Subcutaneous Epcoritamab With or Without Lenalidomide as First Line Therapy for Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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The purpose of the study is to examine efficacy and safety of epcoritamab with and without lenalidomide in newly diagnosed elderly patients with Diffuse Large B-Cell Lymphoma (DLBCL) who cannot tolerate anthracycline therapy. Epcoritamab (also known as EPKINLY™, GEN3013 and DuoBody®-CD3xCD20) is an antibody that has already been tested in several clinical studies. All patients will receive active treatment. There is an equal chance of receiving epcoritamab or epcoritamab plus lenalidomide.

Detailed Description
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This is an open-label, multicenter, global phase-2 trial evaluating the efficacy and safety of epcoritamab monotherapy and epcoritamab plus lenalidomide in elderly patients who are deemed anthracycline ineligible. The trial is designed in two stages: Stage 1 which includes a safety run-in phase in each arm Stage 2, an expansion of the selected treatment from Stage 1

Official Title
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Efficacy and Safety of Epcoritamab Monotherapy and in Combination With Lenalidomide as First-line Therapy for Anthracycline-ineligible Diffuse Large B-Cell Lymphoma Patients, an Open-label, Randomized, Multicenter, Global Phase 2 Trial

Conditions
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Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Biological: Epcoritamab
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have newly diagnosed CD20+ large cell lymphoma. Is ineligible for anthracycline-based therapy/cytotoxic chemotherapy due to: Being age ≥80 years; AND/OR Being age ≥75 years and having important comorbid condition(s), which are likely to have a negative impact on tolerability of anthracycline-based therapy/cytotoxic chemotherapy. Have Immune Effector Cell-Associated Encephalopathy (ICE) score of at least 8 out of 10. Have Ann Arbor Stage II-IV disease. Have ECOG PS of 0, 1, or 2; (ECOG PS of 3 may be considered if impairment is attributed to current lymphoma/DLBCL and if pre-phase treatment during the screening phase results in an improvement of ECOG PS to ≤2 prior to enrollment). Have measurable disease as per Lugano criteria. Have acceptable organ function based on baseline bloodwork. Must have fresh (preferred) or archival biopsy material at screening. Exclusion Criteria: Has known active, clinically significant bacterial, viral, fungal, mycobacterial, parasitic, or other infection at trial enrollment, including COVID-19 infection. Has severe cardiovascular disease (other than those eligibility criteria that preclude the subject from receiving anthracycline-based therapy/cytotoxic chemotherapy), Has been exposed to/received any of the following prior therapies, treatments, or procedures within the specified timeframes: Major surgery within 4 weeks prior to the first dose of epcoritamab; Non-investigational antineoplastic agents (except anti-CD20 monoclonal antibodies) or any investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of epcoritamab; Autologous hematopoietic stem cell transplantation (HSCT), CAR-T, allogeneic stem cell transplantation, or solid organ transplantation; Live, attenuated vaccines within 30 days prior to initiation of epcoritamab; Investigational vaccines within 28 days before the planned first dose of epcoritamab (ie, experimental and/or non-authorized SARS-CoV-2 vaccinations and therapies are not allowed); Invasive investigational medical device use within 28 days before the planned first dose of epcoritamab. Has primary central nervous system (CNS) tumor or known CNS involvement or intracranial involvement as confirmed by mandatory brain magnetic resonance imaging/computed tomography (MRI/CT) scan at screening and, if clinically indicated, by lumbar puncture. Has a seizure disorder requiring anti-epileptic therapy or experienced a seizure within 6 months of signing an informed consent form. Has known past or current malignancy other than inclusion diagnosis, with exceptions as stated in protocol. Has known or suspected allergies, hypersensitivity, or intolerance to either of the trial treatments or has known or suspected contraindication to the use of all locally available anti-cytokine therapies per local guidelines for management of cytokine release syndrome (CRS). Has active hepatitis B virus (HBV) (DNA polymerase chain reaction [PCR]-positive) or hepatitis C virus (HCV) (RNA PCR-positive) infection, current alcohol abuse, or cirrhosis. Has active cytomegalovirus (CMV) infection (DNA PCR-positive) requiring treatment. Has suspected active or inadequately treated latent tuberculosis. Has a known history of seropositivity for HIV. Note: HIV testing is required at screening only if required per local health authorities or institutional standards. Note: Other protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epcoritamab monotherapy<br> | Biological: Epcoritamab<br>* Epcoritamab will be administered by subcutaneous (SC) injections in 28-day cycles for up to 12 cycles.<br>* Other names: EPKINLY™;|
