Safety and Efficacy Study of Epcoritamab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome

Study Overview
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Brief Summary
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The study is a global, multi-center safety and efficacy trial of epcoritamab, an antibody also known as EPKINLY™ and GEN3013 (DuoBody®-CD3xCD20). Epcoritamab will either be studied as: Monotherapy, or Combination therapy: epcoritamab + venetoclax epcoritamab + lenalidomide epcoritamab + R-CHOP (i.e., rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone). The study includes patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL)/small lymphocytic lymphoma (SLL) and patients with Richter's Syndrome (RS). Study participants with R/R CLL/SLL are treated either with epcoritamab as monotherapy or epcoritamab + venetoclax. Study participants with RS are treated either with epcoritamab as monotherapy or epcoritamab + lenalidomide or epcoritamab + R-CHOP. The trial consists of two parts, a dose-escalation phase (phase Ib) and an expansion phase (phase II). Patients with RS are only included in the expansion phase.

Detailed Description
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The purpose of the dose-escalation phase of the trial is to determine the recommended phase 2 dose (RP2D) and the maximum tolerated dose (MTD; if reached) as well as establish the safety profile of epcoritamab monotherapy and epcoritamab + venetoclax in participants with R/R CLL. The purpose of the expansion phase is to assess and evaluate the preliminary efficacy, safety and tolerability profiles of epcoritamab monotherapy and epcoritamab + venetoclax at the RP2D for patients with R/R CLL/SLL. Along with this, epcoritamab monotherapy, epcoritamab + lenalidomide and epcoritamab + R-CHOP will be evaluated in patients with RS to assess their efficacy, safety and tolerability profiles.

Official Title
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A Phase 1b/2, Open-Label, Safety and Efficacy Study of Epcoritamab (GEN3013; DuoBody®-CD3xCD20) in Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome

