Lenalidomide versus investigator choices in Patients with Relapsed or Refractory Marginal Zone Lymphoma
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- Lysarc
- 入组人数
- 260
- 试验地点
- 47
- 主要终点
- Progression – Free Survival (PFS) as determined by investigator (Lugano criteria 2014) from randomization to progression or death from any cause
研究概览
简要总结
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 (Lugano criteria 2014).
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Follow-up period
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •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.
- •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.
- •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.
- •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.
- •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.
- •For women of childbearing potential (WOCBP) (refer to section 14.6.1 and 14.6.1.1): Serum test pregnancy at screening and Day 1 before first dose. And then monthly until end of treatment. 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.
- •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 (if applicable) 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
- •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 C1D
- •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).
排除标准
- •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 patients have recovered from the acute side effects incurred as a result of previous therapy: - 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 anti-tumor necrosis factor agents) within 2 weeks prior to first dose of study treatment (C1D1); Systemic corticosteroid treatment <20 mg/day Prednisone or equivalent and inhaled corticosteroids are permitted. Last dose of corticosteroid ≥20 mg/day Prednisone or equivalent will not be permitted during the last 15 days before inclusion. 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.
- •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).
- •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
- •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
- •Patients unable to receive adequate prophylaxis and/or therapy for thromboembolic events (aspirin or low molecular weight heparin)
- •MZL with high tumor burden defined as: - Total lymphocyte count ≥ 25 G/L, and/or - Spleen ≥ 17 cm of greatest axis, and/or - Lymph node(s) ≥ 100 mm
- •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
结局指标
主要结局
Progression – Free Survival (PFS) as determined by investigator (Lugano criteria 2014) from randomization to progression or death from any cause
Progression – Free Survival (PFS) as determined by investigator (Lugano criteria 2014) from randomization to progression or death from any cause
次要结局
- Complete response rate at 24 months (CR24). The CR24 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 CR24 will be determined by blinded central review and the investigator (at 24 months from the D1C1 (-0/+30 days)). This endpoint will be analyzed on ITT Set (ITT).
- 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.
- 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.
- 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 ITT Set (ITT).
- 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 ITT Set (ITT).
- Event-free survival (EFS). The EFS is defined as the time from the date of randomization to event of death of 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 (ITT)
- 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 ITT Set (ITT).
- Histological transformation rate. The time histological transformation rate is defined as the percentage of transformation to diffuse large B-cell lymphoma (DLBCL) among all patients. This endpoint will be analyzed on ITT Set (ITT).
研究者
Coordinating Investigator
Scientific
Lysarc
研究点 (47)
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