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 EPCORITAMAB
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What's the purpose of this trial?

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 (Oncovin®) 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. Epcoritamab will be injected subcutaneously (under the skin). Standard-of-care and combination treatments (venetoclax, 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. * The treatment duration for each participant will be between 18 months (1.5 years) 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.

This trial is currently open and accepting patients.


What will happen during the trial?

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

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 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.

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 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.


Additional Trial Information

Phase 1/2

Enrollment: 304 patients (estimated)

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Published Results

Epcoritamab Monotherapy in Patients (Pts) with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Results from CLL Expansion and Optimization Cohorts of Epcore CLL-1

November 05, 2024

Results: As of May 28, 2024, 23 pts in EXP and 17 pts in OPT had received epcoritamab (median follow-up, 22.8 and 2.9 mo, respectively). Baseline characteristics were similar between cohorts, and across all 40 pts, median age was 71.5 y, median number of prior tx lines was 4 (range, 2-10), and median time from initial diagnosis to first epcoritamab dose was 11.6 y. All pts had prior BTKi, 88% had prior chemoimmunotherapy, and most had high-risk disease characteristics (TP53 aberrations, 63%; unmutated IGHV, 70%) and were double exposed to BTKi and BCL2i (85%). In EXP, ORR was 61% and CR rate was 39%. Median time to response was 2.0 mo and median time to CR was 5.6 mo. ORR/CR rate was 67%/33% among pts with TP53 aberrations (n=15), 63%/44% among pts with IGHV-unmutated disease (n=16), and 53%/37% among double-exposed pts (n=19). Among all pts in EXP, median progression-free survival was 12.8 mo and median OS was not reached, with an estimated 65% of pts remaining alive at 15 mo. Among 12 responders evaluable for minimal residual disease (MRD) by next-generation sequencing in peripheral blood, 9 (75%) had undetectable MRD (uMRD) at the standard 10−4 cutoff and 8 (67%) had uMRD at 10−6.

The most frequent nonhematologic tx-emergent AEs (TEAEs) in EXP were CRS (96%), diarrhea (48%), peripheral edema (48%), fatigue (43%), and injection-site reaction (43%). Cytopenias were common (anemia, 65%; thrombocytopenia, 65%; neutropenia, 48%); however, most pts had baseline anemia and thrombocytopenia, indicating that these AEs are disease related. Four fatal TEAEs occurred in EXP (pneumonia [n=2], sepsis [n=1], and squamous cell carcinoma of the skin [n=1]). No fatal TEAEs occurred in OPT. In EXP, CRS was manageable and primarily low grade (G; 9% G1, 70% G2, 17% G3); in OPT, CRS severity was substantially reduced, with only low-grade events (71% G1, 12% G2). In both cohorts, CRS events primarily occurred following the first full dose, and none led to tx discontinuation. In EXP, 3 ICANS events (G1, n=1; G2, n=2) and 1 CTLS event (G2) were reported; none led to tx discontinuation. No ICANS or CTLS occurred in OPT. Consistent with the reduced CRS severity in OPT, median IL-6 levels 24 h after the first full dose were markedly lower in OPT vs EXP.

Conclusions: Single-agent epcoritamab led to encouraging CR and uMRD rates in heavily pretreated R/R CLL, regardless of high-risk features. Immune-related toxicities were markedly improved with an adapted SUD schedule, with primarily G1 CRS and no ICANS. These findings provide evidence of efficacy and potential therapeutic applicability of epcoritamab in CLL and support its continued evaluation.

Trial Locations

All Trial Locations

View all clinical trial locations sorted by state.

California

City of Hope Comprehensive Cancer Center Beckman Research Institute

Duarte, CA

Open and Accepting

University of California Davis Comprehensive Cancer Center

Sacramento, CA

Open and Accepting

Stanford University Cancer Institute (Palo Alto)

Stanford, CA

Open and Accepting

Florida

Mount Sinai Comprehensive Cancer Center

Miami Beach, FL

Open and Accepting

Memorial Cancer Institute Memorial Hospital West

Pembroke Pines, FL

Open and Accepting

Massachusetts

Massachusetts General Hospital

Boston, MA

Open and Accepting

New Jersey

Memorial Sloan Kettering Basking Ridge

Basking Ridge, NJ

Open and Accepting

Memorial Sloan Kettering Bergen

Montvale, NJ

Open and Accepting

New York

Memorial Sloan Kettering Cancer Center

New York, NY

Open and Accepting

Memorial Sloan Kettering Commack

Commack, NY

Open and Accepting

Northwell Health Center for Advanced Medicine Monter Cancer Center

Lake Success, NY

Open and Accepting

Texas

MD Anderson Cancer Center The University of Texas

Houston, TX

Open and Accepting

Washington

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