Phase II multicenter clinical trial: Mosunetuzumab for early relapse of follicular lymphoma in the Nordic countries (MERLIN/NLG-FL6/ML43841)

Trial ID: 2022-500100-21-01
Sponsor: Oslo University Hospital HF

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Diseases & Conditions

Follicular lymphoma Follicle centre lymphoma follicular grade I, II - III Follicle centre lymphoma follicular grade I, II - III recurrent

Objectives

The primary objective of this Phase II multicenter clinical trial is to investigate the **efficacy** of second-line treatment with subcutaneous **mosunetuzumab** monotherapy in patients with **follicular lymphoma** who exhibit refractory disease, progression, or relapse within 24 months of initiating first-line treatment (POD24). This objective is clinically relevant as it addresses the need for effective treatment options in patients with early relapse, a group that typically has a poorer prognosis.

Secondary objectives include:

Investigating response rates as determined by the investigator and survival.
Assessing the safety of subcutaneous mosunetuzumab monotherapy in patients with a current or recent POD24 event.
Evaluating the prognostic significance of FDG-PET-CT response to mosunetuzumab in second-line treatment of POD24 patients.
Determining the rate of transformation to higher-grade lymphoma following single-agent mosunetuzumab in second-line treatment of POD24 patients.
Investigating patients' self-reported quality of life during and after single-agent mosunetuzumab therapy.
Examining resource usage related to subcutaneous mosunetuzumab monotherapy.

These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on various clinical and patient-centered outcomes.

Participants

The clinical trial focuses on participants diagnosed with **follicular lymphoma**, specifically those experiencing refractory disease, progression, or relapse within 24 months of initiating first-line treatment. The study population includes both male and female subjects aged 18 years and older, with no vulnerable populations selected. Participants are required to have a WHO performance status of 0-2, although those with a status greater than 2 may be considered if the reduction is attributed to lymphoma. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria emphasize the presence of at least one two-dimensionally measurable lesion with a longest diameter greater than 15mm. Lifestyle factors such as diet and physical activity are not detailed in the available data.

Plans and Procedures

The clinical trial is a **Phase II** multicenter study designed to evaluate the efficacy and safety of subcutaneous **mosunetuzumab** monotherapy in patients with **follicular lymphoma** who experience early relapse or progression within 24 months of starting first-line treatment. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from February 2023 to June 2028, with participant involvement expected to last up to 51 weeks, depending on individual response and treatment cycles.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and previous treatment history. Following successful screening, participants will be randomized to receive mosunetuzumab via subcutaneous injection. The primary endpoint is progression-free survival, with secondary endpoints including complete response rate, overall response rate, and safety assessments. Study visits will include regular follow-up assessments to monitor treatment response and adverse events, with imaging studies such as FDG-PET-CT and CT scans conducted at specified intervals.

The end-of-study visit will occur after the completion of the treatment cycles or upon early termination due to disease progression, adverse events, or withdrawal of consent. Conditions that may lead to early termination include significant adverse events or lack of response to treatment. Participants will be closely monitored throughout the trial to ensure safety and adherence to the protocol. The trial aims to provide valuable insights into the potential benefits of mosunetuzumab for patients with follicular lymphoma, contributing to the advancement of therapeutic options for this condition.

Treatment

The clinical trial involves the administration of **Mosunetuzumab**, a full-length, humanized, T-cell recruiting bispecific antibody targeting CD20-expressing B-cells. This experimental medication is provided in the form of a **solution for injection**. The pharmaceutical form is specifically designed for **subcutaneous injection**. Two different dosing regimens are employed in the study. The first regimen involves a maximum daily dose of 45 mg, with a total maximum dose of 815 mg over a treatment period of up to 51 weeks. The second regimen involves a maximum daily dose of 5 mg, also with a total maximum dose of 815 mg over the same treatment period. The administration schedule is determined based on the specific needs of the trial and the participant's response to the treatment.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the efficacy of Mosunetuzumab as a monotherapy for patients with follicular lymphoma experiencing early relapse or progression of the disease within 24 months of starting first-line treatment. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial is conducted under the sponsorship of F. Hoffmann-La Roche Ltd, and the medication is not formulated for pediatric use. The study aims to provide insights into the potential benefits of Mosunetuzumab in this specific patient population.

