Refractory Diffuse Large B-Cell Lymphoma (DLBCL), Refractory Follicular Lymphoma Grade 3B, Refractory High-Grade B-Cell Lymphoma, Refractory Large B-cell Lymphoma (LBCL), Refractory T-cell/Histiocyte-rich Large B-cell Lymphoma, Refractory Transformed Follicular Lymphoma
Conditions
Keywords
Post CAR T cells therapy
Brief summary
The goal of this Phase 2, open-label, multicenter clinical trial is to assess the efficacy and safety of accelerated ramp-up and fixed-dose subcutaneous epcoritamab combined with lenalidomide in adults with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) following progression after second-line CAR T-cell therapy. The main question it aims to answer is : \- What is the overall response rate (ORR) after Cycle 2, or at premature treatment discontinuation (PTD), according to the 2014 Lugano Response Criteria? Participants will: * Receive subcutaneous epcoritamab administered according to an accelerated ramp-up schedule followed by fixed dosing, in combination with lenalidomide. * Undergo clinical evaluations, laboratory assessments, and PET-CT imaging to determine disease status based on the 2014 Lugano Response Criteria. * Continue study therapy for up to 48 weeks. * Enter a follow-up period of at least 24 months after the last dose to monitor long-term outcomes and safety. Approximately 55 adults will be enrolled across multiple centers in France. Eligible individuals must have R/R LBCL, including diffuse large B-cell lymphoma and other eligible LBCL subtypes, with progressive metabolic disease documented by PET-CT at least 1 month after second-line CAR T-cell therapy. The overall study duration is expected to be approximately 5 years.
Interventions
DRUGEpcoritamab
Epcoritamab will be administered subcutaneously in combination with lenalidomide. During Cycle 1, participants will receive an accelerated ramp-up dosing schedule consisting of 0.16 mg on Day 1, 0.8 mg on Day 3, and 48 mg on Days 8, 15, and 22. During Cycle 2, participants will receive 48 mg once weekly on Days 1, 8, 15, and 22. During the consolidation phase (Cycles 3 to 12), participants will receive 48 mg subcutaneously on Day 1 of each 28-day cycle.
DRUGLenalidomide
Lenalidomide will be administered orally in combination with epcoritamab from Cycles 2 through 12. Lenalidomide will be given once daily on Days 1 to 21 of each 28-day cycle, followed by a 7-day rest period (Days 22 to 28). The starting dose will be 20 mg for participants with creatinine clearance (CrCL) ≥60 mL/min and 10 mg for participants with CrCL between 30 and \<60 mL/min, according to the study protocol.
Sponsors
The Lymphoma Academic Research Organisation
AbbVie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant (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 2. Aged ≥ 18 years at the time of signing the informed consent form (ICF) with no upper age limit 3. Diagnosis at relapse/progression post CAR T-cells of LBCL (de novo or histologically transformed from follicular lymphoma) with histologically confirmed CD20+ disease, inclusive of the following according to WHO 2022 classification and documented in pathology report: * Diffuse large B-cell lymphoma (DLBCL), NOS * Large B-cell lymphoma (LBCL) * T-cell/histiocyte-rich large B-cell lymphoma * Transformed follicular lymphoma * DLBCL/High-grade B cell lymphoma with MYC and BCL-2 translocations per WHO 2022. * High-grade B-cell lymphoma, NOS * Follicular lymphoma Grade 3B Note: The following, non-exhaustive list of histologies excluded from enrollment: patients with CLL, Richter's, indolent non-Hodgkin lymphoma, transformed WM, transformed MZL and Burkitt lymphoma 4. Participant must have no prior treatment with epcoritamab or any other bispecific antibody targeting CD3 and CD20 5. Relapsing or refractory after two systemic lines of treatment including CAR T-cells therapy (Note: bridging therapy is not considered as a line of treatment) R/R status will be determined by a PET scan performed approximately 1 month after CAR T cells infusion or on subsequent PET scans Note: Participant who received a combination of CAR T-cells therapy and immunomodulatory drugs (IMids) as second line are not eligible 6. ECOG performance status 0 to 2 7. Presence of disease specific criteria allowing response evaluation: * Bi-dimensionally measurable disease defined by at least one lymph node \> 15 mm or extranodal lesion \> 10mm * At least one hypermetabolic lesion demonstrated by 18FDG PET-CT (PET0) 8. Adequate hematopoietic function at screening as follows (unless cytopenia is clearly due to bone marrow involvement, or hypersplenism): * Hemoglobin level \> 8g/dL without RBC transfusion performed within 7 days before epcoritamab infusion * ANC ≥ 1 G/L (except if related to lymphoma involvement, ANC must be \> 0.5 G/L) * Platelets ≥ 50 G/L without platelet transfusion performed within 7 days before epcoritamab (except if related to lymphoma, hypersplenism, platelets must be \> 30 G/L) 9. Adequate renal function (calculated MDRD or Cockcroft-Gault): Creatinine Clearance ≥ 40 ml/min 10. 