Beschreibung

A Phase III randomized, open-label, international, multicenter study evaluating the efficacy and safety of mosunetuzumab plus lenalidomide in comparison to anti-CD20 mAb plus chemotherapy in subjects with previously untreated high-tumor burden follicular lymphoma

Studientherapie

Siehe auch Synopsis:

Experimental arm:

*Mosun-Len
The experimental arm will include mosunetuzumab administered subcutaneously (SC) using a step-up dosing method in combination with lenalidomide given orally (PO) and divided into two parts as follows:
Induction
• Induction 1, i.e., I1 will be a 3-week cycle of mosunetuzumab alone (step up dosing: 5 mg on Day 1; 45 mg on Day 8; and 45 mg on Day 15 via SC injection).
• I2 to I12 will be 4-week cycles of mosunetuzumab (45 mg on Day 1 via SC injection) in combination with lenalidomide (20 mg PO daily on D1-21).

Patients must achieve the threshold clinical activity of at least partial metabolic response (PMR) at mo6 evaluation (PET assessment) to continue the induction treatment (i.e., I8 to I12).

Maintenance
Patients exhibiting a PMR or CMR at mo12 evaluation, i.e., after I12 (PET assessment) will then receive mosunetuzumab maintenance every 8 weeks for a total of 9 cycles (72 weeks; Maintenance 1 to 9, i.e., M1 to M9).
If one cycle of maintenance is delayed for 2 weeks (i.e., cycle lasting more than 10 weeks) or more, then the patient must have a new step-up dosage with mosunetuzumab 5mg SC at Day 1 and 45mg SC at Day 8 of the involved maintenance cycle.
In this arm, patients who do not achieve the threshold clinical activity of at least PMR (compared to baseline) at mo12 evaluation (PET assessment) will be withdrawn from the study treatment and followed for PFS and survival. Patients who withdraw from the study treatment for toxicity or any other reason than not achieving a PMR will be followed for PFS and survival.

Control arms (per patient decision possible!):

CD20 antibodies can be either branded Rituximab or branded Obinutuzumab (GA101), depending on investigators’ choice on a patient’s basis before randomization. Biosimilar products are not permitted in the study.

G-CHOP followed by G-maintenance or
R-CHOP followed by R-maintenance or
G-Benda followed by G-maintenance or
R-Benda followed by R-maintenance

Studienstatus

Rekrutierungsziel erreicht/keine neuen Patienten

Allgemeine Infos zum Antrag

Herr Prof. Dr. med. Christian Buske
Wildes Ried 2
88456 Ingoldingen
christian.buske@uni-ulm.de

Universitätsklinikum Ulm - Ulm (Institution, 12054)
Institut für Experimentelle Tumorforschung
Albert-Einstein-Allee 11
89081 Ulm

To demonstrate the superiority of mosunetuzumab + lenalidomide combination versus CD20 Ab plus chemotherapy with regards to Progression Free Survival (PFS) assessed by Independent Review Committee (IRC), blind of treatment arms in previously untreated patients with high-tumor burden (International Prognostic Index (FLIPI) 2-5) Follicular Lymphoma.
PFS is defined as the time from randomization to the date of first documented disease progression/relapse or death from any cause, according to the Lugano 2014 criteria.

o To compare the efficacy between arms using the following secondary efficacy endpoints:
- Overall Response (OR) and CMR rate at 6 months and 12 months by Lugano 2014 and by Deauville criteria, assessed by investigator and IRC
- Overall Response (OR) and CMR rate at EOT (i.e., end of maintenance or at permanent treatment discontinuation), by Lugano 2014 and by Deauville criteria, assessed by investigator and IRC
- Best Overall Response (CMR or PMR) rate by Lugano 2014 and by Deauville criteria, assessed by investigator and IRC
- POD24, defined as rate of progression of disease (POD) within 2 years of first line therapy
- Progression Free Survival assessed by investigator
- Event Free Survival (EFS) by Lugano 2014, 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
- Time to Next Anti-Lymphoma Treatment (TTNLT), defined as time between randomization and date of first documented administration of any new anti-lymphoma treatment
- Duration of response, defined for patients with a best overall response of CMR or PMR determined by Lugano 2014, defined as the time of 1st occurrence of CMR or PMR to disease progression/relapse or death from any cause
- Duration of complete response, defined for patients with a best overall response of CMR determined by Lugano 2014, define as the time of first occurrence of CMR to disease progression/relapse or death from any cause
- Overall Survival (OS) defined as time from randomization to death from any cause
o To describe mosunetuzumab PK in combination with Len in a subset of mosunetuzumab-treated patients (n~125)
o To describe anti-drug antibodies (ADA) in a subset of mosunetuzumab-treated patients (n~125)
o To evaluate PROMs via a digital tool
o To compare health related quality of life:
- Time to deterioration in physical functioning, as measured by the EORTC QLQ-C30
- Time to deterioration in lymphoma symptoms, as measured by FACTLym
o 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 Secondary Primary Malignancies (SPM)

