Epcoritamab for Chronic Lymphocytic Leukemia

(EPCORE™ CLL-1 Trial)

Recruiting at 89 trial locations

Overseen By Genmab Trial Information

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Genmab

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune disease, Cardiac disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

424 Participants Needed

Trial Summary

What is 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 be tested either in Relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as: * Monotherapy, or * Combination therapy: * epcoritamab + venetoclax * epcoritamab + pirtobrutinib 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/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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, certain prior treatments like CD3×CD20 bispecific antibodies, recent CAR T-cell therapy, or venetoclax within 24 months may exclude you from participation. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Epcoritamab for treating chronic lymphocytic leukemia?

While there is no direct data on Epcoritamab for chronic lymphocytic leukemia (CLL), similar treatments targeting B-cell pathways, like BTK and BCL2 inhibitors, have shown success in CLL. These treatments have improved outcomes by targeting specific pathways that help cancer cells survive, suggesting potential for Epcoritamab, which also targets B-cells. ^{1 2 3 4 5}

What is known about the safety of Epcoritamab for human use?

There is no specific safety data available for Epcoritamab in the provided research articles. ^{6 7 8 9 10}

What makes the drug Epcoritamab unique for treating chronic lymphocytic leukemia?

Epcoritamab is unique because it is a monoclonal antibody that targets CD20, a protein on the surface of B-cells, which are involved in chronic lymphocytic leukemia. This drug offers a novel approach by potentially providing a chemo-free treatment option, differing from traditional chemotherapy regimens. ^{3 11 12 13 14}

Eligibility Criteria

This trial is for patients with relapsed/refractory chronic lymphocytic leukemia or Richter's Syndrome who have tried other treatments. They must have a life expectancy over 3 months, acceptable organ function, and specific performance status. Prior therapies are required for certain arms of the study, and they must not have had certain conditions like HIV or recent major surgery.

Inclusion Criteria

I have CLL and have had at least one treatment before considering venetoclax.

I am eligible for R-CHOP treatment.

My bloodwork shows my organs are functioning well.

Exclusion Criteria

I have a serious heart condition.

I took venetoclax in the last 2 years and my condition worsened on it.

I have had more than 2 treatments for my condition before considering this therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Determine the recommended phase 2 dose (RP2D) and the maximum tolerated dose (MTD) for epcoritamab monotherapy and epcoritamab + venetoclax in participants with R/R CLL.

1-2 months

Weekly visits

Safety Run-in

Evaluate the safety and tolerability profiles of pirtobrutinib in combination with epcoritamab.

1-2 months

Weekly visits

Expansion

Assess and evaluate the preliminary efficacy, safety, and tolerability profiles of various combinations of epcoritamab in participants with R/R CLL/SLL and RS.

12-24 months

Weekly, bi-weekly, or monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Epcoritamab

Trial Overview Epcoritamab is being tested both alone and in combination with venetoclax, lenalidomide, or R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) to treat chronic lymphocytic leukemia and Richter's Syndrome. The trial has two phases: dose escalation to find safe levels and expansion to test effectiveness.

Participant Groups

Group I: Fixed Duration Epcoritamab in R/R CLL/SLL Experimental Treatment 1 Intervention

Only in expansion phase.

Group II: Epcoritamab in RS Experimental Treatment 1 Intervention

Only in expansion phase.

Group III: Epcoritamab in R/R CLL/SLL Experimental Treatment 1 Intervention

In both study phases. Participants in the expansion phase will be treated at the RP2D defined in the dose-escalation phase.

Group IV: Epcoritamab + Venetoclax in R/R CLL/SLL Experimental Treatment 2 Interventions

In both study phases. Participants in the expansion phase will be treated at the RP2D defined in the dose-escalation phase.

Group V: Epcoritamab + R-CHOP in RS Experimental Treatment 2 Interventions

Only in expansion phase.

Group VI: Epcoritamab + Pirtobrutinib in R/R CLL, TN HR CLL and SLL Experimental Treatment 2 Interventions

Safety run-in and expansion phases.

Group VII: Epcoritamab + Lenalidomide in RS Experimental Treatment 2 Interventions

Only in expansion phase.

Epcoritamab is already approved in United States, European Union for the following indications:

Approved in United States as Epkinly for:

• Relapsed or refractory follicular lymphoma after two or more lines of systemic therapy
• Diffuse large B-cell lymphoma after two or more lines of systemic therapy

Approved in European Union as Tepkinly for:

• Relapsed or refractory follicular lymphoma after two or more lines of systemic therapy
• Relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy

Who Is Running the Clinical Trial?

