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

Purpose

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 for relapsed/refractory chronic lymphocytic leukemia (R/R CLL): - epcoritamab + venetoclax - 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 CLL/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.

Conditions

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

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 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.

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 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.

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Epcoritamab in R/R CLL/SLL 		In both study phases. Participants in the expansion phase will be treated at the RP2D defined in the dose-escalation phase.
  • Biological: Epcoritamab
    Epcoritamab will be administered subcutaneously in cycles of 28 days (except Cycle 1 for high-dose cohorts = 35 days).
    Other names:
    • EPKINLY™
    • GEN3013
    • DuoBody®-CD3xCD20
  • Biological: Epcoritamab
    Epcoritamab will be administered subcutaneously in cycles of 28 days from Cycles 1 to 12. If dMRD at Cycle 11, epcoritamab can be continued up to maximum of Cycle 21. Also, if Cycle 11 Day 1 dMRD assessment is not available, epcoritamab may be continued until Cycle 21.
    Other names:
    • EPKINLY™
    • GEN3013
    • DuoBody®-CD3xCD20
Experimental
Epcoritamab in RS 		Only in expansion phase.
  • Biological: Epcoritamab
    Epcoritamab will be administered subcutaneously in cycles of 28 days up to 26 cycles.
    Other names:
    • EPKINLY™
    • GEN3013
    • DuoBody®-CD3xCD20
Experimental
Epcoritamab + Venetoclax in R/R CLL/SLL 		In both study phases. Participants in the expansion phase will be treated at the RP2D defined in the dose-escalation phase.
  • Biological: Epcoritamab
    Epcoritamab will be administered subcutaneously in cycles of 28 days (except Cycle 1 for high-dose cohorts = 35 days).
    Other names:
    • EPKINLY™
    • GEN3013
    • DuoBody®-CD3xCD20
  • Drug: Venetoclax
    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.
Experimental
Epcoritamab + Lenalidomide in RS 		Only in expansion phase.
  • Biological: Epcoritamab
    Epcoritamab will be administered subcutaneously in cycles of 28 days up to 26 cycles.
    Other names:
    • EPKINLY™
    • GEN3013
    • DuoBody®-CD3xCD20
  • Drug: Lenalidomide
    Lenalidomide capsules will be administered once daily for 21 days in each cycle of 28 days up to 12 cycles.
Experimental
Epcoritamab + R-CHOP in RS 		Only in expansion phase.
  • Biological: Epcoritamab
    Epcoritamab will be administered subcutaneously in cycles of 21 days (Cycle 1-6) and 28 days for Cycle 7 and beyond (up to 15 cycles).
    Other names:
    • EPKINLY™
    • GEN3013
    • DuoBody®-CD3xCD20
  • Drug: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone
    R-CHOP will be administered intravenously in cycles of 21 days for the first 6 cycles.
Experimental
Epcoritamab + Pirtobrutinib in R/R CLL/SLL 		Safety run-in and expansion phases.
  • Biological: Epcoritamab
    Epcoritamab will be administered subcutaneously in cycles of 28 days up to 12 cycles. If detectable minimum residual disease (dMRD) at Cycle 11 Day 1 or partial remission (PR) at Week 36 response assessment, epcoritamab may be continued until Cycle 21. Also, If Cycle 11 Day 1 dMRD assessment is not available, epcoritamab may be continued until Cycle 21.
    Other names:
    • EPKINLY™
    • GEN3013
    • DuoBody®-CD3xCD20
  • Drug: Pirtobrutinib
    Pirtobrutinib tablets will be administered in cycles of 28 days for a total of 24 cycles.
Experimental
Fixed Duration Epcoritamab in R/R CLL/SLL 		Only in expansion phase.
  • Biological: Epcoritamab
    Epcoritamab will be administered subcutaneously in cycles of 28 days from Cycles 1 to 12. If dMRD at Cycle 11, epcoritamab can be continued up to maximum of Cycle 21. Also, if Cycle 11 Day 1 dMRD assessment is not available, epcoritamab may be continued until Cycle 21.
    Other names:
    • EPKINLY™
    • GEN3013
    • DuoBody®-CD3xCD20

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 02114

More Details

Status
Recruiting
Sponsor
Genmab

Study Contact

Genmab Trial Information
+4570202728
clinicaltrials@genmab.com

Detailed Description

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/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.