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

Open to people ages 18 years and up

1. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
2. Evidence of CD20 positivity in a sample representative of the disease at Screening.
3. Acceptable hematology parameters and organ function based on baseline bloodwork.
4. Life expectancy >3 months on standard of care (SOC) for CLL, >3 months for RS.
5. For R/R CLL arms - Must have active CLL/SLL disease requiring treatment per iwCLL 2018 criteria.
6. For R/R CLL monotherapy arm - Received at least 2 prior lines of systemic anti-neoplastic therapy including a Bruton's tyrosine kinase (BTK) inhibitor.
7. For all RS arms - Have tumor biopsy-proven CD20+ Diffuse large B-cell Lymphoma (DLBCL) and a clinical history of CLL/SLL.
8. 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.
9. For all RS arms - Must provide mandatory formalin-fixed, paraffin-embedded (FFPE) tumor biopsy sample.
10. For RS - monotherapy arm: Deemed as ineligible for chemoimmunotherapy at investigator's discretion or participant who refuses to receive intensive chemotherapy
11. 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.
12. 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.
13. For R/R CLL - venetoclax combination Therapy arm - after receiving at least 1 prior line of systemic antineoplastic therapy.
    • Presence of measurable disease (absolute lymphocyte count >5,000/microliter [μL], measurable lymph nodes ≥1.5 centimeters (cm) on imaging, or bone marrow involvement of CLL ≥30%).
    • Females of childbearing potential must use highly effective contraceptive measures while taking venetoclax and for 30 days after stopping treatment.
    • Must take prophylaxis for tumor lysis syndrome (TLS).
14. A woman must agree not to breastfeed a child during treatment and for 4 months after last treatment.
15. For R/R CLL pirtobrutinib combination Therapy arm:
    • Must have active CLL/SLL disease requiring treatment per iwCLL 2018 criteria.
    • Presence of measurable disease (absolute lymphocyte count >5,000/μL, measurable lymph nodes ≥1.5cm on imaging, or bone marrow involvement of CLL ≥30%).
    • Previous treatment with at least one and a maximum 3 prior lines of therapy.
    • Diagnosis of CLL/SLL that meets published diagnostic criteria.
    • Females of childbearing potential must use highly effective contraceptive measures while taking pirtobrutinib and for 5 weeks after the last dose.
    • A woman must agree not to breastfeed a child during treatment and until one week after last dose.
    • A man who is sexually active with a woman of childbearing potential must use an effective method of contraception during treatment and for 3 months after last dose.

1. Received prior treatment with a CD3×CD20 bispecific antibody.
2. Received any prior allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation.
3. Received chimeric antigen receptor (CAR) T-cell therapy within 100 days or an investigational drug within 4 weeks, prior to first dose of epcoritamab.
4. Autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy.
5. Received vaccination with live vaccines within 28 days.
6. Clinically significant cardiac disease.
7. Known current malignancy other than inclusion diagnosis.
8. Has had major surgery within 4 weeks.
9. Any of the following active infections:
   • Hepatitis C
   • Human T cell leukemia virus infection
   • Active cytomegalovirus (CMV) infection
10. Known history of human immunodeficiency virus (HIV).
11. For R/R CLL arms - Any history of RS or evidence indicating a potential Richter's transformation. R/R CLL - Pirtobrutinib Combination Therapy Arm - Any history of RS or evidence indicating a potential Richter's transformation.
12. Received venetoclax within 24 months prior to beginning venetoclax ramp-up for this trial or progressed on venetoclax treatment.
13. For all RS arms - Diagnosis of Richter's syndrome not of the DLBCL subtype such as Hodgkin's lymphoma, prolymphocytic leukemia.
14. RS - Lenalidomide Combination Therapy and RS Monotherapy Arms - received more than 2 prior lines of therapy for RS.
15. R/R CLL - Pirtobrutinib Combination Therapy Arm - history of bleeding disorders or participants requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
16. Additional exclusion criteria specific to participants in epcoritamab monotherapy, venetoclax + epcoritamab, R-CHOP + epcoritamab, Pirtobrutinib + epcoritamab arms, participants with paraimmunoblastic transformation, prolymphocytic progression, or accelerated phase CLL.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.