Phase III Study of Mosunetuzumab and Lenalidomide Versus Anti-CD20 Monoclonal Antibody and Chemotherapy in Untreated FLIPI 2-5 Follicular Lymphoma
- Trial ID
- 2023-505436-35-00
- Protocol
- MO44842-MorningLyte
- Sponsor
- Lysarc
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the superiority of the combination of **mosunetuzumab** and **lenalidomide** over anti-CD20 monoclonal antibody plus chemotherapy in terms of **Progression Free Survival (PFS)**. This is assessed by a blinded Independent Review Committee in patients with previously untreated **FLIPI 2-5 Follicular Lymphoma**. The clinical relevance of this objective lies in potentially improving the management and outcomes for patients with this subtype of lymphoma, which is characterized by its indolent nature but potential for progression.
Secondary objectives include:
- Comparing efficacy between treatment arms using endpoints such as Overall Response (OR) and Complete Response (CR) rates at various time points, Best Overall Response, Progression of Disease within 2 years (POD24), Progression Free Survival, Event Free Survival, Time to Next Anti-Lymphoma Treatment, Duration of Response, Duration of Complete Response, and Overall Survival.
- Comparing safety between treatment arms by evaluating the incidence and severity of adverse events, including serious adverse events and adverse events of special interest, as well as tolerability and incidence of second primary malignancies.
- Describing pharmacokinetics of mosunetuzumab and lenalidomide, and anti-drug antibodies to mosunetuzumab in a subset of patients.
- Comparing health-related quality of life by assessing time to deterioration in physical functioning, fatigue, and lymphoma symptoms.
Participants
The clinical trial involves a total of **116 participants** diagnosed with **untreated FLIPI 2-5 Follicular Lymphoma**. The study population includes both male and female subjects, aged 18 years and older, with an **ECOG performance status** ranging from 0 to 2, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants were selected based on their diagnosis of CD20+ follicular lymphoma, as confirmed by histological analysis, and must have adequate hematological function and normal laboratory values. The trial includes individuals who are able to adhere to the study visit schedule and other protocol requirements. Lifestyle considerations such as the ability to receive prophylaxis and/or therapy for thromboembolic events are taken into account. The trial population is not limited by gender, and both male and female subjects are included. Participants must have a minimum life expectancy of three months and must not have any significant comorbidities that would interfere with the study. The selection criteria ensure that the participants are representative of the broader population affected by this condition, while also meeting specific health and diagnostic criteria necessary for the study's objectives.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, international, multicenter study to evaluate the efficacy and safety of a combination therapy involving **mosunetuzumab** and **lenalidomide** compared to an anti-CD20 monoclonal antibody plus chemotherapy in subjects with previously untreated FLIPI 2-5 **follicular lymphoma**. The primary objective is to demonstrate the superiority of the combination therapy in terms of progression-free survival (PFS), assessed by a blinded Independent Review Committee (IRC). The trial is expected to commence recruitment in April 2024 and conclude by April 2034.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histologically proven CD20+ follicular lymphoma and adequate hematological function. Following randomization, participants will receive treatment according to their assigned group. Regular follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted using the Lugano 2014 criteria. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination.
The expected duration of participant involvement varies depending on the treatment arm and individual response, with a maximum treatment period of up to 30 days for certain medications. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to adhere to the study visit schedule and protocol requirements, including the use of effective contraceptive methods for a specified period post-treatment, to ensure the integrity of the trial data.
Treatment
The clinical trial involves the administration of **Mosunetuzumab**, a cancer medicine classified as a CD20xCD3 T-cell engaging bispecific antibody. It is provided in the form of a **solution for injection** and is administered via **subcutaneous injection**. The maximum daily dose is 45 mg, with a total maximum dose of 1035 mg over a treatment period of 30 days. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
**Lenalidomide** is another experimental medication used in this trial. It is an anticancer medicine categorized as an antineoplastic agent. The pharmaceutical form is **hard capsules**, and it is administered **orally**. The maximum daily dose is 20 mg, with a total maximum dose of 4620 mg over an 11-day treatment period. The blisters are removed from the original packaging and relabeled with Roche standard IMP labels to ensure proper identification and compliance monitoring.