Efficacy

The efficacy of the clinical trial investigating **follicular lymphoma** will be assessed using several primary and secondary endpoints. The primary endpoint is progression-free survival (PFS), which will be observed over a minimum of two years and a maximum of four years, depending on the timepoint of patient inclusion in the trial. Secondary endpoints include the complete response rate (CRR) and overall response rate (ORR) as determined by FDG-PET-CT after 8 cycles of mosunetuzumab, as well as the best CRR and ORR by CT for all administered cycles. Additional secondary endpoints are CRR and ORR by CT at 30 months post-treatment initiation, duration of response (DOR) from the first documented response to disease progression or death, and time to new lymphoma treatment.

Other secondary endpoints include PFS stratified by the type of first-line treatment, PFS by FDG-PET-CT response groups according to the 2014 Lugano Classification, overall survival (OS) from inclusion to death, and safety and tolerability of treatment measured by the percentage of patients with adverse events and dropout rates due to adverse events. The trial will also assess histology at relapse or progression, the rate of transformation to higher-grade lymphoma, resource usage during treatment, and quality of life during and after treatment using the EORTC QLQ-C30 and EQ-5D instruments. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent according to ICH-GCP guidelines
Age ≥ 18 years
Follicular lymphoma grade 1-3a with a current relapse or progression within 24 months of starting 1st line treatment or refractory to 1st line treatment (POD24), more specifically: a. Documented current relapse or progression of FL within 24 months of starting first line treatment containing a monospecific anti-CD20 antibody (such as rituximab or obinutuzumab with or without chemotherapy, small molecular inhibitors or immunomodulating agents such as lenalidomide). b. Alternatively, current lack of response/refractoriness to first line treatment, i.e., no objective response or documented progression within 6 months following at least four cycles of monotherapy with a monospecific anti-CD20 antibody (such as rituximab 375mg/m2 iv or 1400 mg SC or equal) or following at least three cycles of a monospecific anti CD20 antibody combined with chemotherapy, small molecular inhibitors or immunomodulating agents such as lenalidomide. c. Received one prior treatment line of systemic therapy. d. If the POD24 event was diagnosed more than three months ago, then study inclusion has been clarified with the coordinating investigator. e. Patients may have received localized radiotherapy previously. Patients may have received localized radiotherapy previously. If the radiotherapy was recent, the patient must have at least one progressive and measurable lesion outside the radiation field.
At least one two-dimensionally measurable lesion with a longest diameter >15mm.
WHO performance status 0-2. Patients with reduced WHO performance status (> 2) can be considered if reduction in performance is caused by the lymphoma as determined by the investigator.

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Exclusion Criteria

Received 2 or more previous treatment lines.
Other current severe medical problems or expected survival of less than approximately five years for non-lymphoma reasons.
Current or previous other malignancy within three years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other non-invasive or indolent malignancy without sponsor approval.
CD20-negative lymphoma
Psychiatric disorder or dementia which make the patient unable to give an informed consent and/or adhere to the schedule.
Pregnancy or breast-feeding.
CNS involvement (current or previous)
Impaired bone marrow function (neutrophils < 1.0 x 10^9/L or platelets < 50 x 10^9/L) unless due to lymphoma involvement
Severe cardiac disease: impaired cardiac function (NYHA class III or IV), myocardial infarction within the last 6 months, unstable arrythmias and/or unstable angina pectoris.
Impaired liver function not caused by lymphoma, defined as serum total bilirubin ≥ 1.5 x ULN (unless elevated due to Gilbert’s syndrome) or serum ALT and AST ˃ 3 x ULN
Impaired renal function not caused by lymphoma, defined as calculated creatinine clearance <= 40 ml/minute
Grade 3b FL.
Other major organ dysfunction not caused by lymphoma
Known history of drug induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, primary biliary cirrhosis, on-going extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver or portal hypertension.
HIV positivity: Subjects that are on HIV-treatment with undetectable HIV-RNA and CD4-counts above 200 will be eligible.
Women of reproductive potential not agreeing to use an acceptable method of birth control during treatment and for three months after completion of treatment.
Hepatitis B (HBV) or hepatitis C (HCV) infection: Subjects with a previous hepatitis B infection will be eligible if they are negative for HBV-DNA; these subjects must be given prophylactic antiviral therapy. Subjects with a previous HCV infection will be eligible if they are negative for HCV-RNA.
Known or suspected chronic active Epstein-Barr virus (EBV) infection.
Received systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within two weeks prior to the first dose of mosunetuzumab.
Administration of live vaccines within four weeks of the first dose of mosunetuzumab or anticipation that live vaccine will be required during the study.
History of severe allergic or anaphylactic reactions to chimeric, human, or humanized antibodies, or fusion proteins.
Known or suspected hemophagocytic syndrome.
Prior allogeneic hematopoietic stem cell transplant.
Active severe infection.