Phase 2 Evaluation of Epcoritamab with Lenalidomide and Rituximab in Relapsed/Refractory Primary CNS Diffuse Large B-Cell Lymphoma
- Trial ID
- 2023-505834-84-00
- Protocol
- e-REVRI
- Sponsor
- Lysarc
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 study is to evaluate the **efficacy** of epcoritamab in subjects with relapsed and refractory primary diffuse large B-cell lymphoma of the central nervous system (CNS) who are treated with lenalidomide and rituximab. This is measured by the best objective response rate, including complete response (CR), unconfirmed complete response (CRu), and partial response (PR) during the first eight cycles of the induction phase, following the recommendations of the International Primary CNS Lymphoma Collaborative Group. The clinical relevance of this objective lies in its potential to improve treatment outcomes for patients with this aggressive and difficult-to-treat form of lymphoma.
Secondary objectives include:
- Assessing the anti-tumor activity of epcoritamab in the same patient population.
- Evaluating the toxicity profile of epcoritamab.
- Assessing the quality of life of the subjects.
- Monitoring the evolution of cognitive functions under treatment with epcoritamab.
Participants
The clinical trial involves participants diagnosed with **relapsed and refractory primary diffuse large B-cell lymphoma of the CNS**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a confirmed histology of primary diffuse large B-cell lymphoma of the CNS or primary vitreoretinal diffuse large B-cell lymphoma, with CD20 positivity. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and an estimated minimum life expectancy of at least 2 months. Adequate renal, liver, and hematopoietic functions are necessary for inclusion. Lifestyle considerations such as the ability to swallow capsules are noted, and participants must have evaluable disease on brain MRI. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **epcoritamab** in subjects with relapsed and refractory primary diffuse large B-cell lymphoma of the CNS, treated with **lenalidomide** and **rituximab**. This is a Phase II, randomized, double-blind, controlled study. The trial will assess the best objective response rate during the first 8 cycles, which constitutes the induction phase, according to the International Primary CNS Lymphoma collaborative group recommendations. The trial is expected to conclude by March 31, 2030, with recruitment starting on June 30, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate renal and liver function, and a confirmed diagnosis of the specified lymphoma. The study will include follow-up visits to monitor the response to treatment and any adverse effects. The end-of-study visit will evaluate the overall response and gather final data. The expected length of participant involvement is up to 34 months, depending on individual response and treatment tolerance.
Participants may be terminated early from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator determines it is in the participant's best interest. The study will ensure that all procedures adhere to ethical standards and regulatory requirements, maintaining the safety and well-being of participants throughout the trial duration.
Treatment
The clinical trial involves the administration of several treatments, including **Rituximab**, **Lenalidomide**, and **Epcoritamab**, each with specific dosing regimens and administration routes. **Rituximab** is provided as a concentrate for solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 375 mg/m² and a total maximum dose of 4125 mg/m² over a treatment period of up to 11 cycles. This medication is not formulated for pediatric use and is authorized for use in the trial.
**Lenalidomide** is administered in the form of hard capsules, taken **orally**. The maximum daily dose is 20 mg, with a total maximum dose of 8400 mg over a treatment period of up to 420 days. Like Rituximab, Lenalidomide is not a pediatric formulation and is authorized for use in this clinical trial.
**Epcoritamab** is provided as a solution for injection and is administered **subcutaneously**. The maximum daily dose is 48 mg, with a total maximum dose of 1537 mg over a treatment period of up to 34 cycles. The dosing schedule for Epcoritamab involves two injections per cycle up to cycle 8, transitioning to one injection per month starting from cycle 9. This medication is also not formulated for pediatric use and is authorized for use in the trial. The administration schedule for Epcoritamab in the trial differs slightly from the marketing authorization, with fewer injections in cycle 9 as per the trial protocol.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy of Epcoritamab in combination with Lenalidomide and Rituximab in subjects with relapsed and refractory primary diffuse large B-cell lymphoma of the central nervous system.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the best objective response rate (ORR) during the first 8 cycles, which corresponds to the induction phase. This assessment will be conducted according to the International Primary CNS Lymphoma Collaborative Group (IPCG) recommendations. The primary endpoint is the best ORR, which includes complete response (CR), unconfirmed complete response (CRu), and partial response (PR), as determined by central review in the cohort of patients with relapsed and refractory primary diffuse large B-cell lymphoma of the central nervous system (R/R PCNSL).
