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
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 be tested either in Relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as: * Monotherapy, or * Combination therapy: * epcoritamab + venetoclax * epcoritamab + pirtobrutinib In Non-United States (US) Participants Only: Treatment-naïve (TN) high risk (HR) (CLL): • epcoritamab + pirtobrutinib Combination therapy for Richter's Syndrome (RS): * epcoritamab + lenalidomide * epcoritamab + R-CHOP (i.e., rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine \[Oncovin®\] and prednisone). The study includes participants with R/R or TN HR CLL (non-US participants only)/small lymphocytic lymphoma (SLL) and participants with RS. The trial consists of two parts, a dose-escalation phase (phase Ib) and an expansion phase (phase II). Participants with RS are only included in the expansion phase. Epcoritamab will be injected subcutaneously (under the skin). Standard-of-care and combination treatments (venetoclax, pirtobrutinib, lenalidomide, and R-CHOP) will be given either orally (by mouth) or intravenously (in a vein). Study details include: * Study duration will be up to 5 years after the last participant's first treatment in the trial. * The treatment duration for each participant will be between 12 months (1 year) and 24 months (2 years), depending upon the treatment arm assigned. * The visit frequency will be either weekly, every other week, or monthly, depending upon the part of the study. All participants will receive active drug; no one will be given placebo.
• 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.
• Life expectancy \>3 months on standard of care (SOC) for CLL, \>3 months for RS.
• For R/R CLL arms - Must have active CLL/SLL disease requiring treatment per iwCLL 2018 criteria.
• For R/R CLL monotherapy arms - Received at least 2 prior lines of systemic anti-neoplastic therapy including a Bruton's tyrosine kinase (BTK) inhibitor or at least 1 prior line of systemic antineoplastic therapy, including treatment with (or intolerance of) a covalent BTK inhibitor (cBTKi) and a B-cell lymphoma 2 (BCL-2) 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.
⁃ 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
‣ A woman must agree not to breastfeed a child during treatment and for at least 28 days after discontinuation from study.
⁃ For RS - R-CHOP combination Therapy Arm -
∙ Eligible for treatment with R-CHOP.
‣ Females of childbearing potential must use highly effective contraceptive measures while taking R-CHOP and for 12 months after stopping treatment.
‣ A woman must agree not to breastfeed a child during treatment or until 12 months after last treatment.
⁃ For R/R CLL - venetoclax combination Therapy arm - after receiving at least 1 prior line of systemic antineoplastic therapy.
∙ Presence of measurable disease.
‣ Must take prophylaxis for tumor lysis syndrome (TLS).
⁃ For R/R CLL pirtobrutinib combination Therapy arm:
∙ Must have active CLL/SLL disease requiring treatment per iwCLL 2018 criteria.
‣ Presence of measurable disease.
‣ Previous treatment with at least one and a maximum 3 prior lines of therapy including a cBTKi.
‣ Diagnosis of CLL/SLL that met published iwCLL criteria.
⁃ Non-US Participants Only - Participants with TN HR CLL - Pirtobrutinib Combination Therapy Expansion:
∙ Diagnosis of CLL/SLL that met published iwCLL criteria 2018.
‣ Must have active CLL/SLL disease that needs treatment per iwCLL
‣ Must take prophylaxis for TLS based on their TLS risk evaluation upon initiation of trial drug.
‣ Must have one or more high-risk features.
‣ Presence of measurable disease.