Genmab

Lead Sponsor

Trials

76

Recruited

15,300+

Dr. Jan van de Winkel

Genmab

Chief Executive Officer since 2010

PhD in Immunology, University of Utrecht

Dr. Judith Klimovsky

Genmab

Chief Medical Officer since 2019

MD, University of Copenhagen

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Findings from Research

The consensus document updates treatment strategies for chronic lymphocytic leukemia (CLL) by incorporating novel therapies developed in the last five years, including B-cell receptor inhibitors like ibrutinib and idelalisib, anti-CD20 monoclonal antibodies such as ofatumumab and obinutuzumab, and Bcl-2 inhibitors like venetoclax.

Despite the advancements in treatment options, the management of CLL remains complex due to the biological diversity of patients, leading to many areas where strong scientific evidence is lacking, necessitating expert consensus for recommendations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update of the Grupo Español de Leucemia Linfocítica Crónica clinical guidelines of the management of chronic lymphocytic leukemia. García-Marco, JA., Delgado, J., Hernández-Rivas, JA., et al.[2021]

B-cell chronic lymphocytic leukemia (CLL) is driven by genetic and epigenetic changes that disrupt normal B-cell signaling, particularly through the B-cell antigen receptor (BCR) pathway, leading to cancer cell survival.

New targeted therapies that inhibit key components of the BCR signaling pathway, such as SYK, BTK, PI3K, and BCL-2, show promise in treating CLL and may complement existing chemo-immunotherapy options, including rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B-cell antigen receptor signaling in chronic lymphocytic leukemia: therapeutic targets and translational opportunities. Hill, RJ., Lou, Y., Tan, SL.[2019]

Recent advancements in chronic lymphocytic leukemia (CLL) treatment have shown that combining anti-CD20 monoclonal antibodies with BTK and BCL2 inhibitors is more effective than traditional chemotherapy regimens, benefiting patients of all ages and those with poor prognostic features.

Ongoing clinical trials are exploring the efficacy of triplet therapies that include BTK inhibitors, venetoclax, and obinutuzumab, which may offer remarkable results while allowing for an all-oral treatment regimen with a fixed duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual-targeted regimens for the frontline treatment of CLL. Ujjani, C.[2023]

Since 2014, the treatment of chronic lymphocytic leukemia (CLL) has significantly improved with the introduction of targeted therapies like ibrutinib and venetoclax, which have been shown to be more effective than traditional chemotherapy.

Ongoing research is focused on developing next-generation treatments that promise better safety profiles and the ability to overcome resistance to earlier therapies, while also exploring early intervention strategies that could change the current 'watch and wait' approach for asymptomatic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Therapies in Chronic Lymphocytic Leukemia: A Rapidly Changing Landscape. Iovino, L., Shadman, M.[2021]

Chronic lymphocytic leukemia (CLL) is primarily treated with targeted therapies like BTK inhibitors and venetoclax, which have significantly improved clinical outcomes compared to traditional chemotherapy, especially for patients with high-risk features such as TP53 mutations.

For patients requiring treatment, oral BTK inhibitors or venetoclax combined with anti-CD20 therapy are recommended as first-line options, demonstrating efficacy even in those without high-risk genetic abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia: Chemotherapy Free and Other Novel Therapies Including CAR T. Wiedmeier-Nutor, J., Leis, J.[2022]

Immunotherapy, particularly immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1, has shown high efficacy in treating various cancers, with approvals for at least 16 tumor types, including those with specific genetic markers like MSI-H.

Despite their effectiveness, immunotherapies can lead to significant adverse events, including immune-related adverse events (irAEs) and other toxicities, highlighting the need for careful monitoring and management in patients undergoing these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The dark side of immunotherapy. Okwundu, N., Grossman, D., Hu-Lieskovan, S., et al.[2022]

In a study involving 364 patients with systemic lupus erythematosus (SLE), long-term treatment with belimumab combined with standard therapy demonstrated a stable or declining incidence of adverse events over 4 years, indicating a favorable safety profile.

The most common side effects were mild, such as arthralgia and upper respiratory infections, and serious infusion reactions were rare, suggesting that belimumab can be safely administered for extended periods in SLE patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Merrill, JT., Ginzler, EM., Wallace, DJ., et al.[2013]

Evobrutinib, a Bruton's tyrosine kinase inhibitor, was generally well tolerated across multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus trials, with similar rates of treatment-emergent adverse events (TEAEs) compared to placebo (66.2% vs 62.4%).

The analysis included data from 1083 patients across various trials, revealing that serious infections and liver enzyme elevations were comparable between evobrutinib and placebo, indicating a favorable safety profile for this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis. Montalban, X., Wallace, D., Genovese, MC., et al.[2023]

Novel immunotherapies targeting the immune system have transformed cancer treatment, but their safety must be carefully evaluated due to potential toxicity from immune activation.