| Experimental: Epcoritamab in combination with lenalidomide<br> | Biological: Epcoritamab<br>* Epcoritamab will be administered by subcutaneous (SC) injections in 28-day cycles for up to 12 cycles.<br>* Other names: EPKINLY™;Drug: Lenalidomide<br>* Lenalidomide will be administered orally (capsules; starting dose of 10 or 20 mg) once daily on Day 1 to Day 21 of each 28-day cycle for up to 12 cycles.<br>* Other names: Revlimid®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) rate | Percentage of participants achieving CR. Assessed by the Investigator per Lugano criteria | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | Defined as the time between date of first response to the date of first documented tumor progression or death (due to any cause) whichever occurs first | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 2 years | 
| Duration of complete response (DOCR) | Defined as the time between the date of first CR to the date of the first documented tumor progression or death due to any cause, whichever comes first | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 2 years | 
| Time to response (TTR) | Defined as the time from first dose to first documentation of objective tumor response (CR or PR) | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 1 year | 
| Overall Response Rate (ORR) | Defined as the percentage of patients who achieve best overall response of complete response (CR) or partial response (PR) determined by Lugano criteria | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 2 years | 
| Progression-free survival (PFS) | Defined as the time from first dose to date of PD or death (due to any cause) whichever occurs first | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 2 years | 
| Time to next anti-lymphoma therapy (TTNT) | Defined as the time from first dose to administration of subsequent anti-lymphoma therapy | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 2 years | 
| Rate of minimal residual disease (MRD) negativity | Percentage of participants with at least 1 post-screening MRD negative result | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 2 years | 
| Overall survival (OS) | Defined at the timeframe from first dose to death | From randomization (for patients enrolled in stage 1) or from first dose (for patients enrolled in stage 2) and up to 3 years | 
| Incidence and severity of adverse events (AEs) | An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment | From screening until end of the safety follow-up period (60 days after last dose) | 
| Incidence of clinically significant shifts in laboratory parameters | Clinical laboratory parameters assessed: hematology, chemistry, coagulation, tumor lysis, cardiac enzymes, immunoglobulins, and urinalyses | From screening until end of the safety follow-up period (60 days after last dose) | 
| Incidence of anti-drug antibodies (ADAs) to epcoritamab in plasma | To evaluate immunogenicity | From first dose until treatment discontinuation (assessed up to 12 months) | 
| Evaluate patient-reported outcomes (PROs) related to lymphoma symptoms | Changes in lymphoma symptoms as measured by the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym). Scale from 0-168 obtained by summing individual subscale scores. Higher scores for the scales indicate better quality of life | From cycle 1, day 1 until 90 days after last dose (each cycle is 28 days) | 
| Assess pharmacokinetics (PK) of epcoritamab | Total body clearance of drug from the plasma (CL) | From first dose and at multiple time points until treatment discontinuation (assessed up to 12 months) | 
| Assess pharmacokinetics (PK) of epcoritamab | Volume of Distribution | From first dose and at multiple time points until treatment discontinuation (assessed up to 12 months) | 
| Assess pharmacokinetics (PK) of epcoritamab | Area Under the Concentration-Time Curve (AUC) from Time 0 to last quantifiable sample | From first dose and at multiple time points until treatment discontinuation (assessed up to 12 months) | 
| Assess pharmacokinetics (PK) of epcoritamab | Area Under the Concentration-Time Curve (AUC) from Time 0 to infinity | From first dose and at multiple time points until treatment discontinuation (assessed up 12 months) | 
| Assess pharmacokinetics (PK) of epcoritamab | Maximum observed concentration (Cmax) | From first dose and at multiple time points until treatment discontinuation (assessed up to 12 months) | 
| Assess pharmacokinetics (PK) of epcoritamab | Time to reach Cmax (Tmax) | From first dose and at multiple time points until treatment discontinuation (assessed up to 12 months) | 
| Assess pharmacokinetics (PK) of epcoritamab | Terminal Elimination Half-Life (t 1/2) | From first dose and at multiple time points until treatment discontinuation (assessed up to 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Double-hit lymphoma, Triple-hit lymphoma, Follicular grade 3B, T-cell/histiocyte rich LBCL, DuoBody®, Anti-CD3, Anti-CD20, Subcutaneous, Bispecific antibody, EPCORE