MorningLyte: Evaluation of the benefits of the combination of mosunetuzumab plus lenalidomide versus a treatment with anti-CD20 monoclonal antibody plus chemotherapy in subjects with previously untreated FLIPI 2-5 follicular 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

3 Jun 2024 → ongoing

Decision date (initial)

2025-03-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La-Roche Ltd

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate the superiority of mosunetuzumab + lenalidomide combination versus anti-CD20 mAb plus chemotherapy with regards to Progression Free Survival (PFS) assessed by blinded Independent Review Committee (IRC) blind of treatment arms, in previously untreated patients with International Prognostic Index (FLIPI) 2-5 Follicular Lymphoma.

Secondary objectives 6

1. To compare the efficacy between arms using the following secondary efficacy endpoints: ▪ Overall Response (OR) and Complete Response (CR) rate at M6 and M12 evaluations by Lugano 2014, assessed by investigator and IRC ▪ Overall Response (OR) and Complete Rresponse (CR) rate at EOT/M30 (i.e., end of maintenance or at permanent treatment discontinuation), by Lugano 2014, assessed by investigator and IRC. ▪ Best Overall Response (CR or PR) rate by Lugano 2014, assessed by investigator and IRC ▪ POD24, defined as rate of progression of disease (POD) within 2 years of first line therapy, assessed by investigator and IRC ▪ Progression Free Survival assessed by investigator ▪ Event Free Survival (EFS) according to Lugano 2014 criteria, defined as time between randomization and date of first documented disease progression/relapse, initiation of a new anti-lymphoma treatment or death from any cause, assessed by investigator and IRC ▪ Time to Next Anti-Lymphoma Treatment (TTNLT), defined as time between randomization and date of first documented administration of any new anti-lymphoma treatment, assessed by investigator and • Duration of response, defined for participants with a best overall response of CR or PR determined by Lugano 2014 (PET-CT based response), defined as the time of 1st occurrence of CR or PR to disease progression/relapse or death from any cause, assessed by investigator and IRC ▪ Duration of complete response, defined for participants with a best overall response of CR determined by Lugano 2014 (PET-CT based response), define as the time of first occurrence of CR to disease progression/relapse or death from any cause, assessed by investigator and IRC ▪ Overall Survival (OS) defined as time from randomization to death from any cause.
2. To compare the safety between both arms ▪ Incidence and severity of AEs including SAEs and AESIs ▪ Tolerability, as assessed by incidence of dose interruptions, delays, dose reductions, and study treatment discontinuation ▪ Incidence of Second Primary Malignancies (SPM).
3. To describe pharmacokinetic (PK) to mosunetuzumab in a subset of mosunetuzumab-treated participants (n~125)
4. To describe anti-drug antibodies (ADA) to mosunetuzumab in a subset of mosunetuzumab-treated participants (n~125)
5. o To describe pharmacokinetic (PK) lenalidomide in a subset of mosunetuzumab-treated participants (n~125)
6. To compare health-related quality of life: ▪ Time to deterioration in physical functioning and/or fatigue, as measured by the EORTC QLQ-C30 ▪ Time to deterioration in lymphoma symptoms, as measured by FACT-Lym LYMS (15 questions).

Conditions and MedDRA coding

Untreated FLIPI 2-5 Follicular Lymphoma

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. 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.
2. 10. 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).
3. 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.
4. LVEF within normal range (i.e. > 50% as evaluated by Transthoracic Echocardiography or > 45% as evaluated by isotopic method (MUGA scan)).
5. 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.
6. Must be able to adhere to the study visit schedule and other protocol requirements.
7. 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.
8. 16. 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).
9. 17. 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).
10. Patient covered by any social security system (France).
11. FLIPI 2-5.
12. Patient who understands and speaks one of the country official languages, unless local regulation authorizes independent translators.
13. All Ann Arbor stages (including stage I if FLIPI ≥ 2).
14. 4. 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
15. 5. 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).
16. Patient who understood and voluntarily signed and dated an informed consent prior to any study-specific assessments/procedures.
17. Must be ≥ 18 years at the time of signing the informed consent form (ICF).
18. ECOG performance status 0 to 2.
19. Estimated minimum life expectancy of 3 months.

