MARSUN - Phase III, Multicenter, Open label, Randomized, Controlled Study Investigating Mosunetuzumab-Lenalidomide versus investigator choices in Patients with Relapsed or Refractory Marginal Zone Lymphoma
Kategorie: Indolente Lymphome/MCL
Clinical Trials Register (clinicaltrials.gov)
EU Clinical Trials Register (euclinicaltrials.eu)
EU-trial-Nr.: 2022-501810-77-00
Phase III, Multicenter, Open label, Randomized, Controlled Study Investigating Mosunetuzumab-Lenalidomide versus investigator choices in Patients with Relapsed or Refractory Marginal Zone Lymphoma
Mosunetuzumab-Lenalidomide
?Mosunetuzumab will be administered SC (21 days first cycle, then 28 days
next cycles)
• C1 (21-day cycle): step-up dosing schedule 5 mg Day 1, 45 mg on
Day 8 and 45 mg Day 15
• C2 to C12 (28-day cycles): 45 mg on Day 1
?Lenalidomide PO 20 mg/day, D1-21/28 C2 to C6
Rekrutierung gestartet/nimmt Patienten auf
The primary objective of the study is to evaluate the efficacy of mosunetuzumablenalidomide compared with investigator choices. The primary efficacy endpoint for comparison is the Progression–free survival (PFS) as determined by investigator (Lugano criteria 2014).
Secondary objectives:
? CR24 as determined by investigator (at 24 months from the C1D1 (+/- 15 days))
according to Lugano criteria 2014
? CR24 as determined by central review based on PET result (at 24 months from
the C1D1 (+/- 15 days)) according to Lugano Criteria 2014
? Overall response rate (ORR) and CR other than CR24 as determined by
investigator according to Lugano criteria 2014
? ORR and CR other than CR24 as determined by central review based on PET
result according to Lugano Criteria 2014
Time frame:
? Primary response:
? at C6 D22-D28 for Mosunetuzumab -Lenalidomide
? at C6 D22-D28 for Rituximab-Lenalidomide,
? at C3 D22-D28 for Rituximab-Bendamustine. In this cohort,
patients may stop after C4 (if already in CR) or after C6. Those
patients who stop after C4 will not have a repeat imaging before
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beginning the consolidation phase. Patient who will receive 6
cycles of R-Benda will have to repeat evaluation at C6 D22-D28.
? at C6 D56-D63 for R-CHOP treatment
? End of treatment (EOT) i.e 12 months after C1D1 administration
? M24, M36, M48 and M60 after C1D1
? Duration of response (DOR)
? Event-free survival (EFS)
? Time to next anti-lymphoma treatment (TTNLT)
Histological transformation rate
? Safety: incidence and severity of AE, incidence and severity of SAE, incidence
and severity of CRS, Incidence and severity of AE grade 3 or 4 of study-drug
related events, Death, Secondary Primary Malignancies, vital sign and clinical
laboratory
? Tolerability, as assessed by dose interruptions, dose reductions, and dose
intensity, and study treatment discontinuation because of adverse events
? Health related quality of life as measured by the EQ-5D-5L (Appendix 11)
Exploratory objectives:
? Assessment of the prognostic role of the quantitative measures of FDG-PET/CT
scan (quantitative measures to be defined Deauville score, and delta SUV at
each assessment; TMTV and distance at baseline)
? Biomarker with ancillary studies for:
? Histological review
? Tumor microenvironment on biopsy
? MRD in blood (baseline, C2J1, primary response, EOT, M24, and
relapse)
? Radiomics at FDG-PET (baseline, primary response, EOT, M24, and
relapse)
? Cell-free DNA and ctDNA (baseline, C2D1, primary response, EOT,
M24, and relapse)
Participants are eligible to be included in the study only if all the following criteria
apply:
1. Have a diagnosis of MZL, of extranodal (EMZL) or splenic (SMZL) or nodals
(NMZL subtypes. In case of large dissemination, disseminated
MZL will be included as DMZL and included in NMZL subtype.
2. 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) with or without chemotherapy (R-CHOP, Rbendamustine, R-CVP, at least 2 cycles) or targeted treatment
such as ibrutinib (at least 1 month). Patients should not have
received Lenalidomide before. Prior local therapy (including
surgery, radiotherapyn antibiotics for H. pylori-positive gastric
lymphoma, and antiviral for hepatitis C virus) is not considered as
one line of treatment
3. Signed Informed Consent Form
4. Age > 18 years at the time of signing the informed consent form
5. Ability to comply with the study protocol and procedures and required
hospitalizations, in the investigator’s judgement
6. Eastern Cooperative Oncology Group (ECOG) performance score (PS) of ? 2
7. Have a symptomatic disease requiring a systemic treatment
8. Not eligible for a local treatment including radiotherapy or surgery
9. Stage I disease of EMZL, SMZL or NMZL may be eligible only if not candidate
to local therapy (surgery or radiotherapy).
