A Phase III Randomized, Open-label, International, Multicenter Study Evaluating the Efficacy and Safety of Mosunetuzumab Plus Lenalidomide in Comparison to Anti-CD20 Monoclonal Antibody Plus Chemotherapy in Subjects With Previously Untreated FLIPI 2-5 Follicular Lymphoma

The Lymphoma Academic Research Organisation49 sites in 5 countries790 target enrollmentJune 7, 2024

InterventionsLenalidomide Obinutuzumab Mosunetuzumab Rituximab Cyclophosphamide Doxorubicin Vincristin Prednisone Bendamustin

DrugsMosunetuzumab Lenalidomide Rituximab Obinutuzumab Cyclophosphamide Doxorubicin Vincristin Prednisone Bendamustin

Overview

Phase: Phase 3
Intervention: Lenalidomide
Conditions: Follicular Lymphoma
Sponsor: The Lymphoma Academic Research Organisation
Enrollment: 790
Locations: 49
Primary Endpoint: Progression Free Survival (PFS)
Status: Recruiting
Last Updated: last year

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

Detailed Description

This study is a phase III, randomized, open-label, international, multicenter, interventional trial, designed to compare the efficacy and safety of mosunetuzumab in combination with lenalidomide versus anti-CD20 monoclonal antibody (mAb) plus chemotherapy in patients with previously untreated Follicular Lymphoma International Prognostic Index (FLIPI) 2-5 follicular lymphoma This study is composed of a screening period (up to 6 weeks before randomization, i.e., 42 days), a treatment period (30 months i.e., 125w), a safety follow-up period (90 days i.e., 3 months), and a survival follow-up period (up to 7 years after the last randomized patient). The enrollment will last approximately 34 months. The total duration of the study will be therefore approximately 10 years. Once a patient provides written consent, they may enter the screening phase, with a duration up to 6 weeks prior to randomization and initiation of treatment. Upon completion of the required assessments in the screening phase, and fulfillment of the eligibility criteria, patients will be randomized. Investigators will be requested to indicate their treatment choice among permitted immuno-chemotherapy regimens just before randomization. The treatment period for each patient starts with the first intake. The patients will receive protocol-specified treatments until: * inability to achieve a response at the end of induction phase (at M12 evaluation for experimental arm, and at M6 evaluation for control arms), * relapse or progression of the disease, * withdrawal of consent, * or unacceptable toxicity In the experimental arm, patients will be treated for 1 cycle of 3 weeks for mosunetuzumab and then 11 cycles of 4 weeks for mosunetuzumab and lenalidomide (47 weeks, around 11 months) during the induction phase, and for a maximum of 9 additional cycles of 8 weeks during the maintenance phase (72 weeks, around 17 months), up to around 125 weeks (30 months). Patients should start the maintenance phase 7 to 8 weeks after the start of last induction cycle (C12). In the control arm, patients will be treated for 8 or 6 cycles of 3 or 4 weeks for anti-CD20 mAb +cyclophosphamide-doxorubicine-vincristine-prednisone (CHOP) or anti-CD20 mAb + Bendamustine, respectively, depending on the assigned arm (24 weeks, around 5 months) during the induction phase, and for a maximum of 12 additional cycles of 8 weeks during the maintenance phase (96 weeks, around 22 months), up to around 125 weeks (30 months). Patients should start the maintenance phase, 6 to 7 or 7 to 8 weeks after the start of last induction cycle (C8 or C6). The option to cross-over from the control arm to the experimental arm is not allowed. All randomized patients will be followed for progression-free survival and overall survival using the same schedule. Patients will be followed up from End of treatment evaluation every 3 months during the first two years, then every 6 months during the next 3 years, then yearly until the end of study. The end of study will occur when all randomized patients have been followed-up for survival for at least 7 years (or discontinued study early).