Secondary endpoints include the objective response rate after 8 cycles or at permanent treatment discontinuation, best complete response rate during the induction phase, time to objective response, progression-free survival, duration of response, overall survival, and time to next treatment. These secondary endpoints will be assessed according to IPCG recommendations and determined by investigator assessment. The trial will utilize these parameters to comprehensively evaluate the efficacy of **epcoritamab** in combination with **lenalidomide** and **rituximab** in the specified patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject (or their legally acceptable representative/trusted person) who understand and voluntarily signs and dates an informed consent form prior to any study-specific assessments/procedures being conducted.
- Subject ≥ 18 years old at the time of signing the informed consent form (ICF)
- Confirmed histology of primary diffuse large B-cell lymphoma of the CNS (according to the 2022 WHO classification) or confirmed cytology of primary vitreoretinal diffuse large B-cell lymphoma, with CD20 positivity in immunohistochemical staining or flow cytometry at any point in the disease history.
- Subjects with relapsed or refractory (R/R) PCNSL or PVRL after at least one line of systemic therapy. Subject with R/R PCNSL must have previously received at least high dose methotrexate. Subject with R/R PVRL must have received either intravenous high dose methotrexate or intraocular methotrexate (PVRL cohort). Subjects can have received radiotherapy or intensive chemotherapy with hematopoietic stem cell rescue as part of treatment of the PCNSL or PVRL.
- ECOG performance status 0 to 2.
- Estimated minimum life expectancy of ≥ 2 months.
- R/R PCNSL subjects with evaluable disease on brain MRI
- Able to swallow capsules (stomach tube not allowed)
- Adequate hematopoietic function: - Absolute neutrophil count of ≥ 1.0 G/L without G-CSF support for at least 7 days before screening - Platelet count of ≥ 50 G/L without platelet transfusion within 7 days before screening - Hemoglobin ≥ 8.0 g/dL without RBC transfusion within 7 days before screening
- Adequate renal function: calculated by Cockcroft-Gault equation creatinine clearance > 40 ml/min. Subjects with calculated creatinine clearance > 40 and < 60ml/min lenalidomide dose will be adjusted.
- Adequate liver function: Serum total bilirubin level ≤ 2.0 mg/dl [34 μmol/L] (unless bilirubin rise is due to Gilbert’s syndrome) and serum transaminases (AST or ALT) ≤ 3 upper normal limits.
- Able to understand teratogenic risks of the treatment (Lenalidomide).
- Women of childbearing potential (WOCBP) should agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study treatment, 2) while participating in the study, 3) dose interruptions, and 4) for at least 12 months after the final dose of rituximab, or for at least 12 months after the final dose of epcoritamab, or for at least 28 days after the final dose of lenalidomide . WOCBP should also agree to abstain from breastfeeding during study participation and for at least 4 months after discontinuation of all study treatments.
- WOCBP should have a negative serum (beta-hCG) pregnancy test at screening and a negative serum or urine pregnancy test before treatment administration on Day 1 of every cycle.
- Women should agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire study, until 12 months after the last administration of study treatment
- Man who is sexually active with a female of reproductive potential and has not had a vasectomy should agree to use a highly effective / an acceptable method of birth control (ie, condom) and must agree not to donate sperm, until 28 days after the final dose of lenalidomide and/or until 12 months after the final dose of epcoritamab and rituximab.
- Subject covered by any social security system (France).