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 11. No persistent CAR-T neurotoxicity symptoms (regardless of grade) 12. Other adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1 (excepted the events previously described in criteria 8 to 11) 13. Negative HIV test at screening, with the following exception: Individuals with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy for at least 4 weeks, have a CD4 count ≥ 200/uL, have an undetectable viral load, and have not had a history of opportunistic infection attributable to AIDS within the last 12 months. 14. Participant must not have documented refractoriness to IMids and must be suitable for treatment with lenalidomide in the opinion of the investigator. Note: Refractoriness to IMids is defined as: * Best response to prior IMids regimen of SD or PD, OR * Progressive disease within 6 months of completion of prior IMids regimen 15. Participant must not have had lenalidomide exposure within 12 months prior to screening. 16. Participant must be willing to take aspirin prophylaxis or prophylactic anticoagulation for thromboembolic event (or per local guidelines for lenalidomide administration). 17. Participant must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction). 18. Women of childbearing potential (WOCBP): * should have a negative result for pregnancy test (minimum sensitivity of 25mIU/mL, urine or serum) at screening * should agree to use at least one efficient method of birth control from 4 weeks prior to study treatment initiation, during study treatment administration and until 4 weeks after the last dose of lenalidomide and until 19. Men of reproductive potential should agree to use an acceptable method of birth control (condom) and must agree not to donate sperm during treatment and for 7 days after the last dose of lenalidomide and until 12 months after the last dose of epcoritamab
Exclusion criteria
1. Previously known CD20 negative status, excepted if a new biopsy or cytometry analysis proving a CD20 positive status is available before enrollment 2. Prior solid organ transplantation 3. Prior allogeneic SCT 4. Autologous SCT within 100 days prior to epcoritamab infusion 5. Known or current central nervous system or meningeal involvement by lymphoma 6. Current or past history of Progressive Multifocal Leukoencephalopathy (PML) 7. Current or past history of aphasia, delirium, dementia, cerebellar disease, cognitive disorder, epilepsy under treatment, CNS vasculitis, neurodegenerative disease or dysarthria 8. History of cerebrovascular ischemia / hemorrhage with sequelae 9. Any serious psychiatric illness that would prevent the participant from signing the informed consent form 10. Patients with known active infection, or reactivation of a latent infection, whether bacterial, viral (including, but not limited to symptomatic SARS CoV-2 infection), 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) within 1 week prior epcoritamab first injection Note: positive PCR EBV related to lymphoma could be enrolled 11. Known positive HTLV1 serology 12. Active Hepatitis C Virus (HCV) infection (RNA PCR-positive). Participants who received treatment for HCV infection that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable, 13. Active Hepatitis B Virus (HBV) infection (DNA PCR-positive). 14. LVEF \< 45% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan 15. Any serious active disease or co-morbid medical condition (such as New York Heart Association Class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including uncontrolled obstructive pulmonary disease and history of bronchospasm or other according to investigator's decision) 16. Uncontrolled cirrhosis 17. Major surgery or significant traumatic injury \< 28 days prior to the epcoritamab infusion (excluding biopsies) or anticipation of the need for major surgery during study treatment 18. Received systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception ofcorticosteroid treatment \< 25 mg/day prednisone or equivalent within 2 weeks prior to epcoritamab first infusion. Inhaled and topical steroids are permitted. 19. Active malignancy other than the one treated in this Study. 20. Prior history of malignancies unless the participant has been free of the disease (in CR) for ≥ 2 years. However, participants with the following history/concurrent conditions are allowed: 1. Non-invasive basal cell or epidermoid carcinoma 2. In situ carcinoma of the cervix 3. In situ carcinoma of the breast 4. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor, nodes, metastasis \[TNM\] clinical staging system Note: Woman with adjuvant endocrine therapy (i.e., hormonotherapy) after breast cancer treatment can be enrolled if hormonotherapy was started for ≥ 2 years 21. Known or suspected hypersensitivity to the active substance or to any of the excipients. 