Phase II Evaluation of Glofitamab and Obinutuzumab in Relapsed/Refractory Lymphomas Post Anti-CD19 CAR T-Cell Therapy

Trial ID: 2023-508301-25-00
Protocol: BiCAR Therapy
Sponsor: Lysarc

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Diseases & Conditions

Diffuse large B-cell lymphoma Mantle cell lymphoma Primary mediastinal large B-cell lymphoma

Objectives

The primary objective of this study is to assess the anti-lymphoma activity of **glofitamab**, a bispecific CD3xCD20 monoclonal antibody, in patients with relapse/refractory diffuse large B-cell lymphoma (DLBCL) following anti-CD19 CAR T-cells therapy. This evaluation is clinically relevant as it aims to determine the potential of glofitamab to provide therapeutic benefits in a patient population with limited treatment options after CAR T-cell therapy failure.

Secondary objectives include:

Evaluating the safety and tolerability of glofitamab after CAR T-cells therapy failure.
Assessing the efficacy of glofitamab in patients with relapse/refractory disease post anti-CD19 CAR T-cells therapy, focusing on PET-CT results, overall metabolic response rate (OMRR), best metabolic response, progression-free survival (PFS), and duration of response (DoR) according to Lugano 2014 response criteria.
Assessing disease-related symptoms, function, and health-related quality of life (HRQoL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym LymS) subscale.

Participants

The clinical trial involves participants diagnosed with **relapse/refractory lymphomas**, specifically focusing on those with diffuse large B-cell lymphoma (DLBCL) who have previously undergone anti-CD19 CAR T-cells therapy. The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have adequate liver, renal, and hematological function, and a life expectancy of at least three months. They should not have persistent neurotoxicity symptoms from prior CAR T-cells therapy. The sponsor has not provided the total number of participants involved in the study. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with protocol-mandated procedures, including hospitalization for the administration of the first dose of glofitamab. Key inclusion criteria include a confirmed metabolic progression or relapse post-CAR T-cells therapy, and the presence of lymphoma cells expressing CD20 at relapse, as demonstrated by biopsy. Participants must also agree to perform a SARS-CoV-2 PCR test within 48 hours prior to the administration of obinutuzumab and comply with contraceptive measures if applicable.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **glofitamab**, a bispecific CD3xCD20 monoclonal antibody, in patients with relapse/refractory lymphomas following CAR T-cells therapy. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to last until July 31, 2024, with recruitment having commenced on March 1, 2021. Participants will be involved in the study for a maximum treatment period of 32 weeks, depending on their response to the treatment and any adverse events experienced.

The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where eligibility criteria are assessed, including adequate liver, renal, and hematological function, as well as a negative pregnancy test for women of childbearing potential. Following the screening, participants will undergo a series of follow-up visits to monitor their response to the treatment and any side effects. These visits will include assessments of overall survival, tolerability of **glofitamab**, and metabolic response rates. The end-of-study visit will conclude the participant's involvement, where final evaluations will be conducted to assess the primary and secondary endpoints.

Participants may be terminated early from the study if they experience severe adverse events, fail to comply with study procedures, or if the investigator deems it in the participant's best interest. The study aims to provide valuable insights into the treatment of relapse/refractory lymphomas, with a focus on improving overall survival and quality of life for patients.

Treatment

The clinical trial involves the administration of **OBINUTUZUMAB**, a monoclonal antibody, as part of the treatment regimen. OBINUTUZUMAB is provided in the form of a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 1 gram, with a total dose not exceeding 1 gram over the course of the treatment. The treatment period for OBINUTUZUMAB is limited to 1 day. This medication is not a pediatric formulation and is classified under the role of a test product in the trial. The active substance, obinutuzumab, is derived from a protein of non-human origin.

Another key component of the trial is **GLOFITAMAB**, a bispecific CD3xCD20 monoclonal antibody, which is also administered as a **solution for infusion**. The route of administration is **intravenous**, with a maximum daily dose of 30 milligrams and a cumulative dose of up to 342.5 milligrams over the treatment period. The administration of GLOFITAMAB spans a maximum treatment period of 32 weeks. This investigational medicinal product is not used post CAR T-cells therapy and is also not formulated for pediatric use. The active substance, glofitamab, is similarly derived from a protein of non-human origin.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial aims to evaluate the efficacy of GLOFITAMAB in patients with relapse/refractory diffuse large B-cell lymphoma (DLBCL) following anti-CD19 CAR T-cells therapy.

Efficacy

Efficacy in the clinical trial will be assessed using several key endpoints. The primary endpoint is **Overall Survival (OS)**, which will be measured to evaluate the anti-lymphoma activity of glofitamab in patients with relapse/refractory diffuse large B-cell lymphoma (DLBCL) after anti-CD19 CAR T-cells therapy. Secondary endpoints include the tolerability of glofitamab, Overall Metabolic Response Rate (OMRR), best metabolic response and overall best metabolic response rate, Progression Free Survival (PFS), Duration of Response (DoR), and Health-Related Quality of Life (HRQoL).