FL Patenten, fortgeschrittenes Stadium, therapiebedürftig, Erstlinie, FLIPI 2-5

Ausschluss: Grad 3B, transformierte FL

SAMPLE SIZE CALCULATION

The hypotheses are the followings:
- superiority test
- 3-years PFS in the control arm = 78.2% (based on subset of GALLIUM patients, 73.6% in R-Chemo arm and 82.8% in G-chemo arm)
- 3-years PFS in the experimental arm = 85.23%
- HR=0.65
- H0: PFS in the control arm = PFS in the experimental arm
- H1:PFS in the experimental arm > PFS in the control arm
- two-sided alpha = 5%
- power = 80%
- drop-out: 5% per 12 months
- randomization ratio 1:1
- one interim analysis of early efficacy at 75% (130 events) of events with efficacy boundary based on Lan-DeMets spending function with Lan DeMets O'Brien-Fleming approximation

Based on these assumptions, 173 PFS events assessed by IRC would have to be observed on the ITT set for the primary effiacy endpoint analysis.

Assuming the randomization of 790 patients based on an increasing accrual rate (up to 30 patients per month with a ramp-up phase), enrollment period will be 34 months.

PFS is defined as the time from randomization to the date of first documented disease progression/relapse or death from any cause, according to the Lugano 2014 criteria.

- Overall Response (OR) and CMR rate at 6 months and 12 months by Lugano 2014 and by Deauville criteria, assessed by investigator and IRC
- Overall Response (OR) and CMR rate at EOT (i.e., end of maintenance or at permanent treatment discontinuation), by Lugano 2014 and by Deauville criteria, assessed by investigator and IRC
- Best Overall Response (CMR or PMR) rate by Lugano 2014 and by Deauville criteria, assessed by investigator and IRC
- POD24, defined as rate of progression of disease (POD) within 2 years of first line therapy
- Progression Free Survival assessed by investigator
- Event Free Survival (EFS) by Lugano 2014, 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
- Time to Next Anti-Lymphoma Treatment (TTNLT), defined as time between randomization and date of first documented administration of any new anti-lymphoma treatment
- Duration of response, defined for patients with a best overall response of CMR or PMR determined by Lugano 2014, defined as the time of 1st occurrence of CMR or PMR to disease progression/relapse or death from any cause
- Duration of complete response, defined for patients with a best overall response of CMR determined by Lugano 2014, define as the time of first occurrence of CMR to disease progression/relapse or death from any cause
- Overall Survival (OS) defined as time from randomization to death from any cause

Spezifische Infos zum Antrag

Siehe Synopsis für vollständige Liste

Patient must meet all of the following criteria to be enrolled in the study:
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 classification12, or classical follicular lymphoma according to the WHO 2022 classification13. Diagnostic tissue must be available for central pathology review, exploratory endpoints and secondary data use.
2. FLIPI 2-5.
3. All Ann Arbor stages (including stage I if FLIPI e 2).
4. Must need treatment

Siehe Synopsis für vollständige Liste

Patient who meets any of the following criteria should be excluded from enrollment in the study:
1. Grade 3b follicular lymphoma according to the WHO 2016 classification12, or follicular large B-cell lymphoma according to the WHO 2022 classification13
2. Suspicion or clinical evidence of transformed lymphoma at enrollment by investigator assessment (e.g., very high SUV 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)
3. Prior localized radiotherapy for the FL
4. Prior history of another lymphoma
5. Use of any standard or experimental anti-cancer drug therapy within 42 days of the start (Day 1) of study treatment.

Patients will be enrolled for approximately 34 months.
Treatment will associate an induction phase followed by a maintenance phase, according to their assigned arms.
Patients will be followed up to 7 years after the last randomized patient. The total duration of the study is therefore approximately 10 years.

40 Zentren in Deutschland, 5 Zentren in Österreich

Insgesamt ca. 120 Zentren europäisch

IIT: Sponsor LYSARC, Kooperationsprojekt LYSA/GLA

Finanzierung: Roche

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wird derzeit verhandelt

Ja

• MORNINGLYTE_Protocol Synopsis_11 Oct 2024 (1)