22. Prior treatment within 4 weeks or five half-lives of the drug, whichever is shorter, before epcoritamab infusion with: - standard radiotherapy * any chemotherapeutic agent or treatment with any other investigational anti-cancer agents (defined as treatment for which there is currently no regulatory authority approved indication) * systemic immunotherapeutic agents, including, but not limited to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (e.g., anti-CTLA4, anti-PD1 and anti-PDL1) 23. Pregnant, planning to become pregnant or lactating or breastfeeding woman of childbearing potential 23. Pregnant, planning to become pregnant or lactating or breastfeeding woman of childbearing potential 24. Any significant medical conditions, or laboratory abnormality or psychiatric illness likely to interfere with participation in this clinical study (according to the investigator's decision) 25. Participant deprived of his/her liberty by a judicial or administrative decision 26. Participant hospitalized without consent 27. Adult participant under legal protection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | At the end of Cycle 2 (each cycle is 28 days) or until premature treatment discontinuation (PTD) from any cause, whichever occurs first, assessed up to 56 days | Overall response rate (ORR), defined as the proportion of participants achieving a complete response (CR) or partial response (PR) according to the 2014 Lugano Response Criteria following treatment with accelerated ramp-up dosing and fixed-dose epcoritamab in combination with lenalidomide. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (Best ORR) | From Cycle 1 through the end of Cycle 8 (each cycle is 28 days) or until premature treatment discontinuation (PTD) from any cause, whichever occurs first, assessed up to 224 days. | Best overall response rate (Best ORR), defined as the proportion of participants achieving a complete response (CR) or partial response (PR) as their best overall response according to the 2014 Lugano Response Criteria during study treatment. |
| Complete Metabolic Response (CMR) Rate | At Cycles 1, 2, 5, 8, and 12 (each cycle is 28 days), assessed up to 336 days. | Proportion of participants achieving a complete metabolic response (CMR) according to the 2014 Lugano Response Criteria. |
| Duration of Response (DoR) | From the date of first documented partial or complete response until the date of first documented disease progression, relapse, or death from any cause, whichever occurs first, assessed up to 54 months ( end of follow-up). | Duration of response (DoR), defined as the time from the first documented complete metabolic response (CMR) or partial metabolic response (PMR) according to the 2014 Lugano Response Criteria until the first documented disease progression, relapse, or death from any cause. |
| Progression-Free Survival (PFS) | From date of Cycle 1 (each cycle is 28 days)until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 54 months | Progression-free survival (PFS), defined as the time from the first dose of study treatment to the first documented disease progression according to the 2014 Lugano Response Criteria or death from any cause, whichever occurs first. |
| Overall Survival (OS) | From Cycle 1 ( 28 days) until date of death, or until end of follow-up (up to 54 months) | Overall survival (OS), defined as the time from the first dose of study treatment until death from any cause. |
| Incidence of Tumor Lysis Syndrome (TLS) | From Cycle 1 until Cycle 12 ( each cycle is 28 days) or until the date of the permanent treatment discontinuation (PTD) or date of death from any cause, whichever occurs first. Assessed up to 336 days. | Number and proportion of participants experiencing tumor lysis syndrome (TLS), graded according to the protocol-specified toxicity criteria. |
| Incidence of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) | From Cycle 1 until Cycle 12 ( each cycle is 28 days) or until the date of the permanent treatment discontinuation (PTD) from any cause, whichever occurs first. Assessed up to 336 days | Number and proportion of participants experiencing ICANS. |
| Incidence of Cytokine Release Syndrome (CRS) | From Cycle 1 until Cycle 12 ( each cycle is 28 days) or until the date of the permanent treatment discontinuation (PTD) from any cause, whichever occurs first. Assessed up to 336 days | Number and proportion of participants experiencing cytokine release syndrome (CRS). |
| Incidence of Cytopenias | From Cycle 1 until Cycle 12 ( each cycle is 28 days) or until the date of the permanent treatment discontinuation (PTD) from any cause, whichever occurs first. Assessed up to 336 days | Number and proportion of participants experiencing treatment-emergent cytopenias. |
| Incidence of Infections | From Cycle 1 until Cycle 12 ( each cycle is 28 days) or until the date of the permanent treatment discontinuation (PTD) from any cause, whichever occurs first. Assessed up to 336 days | Number and proportion of participants experiencing treatment-emergent infections. |
Countries
France
Contacts
CONTACTStéphanie Doyen
CONTACTNina Pronina
Outcome results
None listed