**Rituximab**, marketed as MabThera, is used as a comparator treatment in this study. It is an antineoplastic monoclonal antibody provided as a **concentrate for solution for infusion**. The administration route is **intravenous infusion**, with a maximum daily dose of 375 mg/m² and a total dose of 375 mg/m² over a single treatment period. Compliance is ensured through controlled infusion settings.
**Obinutuzumab**, marketed as Gazyvaro, is another comparator treatment. It is an anticancer medicine classified as an anti-CD20 monoclonal antibody. The pharmaceutical form is a **solution for infusion**, administered via **intravenous infusion**. The maximum daily dose is 1000 mg, with a total maximum dose of 22000 mg over a 30-day treatment period. Participant adherence is monitored through infusion records and follow-up assessments.
**Cyclophosphamide** is included as a comparator treatment. It is an anticancer medicine categorized 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-day treatment period. Compliance is monitored through infusion logs and patient reports.
**Bendamustine Hydrochloride** is also used as a comparator treatment. It is an anticancer medicine classified as an alkylant antineoplastic agent, provided as a **powder for concentrate for solution for infusion**. The administration route is **intravenous infusion**, with a maximum daily dose of 90 mg/m² and a total maximum dose of 1080 mg/m² over a 6-day treatment period. Participant adherence is ensured through infusion documentation and regular follow-ups.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, which is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. This primary endpoint will be evaluated by a blinded Independent Review Committee (IRC) to ensure objectivity and consistency in the assessment of disease progression.
Secondary efficacy endpoints include several measures: the response rate, best response rate, POD24 rate, PFS assessed by the investigator, Event-Free Survival (EFS), Time to Next Anti-Lymphoma Treatment (TTNLT), Duration of Response (DoR), and Overall Survival (OS). The response rate will be assessed using the Lugano 2014 criteria, and the number and percentage of patients in each response category (Complete Response, Partial Response, Stable Disease, Progressive Disease, Not Evaluated) will be documented. The best response rate is defined as patients achieving a Complete Metabolic Response (CMR) or Partial Metabolic Response (PMR) as the best response to study treatment. POD24 rate measures the progression of disease within two years of first-line therapy. EFS is defined as the time from randomization to the date of first documented disease progression, initiation of a new anti-lymphoma treatment, or death from any cause. TTNLT is the time from randomization to the first administration of any new anti-lymphoma treatment. DoR is the time from first overall response to the date of first documented disease progression or death. OS is the time from randomization to death from any cause.
These efficacy parameters will be assessed at various time points throughout the trial, with specific details on the timing and methods of assessment outlined in the study protocol. The assessments will be conducted by both the investigator and the IRC to ensure comprehensive evaluation and validation of the results. The use of validated criteria and independent review aims to provide robust and reliable data on the efficacy of the treatment regimen being studied.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient with histologically proven previously untreated CD20+ follicular lymphoma grade 1, 2, or 3a (including patient watched during up to 10 years after initial diagnosis) as assessed by the investigators according to the WHO 2016 classification, or classical follicular lymphoma according to the WHO 2022 classification. Diagnostic tissue must be available for central pathology review, exploratory endpoints and secondary data use.
- Adequate hematological function within 28 days prior to randomization, including: • Absolute neutrophil count (ANC) ≥ 1 x 10.9/L • Platelet count ≥ 75 x 10.9/L, or ≥ 30 x 10.9/L if bone marrow infiltration or splenomegaly • Hemoglobin ≥ 8.0 g/dL (5 mmol/L) unless related to bone marrow infiltration or splenomegaly. Transfusion is allowed before starting treatment (no required window).
- Normal laboratory values: • Measured or estimated creatinine clearance ≥ 40mL/min calculated by institutional standard method (MDRD or Cockcroft-Gault) • AST or ALT ≤ 2.5 x the upper limit of normal (ULN), except in patients with documented liver or pancreatic involvement by lymphoma ≤ 5 x ULN • Serum total bilirubin ≤ 1.5 x ULN (or ≤ 3 x ULN for patients with Gilbert syndrome), except in patients with documented liver or pancreatic involvement by lymphoma ≤ 3 x ULN.
- LVEF within normal range (i.e. > 50% as evaluated by Transthoracic Echocardiography or > 45% as evaluated by isotopic method (MUGA scan)).