- Subject (or their legally acceptable representative/trusted person) who understands and speaks one of the country official languages unless local regulation authorizes independent translators.
Exclusion Criteria
- T-cell lymphoma
- Cerebral localization of a systemic lymphoma.
- Prior history of organ transplantation or other cause of severe immunodeficiency.
- Known Human Immunodeficiency Virus (HIV) or Positive HTLV1 serology
- Active Hepatitis B Virus (HBV) infection (DNA PCR-positive) or active hepatitis C Virus (HCV) infection (RNA PCR-positive). Subjects with evidence of prior HBV infection but who are PCR-negative are permitted in the study but should receive prophylactic antiviral therapy. Subjects who received treatment for HCV infection that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable.
- Persistent SARS-CoV-2 infection. Subjects who have had or currently have a SARS-CoV-2 infection must demonstrate symptom resolution and provide a negative nasopharyngeal PCR test at time of inclusion. Both of these requirements must be met for the subject to be considered clear of the virus.
- Impossibility to follow the calendar of exams because of geographic, social, or psychological reasons.
- Active malignancy other than the one treated in this Study. Prior history of malignancies (other than inclusion diagnosis) unless the subject has been free of the disease for ≥ 2 years. However, subjects with the following history/concurrent conditions are allowed: a. Non-invasive basal cell or epidermoid carcinoma b. In situ Carcinoma of the cervix c. In situ Carcinoma of the breast d. Non-invasive, superficial bladder cancer e. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor, nodes, metastasis [TNM] clinical staging system f. Any curable cancer with a complete response of >2 years duration
- Known or suspected hypersensitivity to the active substance or to any of the excipients.
- Any previous treatment with CAR-T therapy within 30 days prior to enrollment
- Receiving immunosuppressive therapy, including more than the equivalent of 20 mg of prednisolone daily, unless for control of lymphoma or intermittent prophylaxis/treatment of allergic reactions.
- Any previous treatment with a bispecific antibody targeting CD3 and CD20 and/or with lenalidomide, regardless of the time and duration
- Seizure disorder requiring anti-epileptic therapy unless related to lymphoma
- Vaccination with live, attenuated vaccines within 28 days prior of enrollment (except severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine). Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Experimental and/or nonauthorized SARS-CoV-2 vaccinations are not allowed.
- Use of any standard or experimental anti-cancer drug therapy within 28 days of the start (Day 1) of study treatment.
- Major surgery within 4 weeks prior to enrollment
- Clinically significant cardiovascular disease, including: a. Myocardial infarction within 1 year prior to enrollment, or unstable or uncontrol disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV) cardiac arrhythmia (CTCAE Version 5.0 Grade 2 or higher), or clinically significant ECG abnormalities. b. Stroke within 6 months prior to enrollment.
- Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment at time of enrollment
- Contraindication to all uric acid lowering agents.
- Clinically significant liver disease, including active hepatitis, current alcohol abuse, or cirrhosis
- Active tuberculosis or history of treatment for active tuberculosis within the past 12 months.
- Receiving immunostimulatory agent.
- Prior allogeneic hematopoietic stem cell transplantation
- Any significant medical conditions, laboratory abnormality or psychiatric illness likely to interfere with participation in this clinical study (according to the investigator’s decision).
- Subject deprived of his/her liberty by a judicial or administrative decision.
- Subject hospitalized without consent
- Adult subject under legal protection.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 30 Jun 2025 | 60 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RITUXIMAB | Other | — | INTRAVENIOUS INFUSION | 375 | 11 | SUB12570MIG |
LENALIDOMIDE | Other | — | ORAL | 20 | 420 | SUB25389 |
EPCORITAMAB | Test | — | SUBCUTANEOUS | 48 | 34 | SUB204090 |
RITUXIMAB | Other | — | INTRAVENIOUS INFUSION | 375 | 11 | SUB12570MIG |
EPCORITAMAB | Test | — | SUBCUTANEOUS | 48 | 34 | SUB204090 |