The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial. The trial is designed to ensure that data collection aligns with the study's objectives, focusing on both survival outcomes and metabolic responses. The use of validated scales and imaging techniques, such as PET-CT, will be employed to assess metabolic responses and confirm disease progression or remission. The trial will adhere to rigorous standards for data collection and analysis to ensure the reliability and validity of the efficacy assessments.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients who received CAR T-cells therapy for R/R DLBCL (cohort 1) or R/R PMBL, mantle cell lymphoma, t-iNHL or iNHL (cohort 2), at least 1 month ago
Patients who are not at least in partial metabolic response from 1 month after CAR T-cells infusion (i.e no metabolic response or first metabolic progressive disease or first relapse from 1 month after CAR T-cells infusion)
First metabolic progression, first relapse or no metabolic response after CAR T-cells infusion must be confirmed by PET-CT central review for enrollment
DLBCL with demonstrated lymphoma cells-expressing CD20 at relapse post CAR T-cells as demonstrated by biopsy before enrollment (cohort 1 only)
Aged 18 years or more with no upper age limit
ECOG performance status 0 or 1
Bi-dimensionally measurable disease defined by at least one single node or tumor lesion > 1.5 cm assessed by CT scan, or PET-CT with at least one hypermetabolic lesion
No persistant CAR-T neurotoxicity symptoms or previous experience during CAR T-cells therapy of neurotoxicity grade > 3
Adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1 (hematological toxicities excepted)
Adequate liver function: Total bilirubin ≤ 1.5 x ULN; Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x ULN Note: Patients with documented history of Gilbert’s Syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible)
Adequate hematological function: Neutrophil count of ≥ 1.0 G/L; Platelet count of ≥ 50 G/L (and platelet transfusion free within 14 days prior to administration of obinutuzumab); Hemoglobin (Hb) ≥ 8.0 g/dL (transfusion free within 21 days prior to administration of obinutuzumab) Note: patients who do not meet the above hematologic criteria, due to extensive tumor involvement in the marrow may be enrolled into the trial after the demonstration of involvement and consultation with the LYSARC. Please consult the LYSARC on the need for transfusion support within 21 days of obinutuzumab.
Adequate renal function: creatinine clearance (CrCl) calculated by MDRD/Cockroft-Gault formula of ≥ 30 mL/min 13.
Negative serum or urinary pregnancy test within 7 days prior to study treatment in women of childbearing potential.
Negative serologic or PCR test results for acute or chronic HBV infection. Note: Patients whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation.
Negative test results for HCV and HIV. Note: Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.
Patients must agree to either remain completely abstinent or to use two effective contraceptive methods until: - If the patient is a male: at least 3 months after pre-treatment with obinutuzumab or 2 months after the last dose of glofitamab, whichever is longer Men must refrain from donating sperm during this same period - If patient is a female of childbearing potential: until at least 18 months after pre-treatment with obinutuzumab or 2 months after the last dose of glofitamab, whichever is longer
Patient must be willing and able to comply with protocol-mandated hospitalization upon administration of the first dose of glofitamab. Patient must also be willing to comply with all study-related procedures.
Signed written informed consent
Life expectancy ≥ 3 months
Patient covered by any social security system
Patient who understands and speaks one of the country official languages
Patient with a vaccination status in line with French National guidelines/recommendations (COSV, ANRS MIE)
Patient must agree to perform a SARS-CoV-2 PCR test within 48 hours prior administration of obinutuzumab, then C2 and each subsequent cycle of glofitamab

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Exclusion Criteria

Previously known CD20 negative status, excepted if a new biopsy for cohort 1 or biopsy or cytometry analysis for cohort 2 proving a CD20 positive status is available before enrollment
Patients with CLL, Richter and Burkitt lymphoma.
Patients relapsing or progressing within 1 month after CAR T-cells therapy
History of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents, as follows: - Grade ≥ 3 adverse events with the exception of Grade 3 endocrinopathy managed with replacement therapy - Grade 1-2 adverse events that did not resolve to baseline after treatment discontinuation
Current or past history of detectable cerebrospinal fluid lymphoma cells, or with a history of CNS lymphoma localization or primary CNS lymphoma.
Current or past history of cerebral disorders
Any serious psychiatric illness that would prevent the subject from signing the informed consent form
Patients with history of macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH)
Patients with known acute infection or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, EBV, cytomegalovirus (CMV), hepatitis B, hepatitis C, and HIV), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) in 2 week prior to enrollment.
LVEF < 40% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan or significant cardiovascular disease such as New York Heart Association Class III or IV or Objective Class C or D cardiac disease (see appendix 16), myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina
Any serious active disease or co-morbid medical condition
Clinically significant history of liver disease or cirrhosis
Prior history of malignancies other than lymphoma unless the subject has been free of the disease for ≥ 3 years. Exceptions will be allowed for patients with non-melanoma skin tumors (basal cell or squamous cell carcinoma of the skin) or any surgically removed stage 0 (in situ) carcinoma
Prior solid organ transplantation.
Prior allogeneic SCT
Autologous SCT within 100 days prior to obinutuzumab infusion
Current uncontrolled autoimmune disease Note: History of autoimmune disease currently controlled and stable is acceptable for such therapy. See detailed description in paragraphe 8.2
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug.
Major surgery or significant traumatic injury < 28 days prior to the obinutuzumab infusion (excluding biopsies) or anticipation of the need for major surgery during study treatment
Administration of a live, attenuated vaccine within 4 weeks before obinutuzumab infusion
Treatment between infusion of CAR T-cells and pre-phase (i.e. obinutuzumab infusion on C1/D-3): with standard radiotherapy, systemic immunotherapeutic agents, any chemotherapeutic agent, any systemic immunosuppressive medications or treatment with any other investigational anti-cancer agent (defined as treatment for which there is currently no regulatory authority approved indication). Note: with the exception of corticosteroid treatment < 25 mg/day prednisone or equivalent. Inhaled and topical steroids are permitted
Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
History of illicit drug or alcohol abuse within 12 months prior to enrollment
Person deprived of his/her liberty by a judicial or administrative decision
Inability to comply with protocol mandated hospitalization and restrictions.
Adult person under legal protection
Adult person unabled to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness
Pregnant or breast-feeding or intending to become pregnant during the study.