- Patients should be able to receive adequate prophylaxis and/or therapy for thromboembolic events (aspirin, low molecular weight heparin or direct oral anticoagulants). Patients with a curative anticoagulation therapy can be enrolled. A patient with deep vein thrombosis due to compressive syndrome is eligible if a curative anticoagulation therapy has been started at least 1 week before initiating study treatment: low molecular weight heparin possible at treatment onset, then direct oral anticoagulants according to local practices.
- Must be able to adhere to the study visit schedule and other protocol requirements.
- Negative HIV test before randomization, with the following exception: Patients with a positive HIV test before randomization are eligible provided they are stable on antiretroviral therapy for at least 4 weeks, have a CD4 count ≥ 200/uL, have an undetectable viral load, and have not had a history of opportunistic infection attributable to AIDS within the last 12 months.
- For women of childbearing potential (WOCBP) : - 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), 12 months after the final dose of rituximab (if applicable), and 18 months after the final dose of obinutuzumab (if applicable).
- 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 07 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), and 3 months after the final dose of obinutuzumab (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), and 3 months after the last dose of obinutuzumab (if applicable).
- Patient covered by any social security system (France).
- FLIPI 2-5.
- Patient who understands and speaks one of the country official languages, unless local regulation authorizes independent translators.
- All Ann Arbor stages (including stage I if FLIPI ≥ 2).
- Must need treatment as evidenced by at least one of the following criteria: 4.1. Bulky disease defined as one of the following: 4.1.1. a nodal or extranodal mass/lesion > 70 mm in its largest diameter or, 4.1.2. involvement of at least 3 nodal or extranodal sites (each with a diameter greater than > 30 mm) 4.2. Presence of at least one of the following B symptoms within the prior 6 months: 4.2.1. fever (> 38°C) of unclear etiology 4.2.2. night sweats weight loss greater than 10% 4.3. Symptomatic splenomegaly 4.4. Symptomatic lesion: 4.4.1. painful lesion and/or 4.4.2. any compressive syndrome (for example, but not restricted to- ureteral, orbital, gastrointestinal) 4.5. Any one of the following cytopenias due to lymphoma: 4.5.1. hemoglobin < 10g/dL (6.25 mmol/L) 4.5.2. platelets <100 x 109/L, or 4.5.3. absolute neutrophil count (ANC) < 1.5 x 109/L 4.6. Pleural or peritoneal serous effusion (irrespective of cell content) 4.7. Abnormal biological prognostic parameters: (item not applicable for Germany) 4.7.1. β2microglobulin > ULN or 4.7.2. LDH > ULN
- At least one bi-dimensionally measurable nodal lesion, defined as > 15 mm in its longest dimension, or at least one bi-dimensionally measurable extra nodal lesion, defined as > 10 mm in its longest dimension (and FDG-avid lesion).
- Patient who understood and voluntarily signed and dated an informed consent prior to any study-specific assessments/procedures.
- Must be ≥ 18 years at the time of signing the informed consent form (ICF).
- ECOG performance status 0 to 2.
- Estimated minimum life expectancy of 3 months.
Exclusion Criteria
- Grade 3b follicular lymphoma according to the WHO 2016 classification, or follicular large B-cell lymphoma according to the WHO 2022 classification.
- Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, anti-tumor 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
- Received a live, attenuated vaccine within 4 weeks before the 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 6 months after the final dose of study treatment.
- Major surgery (excluding surgical documentation of FL) within 28 days prior to signing informed consent.
- Seropositive for or active viral infection with hepatitis B virus (HBV): HBsAg positive HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA (Patients who are HBsAg negative, anti-HBs positive and/or anti-HBc positive but viral DNA negative are eligible. They should be treated and perform testing at regular interval described in section 10.9.1.1; Patients who are seropositive due to a history of hepatitis B vaccine (anti-HBs positive) are eligible).
- Known seropositive for, or active infection hepatitis C virus (HCV) (Patients who are positive for HCV antibody with a negative viral RNA are eligible).
- Known or suspected hypersensitivity to biopharmaceuticals produced in CHO cells or any component of the mosunetuzumab, anti-CD20 mAb, tocilizumab, lenalidomide formulation, including mannitol; or to any of the excipients.
- History of solid organ transplantation or allogeneic stem cell transplant (SCT).
- 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, uveitis or glomerulonephritis ▪ Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. ▪ Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. ▪ Participants 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 Coordinating investigator.
- Participants with any active infection such as known active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds), known or suspected chronic active Epstein-Barr virus (EBV) infection are excluded.