10.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.
11.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 autoimmune thrombocytopenia, platelet count should be >
30,000/µL. Washout platelet transfusion is 7 days between
transfusion and D1 of starting treatment
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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
12.Serum total bilirubin ? 1.5 x the upper limit of normal (ULN) (or ?3 x ULN for
patients with Gilbert syndrome),
13.AST or ALT ? 2.5 x ULN, unless directly attributable to the patient’s MZL
14.Measured or estimated creatinine clearance > 40 mL/min by institutional
standard method
15.Contraception:
15.1. For women of childbearing potential (refer to section 14.6.1
and 14.6.1.1): Serum at screening and Day 1 before first dose.
Monthly in WOCBP with regular menstrual cycles or every 2
weeks in WOCBP with irregular menstrual cycles until EOT.
15.2. 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), 3 months after the final dose of tocilizumab (if
applicable), 6 months after the final dose of chemotherapies
(if applicable) and 12 months after the final dose of rituximab)
(if applicable).
16.Patient covered by any social security system (France)
17.Patient who understands and speaks one of the country official languages
Participants are excluded from the study if any of the following criteria apply:
1. MZL with histologic transformation to high-grade lymphoma
2. 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), 6 months after the
final dose of chemotherapies 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.
3. Participants who have received any of the following treatments prior to study
entry:
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- Treatment with mosunetuzumab or other CD20/CD3-directed bispecific
antibodies
- Allogeneic stem cell transplant
4. 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 dexamethasone for nausea or B-symptoms) is permitted
during 4 days without washout.
- Any other anti-cancer investigational therapywithin 4 weeks prior to initiation of
study treatment.
5. 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
6. Active or history of CNS lymphoma or leptomeningeal infiltration
7. History of severe allergic or anaphylactic reactions to humanized or murine
monoclonal antibody therapy (or recombinant antibody-related fusion
proteins) – grade 3 and 4
8. Known hypersensitivity to biopharmaceuticals produced in CHO cells or any
component of the mosunetuzumab, rituximab, tocilizumab, lenalidomide, or
thalidomide formulation, including mannitol
9. Patients should be able to receive adequate prophylaxis and/or therapy for
thromboembolic events (aspirin or low molecular weight heparin)
10. 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
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- Adequately treated cervical carcinoma in situ without evidence of disease
- Surgically/adequately treated low grade, early stage I, localized prostate in situ
11. 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),
12. 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.
13. History of confirmed progressive multifocal leukoencephalopathy (PML)
14. Known Positive serologic HIV test at screening
15. 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
16. 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.
17. Known or suspected history of hemophagocytic lymphohistiocytosis
18. Known or suspected chronic active Epstein-Barr virus (EBV) infection within
the last 4 weeks prior to inclusion
19. History of erythema multiforme, Grade ?3 rash, or blistering following prior
treatment with immunomodulatory derivatives
20. History of interstitial lung disease (ILD), drug-induced pneumonitis, and
autoimmune pneumonitis
21. Active autoimmune disease requiring treatment
22. History of autoimmune disease, including, but not limited to, myasthenia
gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
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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.
- Partients 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.
23. Recent major surgery with risk of bleeding within 4 weeks prior to first study
treatment administration (C1D1)
24. History of solid organ transplantation
25. 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
26. Person deprived of his/her liberty by a judicial or administrative decision
27. Person hospitalized without consent
28. Adult person under legal protection
29. Adult person unable to provide informed consent because of intellectual
impairment, any serious medical condition, laboratory abnormality or psychiatric illness
Patients will be enrolled for 3.7 months for safety run and 3.6 years for randomization
(including temporary stop of the recruitment during safety run), treated for 1 year (47
or 48 weeks depending on the arm) and followed up to 4 years after the last dose of
study treatment for the last randomized patient. The total duration of the study is
therefore 8 years
Theoretical dates of study:
- 1st patient included (FPFV): Q2 2023
- Last patient included (LPFV): Q2 2027
- Last patient treated: Q2 2028
- End of study: Q2 2032
The end of study is defined as the last visit of the last patient who performed his/her
visit 60 months after the beginning of the treatment.
44 sites in France, Belgium, Portugal, Italy, and Germany
Nein