Exclusion criteria 32

1. Grade 3b follicular lymphoma according to the WHO 2016 classification, or follicular large B-cell lymphoma according to the WHO 2022 classification.
2. 10. 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
3. 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.
4. Major surgery (excluding surgical documentation of FL) within 28 days prior to signing informed consent.
5. 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).
6. Known seropositive for, or active infection hepatitis C virus (HCV) (Patients who are positive for HCV antibody with a negative viral RNA are eligible).
7. 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.
8. History of solid organ transplantation or allogeneic stem cell transplant (SCT).
9. Active autoimmune disease requiring treatment.
10. 18. 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.
11. 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.
12. 2. 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.
13. 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.
14. History of confirmed progressive multifocal leukoencephalopathy (PML).
15. Known or suspected history of hemophagocytic lymphohistiocytosis (HLH).
16. History of erythema multiforme, Grade ≥3 rash, or blistering rash following prior treatment with immunomodulatory derivatives.
17. History of interstitial lung disease (ILD), drug-induced pneumonitis, and autoimmune pneumonitis.
18. 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.
19. Presence or history of CNS or meningeal involvement by lymphoma.
20. Pregnant, planning to become pregnant or lactating WOCBP.
21. 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.
22. Person deprived of his/her liberty by a judicial or administrative decision.
23. Prior localized radiotherapy for the FL.
24. Person hospitalized without consent.
25. Adult person under legal protection.
26. Prior history of another lymphoma.
27. 5. 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.
28. 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).
29. 7. 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) ,
30. Use of any standard or experimental anti-cancer drug therapy within 42 days of the start (Day 1) of study treatment.
31. Any contraindication to any drug contained in the study treatment control arms or in the Auxiliary Medicinal Products (AxMPs)
32. 32. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) assessed by IRC. PFS is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause.

Secondary endpoints 8

1. Response rate: Response will be assessed using the Lugano 2014 criteria (see appendix 8). The number and percentage of patients into each category (CR, PR, SD, PD, Not evaluated) of response will also be provided and patients without evaluation will be listed. Response will be assessed by investigator and by IRC.
2. Best response rate: Best overall response is defined as patients who achieved a CMR or a PMR as best metabolic response to study treatment. Response will be assessed by investigator and by IRC.
3. POD24 rate: POD24 is defined as the rate of progression of disease (POD) within 2 years of first line therapy. Progression of disease is defined as progression/relapse or death due to active lymphoma. Patients died for other reason than lymphoma without POD within 2 years and patients lost to FUP without POD within 2 years are excluded. POD24 will be assessed by investigator and by IRC.
4. PFS assessed by investigator: See section 15.1 for definition of PFS details. The disease progression status will be assessed by investigator using the Lugano 2014 criteria (see appendix 0).
5. Event Free Survival (EFS): EFS is defined as the time from randomization to the date of first documented disease progression/relapse, initiation of a new anti-lymphoma treatment or death from any cause. The disease progression status will be assessed using the Lugano 2014 criteria (see appendix 8). EFS will be assessed by investigator and by IRC.
6. Time to Next Anti-Lymphoma Treatment (TTNLT): TTNLT is defined as the time from randomization to the date of first documented administration of any new antilymphoma treatment. If a patient does not have an event, TTNLT will be censored at the time of last visit with adequate assessment. More details about censoring rules will be available in SAP.
7. Duration of response (DoR): DoR is defined as the time from first overall response (CMR or PMR) to the date of first documented disease progression/relapse or death by any cause. DoR will be analyzed on patients who achieved a best response to study treatment. The disease progression status will be assessed using the Lugano 2014 criteria (see appendix 8). DoR will be assessed by investigator and by IRC.
8. Overall Survival (OS): OS is defined as time from randomization to death from any cause. Patients who are alive will be censored at their last contact date. More details about censoring rules will be available in SAP.

Investigational products

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

Test 5

Comparator 8

Auxiliary 9

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

Locations

6 EU/EEA countries · 109 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 1 · Art. 54 CTR

Results and documents

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

Documents 132 files

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

Application history

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