Registry

clinicaltrials.gov

Start Date

June 7, 2024

End Date

April 2034

Last Updated

last year

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

The Lymphoma Academic Research Organisation

Responsible Party

Sponsor

Eligibility 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 World Health Organization (WHO) 2016 classification12, 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. (Patients with absolute lymphocyte count \> 20 G/L must be discussed with the Sponsor before screening/inclusion).
•All Ann Arbor stages (including stage I if FLIPI ≥ 2).
•Must need treatment as evidenced by at least one of the following criteria:
•Bulky disease defined as:
•a nodal or extranodal mass/lesion \> 7 cm in its largest diameter or,
•involvement of at least 3 nodal or extranodal sites (each with a diameter greater than \> 3 cm)
•Presence of at least one of the following B symptoms:
•fever (\> 38°C) of unclear etiology
•night sweats

Exclusion Criteria

•Grade 3b follicular lymphoma according to the WHO 2016 classification12, or follicular large B-cell lymphoma according to the WHO 2022 classification
•Suspicion or clinical evidence of transformed lymphoma at enrollment by investigator assessment (e.g., high SUV in at least one lesion that was not biopsied, and discordant with SUV of biopsied lesion (at least double of the average SUV), LDH \> 2.5 x ULN especially in a context of rapidly progressive disease, etc. (Please contact the Sponsor to discuss any possible inclusion in borderline cases or any doubt)
•Prior localized radiotherapy for the FL.
•Prior history of another lymphoma.
•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).
•Symptomatic lymphomatous epidural lesion (patients whose disease is controlled by neurosurgery or short course of steroids are eligible).
•Use of any standard or experimental anti-cancer drug therapy within 42 days of the start (Day 1) of study treatment.
•Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) or corticosteroid \> 1mg/kg/day prednisone or equivalent within 10 days prior to first dose of study treatment. Systemic corticosteroid treatment \< 20 mg/day of prednisone or equivalent, inhaled corticosteroids and mineralocorticoids for management of orthostatic hypotension is permitted. A single dose of dexamethasone for nausea or B symptoms is permitted.
•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 5 months after the final dose of study treatment.

Intervention: Obinutuzumab

G-Benda

Obinutuzumab-Bendamustin

Intervention: Bendamustin

Outcomes

Primary Outcomes

Progression Free Survival (PFS)

Time Frame: 173 PFS events assessed by IRC (5.8 y)

time from randomization to the date of first documented disease progression/relapse or death from any cause, by Lugano 2014

Secondary Outcomes

PFS(5.8 years)
Overall Response (OR)(End of treatment (12 months for experimental arm, 6 months for comparative arms))
Best Overall Response (CMR + PMR) rate(5.8 years)
Progression of disease within 2 years (POD24)(2 years)
Event Free Survival (EFS) by Lugano 2014(5.8 years)
Incidence of Second Primary Malignancies (SPM)(5.8 years)
Complete Metabolic Rate (CMR)(End of treatment (12 months for experimental arm, 6 months for comparative arms))
Time to Next Anti-Lymphoma Treatment (TTNLT)(5.8 years)
Duration of complete response(5.8 years)
Overall Survival (OS)(5.8 years)
Incidence and severity of AEs including SAEs and AESIs(5.8 years)
Tolerability, as assessed by incidence of dose interruptions, delays, dose reductions, and study treatment discontinuation(5.8 years)
Area under the curve of serum concentration of lenalidomide - AUC(each cycle, 18 months, 24 months, 30 months)
Duration of response(5.8 years)
Incidence and severity of Adverse Events (AE) including Serious and Special Interest AE (SAEs and AESIs)(4.6 years)
anti-drug antibodies (ADA) to mosunetuzumab(each cycle, 18 months, 24 months, 30 months)
Time to deterioration in physical functioning(baseline, 6 months, 12 months, 18 months, 24 months, 30 months or end of treatment)
Time to deterioration in lymphoma symptoms(baseline, 6 months, 12 months, 18 months, 24 months, 30 months or end of treatment)
Maximum serum concentration of mosunetuzumab - Cmax(each cycle, 18 months, 24 months, 30 months)
Minimum serum concentration of mosunetuzumab - Cmin(each cycle, 18 months, 24 months, 30 months)
Area under the curve of serum concentration of mosunetuzumab - AUC(each cycle, 18 months, 24 months, 30 months)
Maximum serum concentration of lenalidomide - Cmax(each cycle, 18 months, 24 months, 30 months)
Minimum serum concentration of lenalidomide - Cmin(each cycle, 18 months, 24 months, 30 months)