- Suspicion or clinical evidence of transformed lymphoma at enrollment by investigator assessment Examples: patients with high or intermediate SUV (>20) in any nodal or extranodal site particularly in the bones (vertebrae etc) unless biopsy proven to be genuine FL grade 1,2, 3A ; and/or discordant (e.g. SUV doubled) with SUV of other sites including the biopsy site.; and/or LDH > 2.5 x ULN in a context of rapidly progressive disease, etc. Please contact the Coordinating Investigator / Sponsor to discuss such cases or if there is any doubt before considering enrolment.
- 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 central nervous system (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 or suspected history of hemophagocytic lymphohistiocytosis (HLH).
- History of erythema multiforme, Grade ≥3 rash, or blistering rash following prior treatment with immunomodulatory derivatives.
- History of interstitial lung disease (ILD), drug-induced pneumonitis, and autoimmune pneumonitis.
- Active malignancy other than the one treated in this research. Prior history of malignancies unless the patient has been free of the disease for ≥ 3 years. However, patients with the following history/concurrent conditions are eligible: Localized non-melanoma skin cancer. Carcinoma in situ of the cervix. Carcinoma in situ of the breast. Incidental histologic finding of prostate cancer (T1a or T1b as per Tumor Node Metastasis [TNM] staging system) or prostate cancer that has been treated with curative intent.
- Presence or history of CNS or meningeal involvement by lymphoma.
- Pregnant, planning to become pregnant or lactating WOCBP.
- Any significant medical conditions, including the presence of laboratory abnormality or psychiatric illness which places the patient at unacceptable risk if he/she were to participate in the study, and likely to interfere with participation in this clinical study (according to the investigator’s decision) or which confounds the ability to interpret data from the study.
- Person deprived of his/her liberty by a judicial or administrative decision.
- Prior localized radiotherapy for the FL.
- Person hospitalized without consent.
- Adult person under legal protection.
- Prior history of another lymphoma.
- Uncontrolled symptomatic pleural or serous effusion requiring urgent treatment (within one week of finding). Participants may only be enrolled after Coordinating investigator / sponsor approval once confirmed participant is durably asymptomatic after adequate pleural/serous drainage or only if an efficient drainage device (e.g.pleurX™) is in place before randomization.
- 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 only if urinary catheter is in place before randomization).
- Presence or history of symptomatic or threatening lymphomatous epidural/nerve root lesion (even such participants whose disease is controlled by short course of steroids are NOT eligible) ,
- Use of any standard or experimental anti-cancer drug therapy within 42 days of the start (Day 1) of study treatment.
- Any contraindication to any drug contained in the study treatment control arms or in the Auxiliary Medicinal Products (AxMPs)
- Patients with absolute lymphocyte count > 20 G/L.Participants with circulating lymphoma cells ≥ 5 G/L must be discussed with the Sponsor before screening/randomization.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 01 Apr 2024 | 35 |
 Belgium | Recruiting | 01 Apr 2024 | 45 |
 France | Recruiting | 01 Apr 2024 | 388 |
 Germany | Recruiting | 01 Apr 2024 | 113 |
 Portugal | Recruiting | 01 Apr 2024 | 10 |
 Spain | Recruiting | 01 Apr 2024 | 68 |
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 |
|---|---|---|---|---|---|---|
Mosunetuzumab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 45 | 30 | PRD9581694 |
MabThera 500 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 375 | 1 | PRD2154043 |
LENALIDOMIDE | Test | — | ORAL USE | 20 | 11 | SUB25389 |
PREDNISONE | Comparator | — | ORAL | 100 | 6 | SUB10020MIG |
VINCRISTINE SULFATE | Comparator | — | INTRAVENOUS | 2 | 6 | SUB05101MIG |
CYCLOPHOSPHAMIDE | Comparator | — | INTRAVENOUS | 750 | 6 | SUB06859MIG |
MabThera 1400 mg solution for subcutaneous injection | Comparator | SOLUTION FOR SUBCUTANEOUS INJECTION | SUBCUTANEOUS INJECTION | 1400 | 28 | PRD1182393 |
Mosunetuzumab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 45 | 30 | PRD9581693 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1000 | 30 | PRD1753415 |
DOXORUBICIN HYDROCHLORIDE | Comparator | — | INTRAVENOUS | 50 | 6 | SUB01827MIG |