Conditions
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Richter's Syndrome, Relapsed/Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Biological: Epcoritamab
* Biological: Epcoritamab
* Drug: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone
* Drug: Venetoclax
* Biological: Epcoritamab
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. Evidence of CD20 positivity in a sample representative of the disease at Screening. Acceptable hematology parameters and organ function based on baseline bloodwork. For R/R CLL arms - Must have active CLL/SLL disease requiring treatment per iwCLL 2018 criteria. For R/R CLL arms - Received at least 2 prior lines of systemic anti-neoplastic therapy including a Bruton's tyrosine kinase (BTK) inhibitor. For all RS arms - Have tumor biopsy-proven CD20+ Diffuse large B-cell Lymphoma (DLBCL) and a clinical history of CLL/SLL. For all RS arms - Must have measurable disease by fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) or magnetic resonance imaging (MRI) scan. For all RS arms - Must provide mandatory formalin-fixed, paraffin-embedded (FFPE) tumor biopsy sample. Life expectancy >3 months on standard of care (SOC). For RS - monotherapy arm: Deemed as ineligible for chemoimmunotherapy at investigator's discretion or participant who refuses to receive intensive chemotherapy For RS - lenalidomide combination therapy arm Deemed as ineligible for chemoimmunotherapy at the investigator's discretion, or participant who refuses to receive intensive chemotherapy. Eligible for treatment with lenalidomide. Must be willing to use contraception and adhere to the Lenalidomide Pregnancy Risk Minimization Plan For RS - R-CHOP combination Therapy Arm - Eligible for treatment with R-CHOP. For R/R CLL - venetoclax combination Therapy arm - after receiving at least 1 prior line of systemic antineoplastic therapy. Key Exclusion Criteria Received prior treatment with a CD3×CD20 bispecific antibody. Received any prior allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. Received (CAR) T-cell therapy within 100 days or an investigational drug within 4 weeks, prior to first dose of epcoritamab. Autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy. Received vaccination with live vaccines within 28 days. Clinically significant cardiac disease. Known current malignancy other than inclusion diagnosis. Has had major surgery within 4 weeks. Active hepatitis B virus or active hepatitis C. Known history of HIV. For R/R CLL arms - Any history of RS or evidence indicating a potential Richter's transformation. Received venetoclax within 24 months prior to beginning venetoclax ramp-up for this trial and progressed on treatment. For all RS arms - Diagnosis of Richter's syndrome not of the DLBCL subtype such as Hodgkin's lymphoma, prolymphocytic leukemia. RS - Lenalidomide Combination Therapy and RS Monotherapy Arms - received more than 2 prior lines of therapy for RS. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epcoritamab in R/R CLL/SLL<br>In both study phases. Participants in the expansion phase will be treated at the RP2D defined in the dose-escalation phase. | Biological: Epcoritamab<br>* Epcoritamab will be administered subcutaneously in cycles of 28 days (except Cycle 1 for high-dose cohorts = 35 days).<br>* Other names: DuoBody®-CD3xCD20;|
| Experimental: Epcoritamab in RS<br>Only in expansion phase. | Biological: Epcoritamab<br>* Epcoritamab will be administered subcutaneously in cycles of 28 days.<br>* Other names: DuoBody®-CD3xCD20;|
| Experimental: Epcoritamab + Venetoclax in R/R CLL/SLL<br>In both study phases. Participants in the expansion phase will be treated at the RP2D defined in the dose-escalation phase. | Biological: Epcoritamab<br>* Epcoritamab will be administered subcutaneously in cycles of 28 days (except Cycle 1 for high-dose cohorts = 35 days).<br>* Other names: DuoBody®-CD3xCD20;Drug: Venetoclax<br>* Venetoclax tablets will be administered orally once daily during the 5-week ramp up period and during Cycle 1-26 of 28 or 35 days each.<br>|
| Experimental: Epcoritamab + Lenalidomide in RS<br>Only in expansion phase. | Biological: Epcoritamab<br>* Epcoritamab will be administered subcutaneously in cycles of 28 days.<br>* Other names: DuoBody®-CD3xCD20;Drug: Lenalidomide<br>* Lenalidomide capsules will be administered once daily for 21 days in each cycle of 28 days up to 12 cycles.<br>|
| Experimental: Epcoritamab + R-CHOP in RS<br>Only in expansion phase. | Biological: Epcoritamab<br>* Epcoritamab will be administered subcutaneously in cycles of 21 days (Cycle 1-6) and 28 days for Cycle 7 and beyond.<br>* Other names: DuoBody®-CD3xCD20;Drug: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone<br>* R-CHOP will be administered intravenously in cycles of 21 days for the first 6 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Phase (R/R CLL arm): Number of Participants with Dose Limiting Toxicities (DLTs) | DLT events were defined as clinically significant adverse events (AEs) or abnormal laboratory values assessed as unrelated to disease progression, underlying disease, intercurrent illness, or concomitant medications as assessed per Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria version 5.0. | During the first cycle for low dose cohorts (Cycle length = 28 days) and for high dose cohorts (Cycle length = 35 days) | 
| Dose Escalation Phase: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | From first dose until the end of the safety follow-up period (60 days after last dose) | 
| Dose Escalation Phase: Number of Participants with Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and Clinical Tumor Lysis Syndrome (CTLS) | CRS and ICANS will be graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria. CTLS will be graded according to Cairo-Bishop criteria. | From first dose until the end of the safety follow-up period (60 days after last dose) | 
| Expansion Phase: Overall Response Rate (ORR) | ORR is defined as the percentage of participants who achieve a response of partial response or complete response, prior to initiation of subsequent therapy. R/R CLL participants will be assessed according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and the RS participants according to Lugano criteria. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expansion Phase: Number of Participants with TEAEs and SAEs |  | From first dose until the end of the safety follow-up period (60 days after last dose) | 
| Dose Escalation Phase: ORR | ORR is defined as percentage of participants who achieve a response of partial response or complete response, prior to initiation of subsequent therapy as assessed by iwCLL criteria. | Up to 5 years | 
| Both Phases: Duration of Response (DOR) | DOR is defined among responders, as the time from the initial documentation of response to the date of disease progression or death, whichever occurs earlier. | Up to 5 years | 
| Both Phases: Number of Participants with Complete Remission (CR) / CR with Incomplete Bone Marrow Recovery (CRi) | CR and CRi for R/R CLL participants will be assessed according to iwCLL criteria and CR for the RS participants, according to Lugano criteria. | Up to 5 years | 
| Both Phases: Time to Response (TTR) | TTR is defined among responders, as the time between first dose of epcoritamab and the initial documentation of response. | Up to 5 years | 
| Both Phases: Progression Free Survival (PFS) | PFS is defined as the time from the first dosing date of epcoritamab and the date of disease progression or death, whichever occurs earlier. | Up to 5 years | 
| Both Phases: Overall Survival (OS) | OS is defined as the time from the first dosing date of epcoritamab and the date of death due to any cause. | Up to 5 years | 
| Both Phases: Time to Next Systemic Anti-cancer Therapy (TTNT) | TTNT is defined as the time from the first dosing date of epcoritamab to the first documented administration of subsequent systemic anticancer therapy. | Up to 5 years | 
| Both Phases: Area Under the Concentration-time Curve (AUC) From Time Zero to Last Quantifiable Sample (AUClast) in Epcoritamab |  | Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days) | 
| Both Phases: AUC From Time Zero to Infinity (AUCinf) in Epcoritamab |  | Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days) | 
| Both Phases: Maximum (Peak) Plasma Concentration (Cmax) in Epcoritamab |  | Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days) | 
| Both Phases: Pre-dose (Trough) Concentrations (Cthrough) in Epcoritamab |  | Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days) | 
| Both Phases: Time to Reach Cmax (Tmax) in Epcoritamab |  | Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days) | 
| Both Phases: Elimination Half-life (T1/2) in Epcoritamab |  | Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days) | 
| Both Phases: Total Body Clearance of Drug From Plasma (CL) in Epcoritamab |  | Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days) | 
| Both Phases: Volume of distribution (Vd) in Epcoritamab |  | Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days) | 
| Both Phases: Lymphoid Cells for Immunophenotyping | Evaluation of B cells, T cells and their activation | Up to 5 years | 
| Expansion Phase: Number of Participants with CRS, ICANS and CTLS | CRS and ICANS will be graded based on ASTCT criteria. CTLS will be graded according to Cairo-Bishop criteria. | From first dose until the end of the safety follow-up period (60 days after last dose) | 
| Expansion Phase: Percentage of Participants with Minimal Residual Disease (MRD) Negativity | MRD negativity rate, is defined as the proportion of participants with at least 1 undetectable MRD result according to the specific threshold, prior to initiation of subsequent therapy. | Up to 5 years | 
| Both Phases: Number of Participants with Anti-drug Antibodies (ADA) to Epcoritamab |  | Up to end of treatment period (Up to 2 years) | 
| Expansion Phase: Number of Participants with Partial Remission (PR)/Nodular Partial Remission (nPR) | nPR is defined as PR with residual nodules or suspicious lymphocytic infiltrates in participants who are in remission. nPR is only calculated for R/R CLL. | Up to 5 years | 
| Both Phases: Duration of MRD Negativity | The time from first achieving MRD negativity after start of treatment to the MRD conversion to positive. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DuoBody®, Bispecific antibodies, Anti-CD3, Anti-CD20