The review highlights challenges in nonclinical safety assessments of monoclonal antibodies, emphasizing the need for better predictive animal models and approaches to ensure safe dosing in human trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer Immunotherapy: Factors Important for the Evaluation of Safety in Nonclinical Studies. Herzyk, DJ., Haggerty, HG.[2019]

In a study of 1535 patients receiving high-dose interleukin-2 (IL-2) therapy, those who experienced immune-related adverse events (irAEs) had significantly better tumor control (71% vs. 56%) and overall survival, particularly in metastatic melanoma (median 48 months vs. 18 months) and metastatic renal cell cancer (median 60 months vs. 40 months).

The majority of irAEs were related to IL-2 therapy, primarily manifesting as vitiligo and thyroid dysfunction, indicating that while these adverse events are concerning, they may also signal a beneficial immune response that enhances treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIMSM registry. Curti, B., Daniels, GA., McDermott, DF., et al.[2018]

The treatment landscape for chronic lymphocytic leukemia (CLL) has improved significantly with the use of anti-CD20 antibodies and kinase inhibitors like ibrutinib and idelalisib, especially for patients with adverse genetic features like del(17p)/TP53 mutation.

Combining ibrutinib with an anti-CD20 antibody, such as obinutuzumab, shows promise for effectively eliminating CLL cells, and adding the Bcl-2 antagonist venetoclax may enhance treatment outcomes by potentially achieving deep remissions and eradicating residual CLL cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Targeted Drugs to Control Chronic Lymphocytic Leukemia: Harnessing the Power of New Monoclonal Antibodies in Combination With Ibrutinib. Cramer, P., Langerbeins, P., Hallek, M.[2021]

Monoclonal antibodies (mAbs) like rituximab and alemtuzumab have revitalized treatment options for chronic lymphocytic leukemia (CLL), showing significant efficacy against the disease.

Newly developed mAbs, such as ofatumumab and GA-101, demonstrate high cytotoxicity against B-cell lymphoid cells and are currently being evaluated in clinical trials, indicating promising advancements in CLL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel monoclonal antibodies for the treatment of chronic lymphocytic leukemia. Robak, T.[2019]

Combining anti-CD20 monoclonal antibodies with Bruton tyrosine kinase inhibitors (BTKi) significantly improves progression-free survival in chronic lymphocytic leukemia (CLL) patients, with a hazard ratio of 0.70 based on a meta-analysis of four randomized controlled trials involving 1056 patients.

The combination therapy also leads to a higher complete response rate and a greater likelihood of achieving undetectable minimal residual disease, while maintaining a similar safety profile to BTKi monotherapy, indicating it is a more effective treatment option without increasing the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of add-on anti-CD20 monoclonal antibody to Bruton tyrosine kinase inhibitor treatment for chronic lymphocytic leukemia: a meta-analysis. Nguyen, TT., Nhu, NT., Tran, VK., et al.[2023]

Chronic lymphocytic leukemia (CLL) is primarily diagnosed through the presence of over 5000 B-lymphocytes/µl and specific surface markers, with treatment decisions heavily influenced by the patient's physical condition and genetic factors like 17p deletion or TP53 mutations.

Current standard treatments for fit patients include immunochemotherapy with fludarabine, cyclophosphamide, and rituximab, while new chemo-free options like ibrutinib and ABT-199 are emerging, potentially changing the treatment landscape for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chronic lymphatic leukemia]. Bergmann, M., Wendtner, CM.[2021]

References

1. Spain pubmed.ncbi.nlm.nih.gov

Update of the Grupo Español de Leucemia Linfocítica Crónica clinical guidelines of the management of chronic lymphocytic leukemia. [2021]

2. England pubmed.ncbi.nlm.nih.gov

B-cell antigen receptor signaling in chronic lymphocytic leukemia: therapeutic targets and translational opportunities. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Dual-targeted regimens for the frontline treatment of CLL. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Novel Therapies in Chronic Lymphocytic Leukemia: A Rapidly Changing Landscape. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia: Chemotherapy Free and Other Novel Therapies Including CAR T. [2022]

6. China pubmed.ncbi.nlm.nih.gov

The dark side of immunotherapy. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Cancer Immunotherapy: Factors Important for the Evaluation of Safety in Nonclinical Studies. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIMSM registry. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Combination of Targeted Drugs to Control Chronic Lymphocytic Leukemia: Harnessing the Power of New Monoclonal Antibodies in Combination With Ibrutinib. [2021]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Novel monoclonal antibodies for the treatment of chronic lymphocytic leukemia. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of add-on anti-CD20 monoclonal antibody to Bruton tyrosine kinase inhibitor treatment for chronic lymphocytic leukemia: a meta-analysis. [2023]

14. Germany pubmed.ncbi.nlm.nih.gov

[Chronic lymphatic leukemia]. [2021]