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.

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, epcoritamab + venetoclax and epcoritamab + pirtobrutinib at the RP2D for participants with R/R CLL, TN HR CLL (in non-US participants only) and SLL. Along with this, epcoritamab monotherapy, epcoritamab + lenalidomide and epcoritamab + R-CHOP will be evaluated in participants with RS to assess their efficacy, safety and tolerability profiles.

The purpose of safety run-in phase for pirtobrutinib combination therapy is to evaluate the safety and tolerability profiles of pirtobrutinib in combination with epcoritamab.

Key Inclusion Criteria

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 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.

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.
    • Must take prophylaxis for tumor lysis syndrome (TLS).

14. 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.

15. 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.

Key Exclusion Criteria

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 trial drug.

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. Known history of human immunodeficiency virus (HIV).

10. For R/R CLL arms - Any history of RS or evidence indicating a potential Richter's transformation.

11. For R/R CLL - Venetoclax Combination Therapy arm: received venetoclax within 24 months prior to beginning venetoclax ramp-up for this trial or has progressed on venetoclax treatment.

12. For all RS arms - Diagnosis of Richter's syndrome not of the DLBCL subtype such as Hodgkin's lymphoma, prolymphocytic leukemia.

13. RS - Lenalidomide Combination Therapy and RS Monotherapy Arms - received more than 2 prior lines of therapy for RS.

14. R/R CLL - Pirtobrutinib Combination Therapy Arm - Prior exposure to a non-covalent (reversible) BTK inhibitor or a BTK degrader.

15. Pirtobrutinib Combination Therapy Expansion Arms:

    • History of bleeding disorders or participants requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist
    • Require continuous treatment with or have received strong cytochrome P450 (CYP) 3A inhibitors or strong/moderate CYP3A inducers within 4 to 5 half-lives or 14 days prior to the first dose of pirtobrutinib.

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