Epcoritamab for Waldenstrom Macroglobulinemia

Recruiting at 2 trial locations

Overseen By Emma Logan, MSN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Gottfried von Keudell, MD PhD

Must be taking: Anti-CD20, BTK inhibitors

Must not be taking: Investigational agents, Immunosuppressants

Disqualifiers: Aggressive lymphoma, Cardiac conditions, Neurologic conditions, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 4

Duration: 12 cycles (approximately 12 months)

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to determine if epcoritamab can be used to treat participants with previously treated Waldenstrom Macroglobulinemia (WM). The names of the study drug involved in this study is: -Epcoritamab (a type of antibody)

Do I need to stop my current medications for the trial?

You will need to stop taking any BTK inhibitors (like ibrutinib or zanubrutinib) before starting the trial, allowing a washout period (time without taking the medication) of at least 4 half-lives. Additionally, you must stop taking rituximab at least 4 weeks before starting the trial. The protocol does not specify other medications, so please consult with the trial team for guidance on other medications you are taking.

How is the drug Epcoritamab different from other treatments for Waldenstrom Macroglobulinemia?

Epcoritamab is unique because it is a bispecific antibody that targets both CD3 on T-cells and CD20 on B-cells, potentially offering a novel mechanism of action compared to existing treatments like chemotherapy and BTK inhibitors, which do not utilize this dual-targeting approach. ^{1 2 3 4 5}

Research Team

Gottfried von Keudell, MD

Principal Investigator

Beth Israel Deaconess Medical Center

Eligibility Criteria

This trial is for individuals with Waldenstrom Macroglobulinemia (WM), a type of B-cell lymphoma, who have already undergone treatment. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may be excluded based on factors like other medical conditions or treatments that could interfere with the study.

Inclusion Criteria

Serum IgM level >2x upper limit of normal (ULN)

My organ and bone marrow functions meet the required levels.

I have been treated with an anti-CD20 antibody and a BTK inhibitor before.

Exclusion Criteria

Pregnancy, breastfeeding, unwillingness to adhere to contraception guidelines

Current alcohol or drug abuse, psychiatric illness, unstable social situation

I have symptoms of thick blood or high IgM levels and cannot have plasmapheresis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Epcoritamab in cycles, with varying frequency of administration over 12 cycles

12 cycles (approximately 12 months)

Frequent in-clinic visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Follow-up visits every 3 months

Treatment Details

Interventions

• Epcoritamab

Trial Overview The trial is testing Epcoritamab, an antibody designed to target and kill cancer cells in patients with WM who have previously been treated. The goal is to see if this drug is effective as a new therapy option for these patients.

Participant Groups

Group I: Safety Lead-In Epcoritamab Experimental Treatment 1 Intervention

Participants will be enrolled using a modified 3+3 dose-escalation design to establish the Recommended Phase 2 Dose of Epcoritamab and will complete study procedures as follows: * Baseline visit with CT scan and bone marrow biopsy. * Bone marrow biopsy before cycle 6. * Cycles 1 - 3: --Days 1, 8, 15, and 22 of 28 day cycle: Predetermined dose of Epcoritamab 1x daily. * Cycles 4 - 9: --Days 1 and 15 of 28 day cycle: Predetermined dose of Epcoritamab 1x daily. * Cycles 10 - 12: --Day 1 of 28 day cycle: Predetermined dose of Epcoritamab 1x daily. * End of Treatment visit with CT scan and bone marrow biopsy. * Follow up visits: every 3 months for 2 years * Off study visit * If there are 0 out of 3 dose-limiting toxicities (DLTs), the study will proceed to phase II. If 1/3 participants experience a DLT, up to 3 additional participants will be treated at the same dose level. If more than 1/6 total participants experience a DLT, then the study will not proceed to phase 2.

Group II: Phase II Epcoritamab Experimental Treatment 1 Intervention

Participants will be enrolled and will complete study procedures as follows: * Baseline visit with CT scan and bone marrow biopsy. * Bone marrow biopsy before cycle 6. * Cycles 1 - 3: --Days 1, 8, 15, and 22 of 28 day cycle: Predetermined dose of Epcoritamab 1x daily. * Cycles 4 - 9: --Days 1 and 15 of 28 day cycle: Predetermined dose of Epcoritamab 1x daily. * Cycles 10 - 12: --Day 1 of 28 day cycle: Predetermined dose of Epcoritamab 1x daily. * End of Treatment visit with CT scan and bone marrow biopsy. * Follow up visits: every 3 months for 2 years * Off study visit

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?

Gottfried von Keudell, MD PhD

Lead Sponsor

Trials

2

Recruited

50+

Genmab

Industry 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

Findings from Research

Ibrutinib monotherapy is preferred for treating Waldenström macroglobulinemia in patients with MYD88 mutations and without CXCR4 mutations, showing better efficacy compared to traditional chemoimmunotherapy or proteasome inhibitors.

For patients with MYD88 and CXCR4 mutations, or those without either mutation, alternative treatments like chemoimmunotherapy or proteasome inhibitors are recommended, while ongoing research into combinations with ibrutinib and novel BTK inhibitors is promising.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How to Sequence Therapies in Waldenström Macroglobulinemia. Sarosiek, S., Treon, SP., Castillo, JJ.[2022]

Waldenstrom macroglobulinemia (WM) primarily affects older males, with common symptoms including fatigue, weight loss, splenomegaly, and lymphadenopathy, based on a study of 15 patients followed for an average of 82 months.

While WM is currently incurable, treatments such as chemotherapy, bortezomib, and thalidomide have been shown to improve therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical analysis of 15 patients with Waldenstrom macroglobulinemia]. Hu, Y., Chen, SL., Zhong, YP., et al.[2015]

In a study of 160 young patients with Waldenström Macroglobulinemia (median age 49), 70% were asymptomatic at diagnosis, and the majority received effective treatments, leading to a favorable overall survival (OS) rate comparable to the general population.

The study found that high-risk patients had significantly shorter 5-year OS rates (92.9%) compared to low-risk patients (100%), highlighting the importance of risk classification and early diagnosis in improving outcomes for young WM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies. Varettoni, M., Ferrari, A., Frustaci, AM., et al.[2021]

Rituximab-based regimens, particularly bendamustine-rituximab (BR), showed higher response rates (46%) compared to bortezomib-dexamethasone (33%) and ibrutinib-rituximab (26%) in treating Waldenstrom macroglobulinaemia, based on a systematic review of 11 trials involving 736 patients.

The two-year progression-free survival rates were also favorable for BR (89%) compared to BDRC (81%) and IR (82%), although different regimens had varying toxicity profiles, with neuropathy being more common in bortezomib treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis. Chan, WL., Chong, VCL., Wee, IJY., et al.[2023]

Waldenström Macroglobulinemia (WM) is primarily driven by recurrent mutations in MYD88L265P and CXCR4, affecting treatment strategies, with standard therapies including rituximab combined with various agents showing effectiveness.

Covalent BTK inhibitors like ibrutinib and acalabrutinib have proven to be safe and highly effective for WM, and future research is focusing on novel agents and combination therapies to enhance treatment responses while reducing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SOHO State of the Art Updates and Next Questions: Targeted therapies and emerging novel treatment approaches for Waldenström Macroglobulinemia. Sermer, D., Sarosiek, S., Branagan, AR., et al.[2022]

References

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

How to Sequence Therapies in Waldenström Macroglobulinemia. [2022]

2. China pubmed.ncbi.nlm.nih.gov

[Clinical analysis of 15 patients with Waldenstrom macroglobulinemia]. [2015]

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

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies. [2021]

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

Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis. [2023]

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

SOHO State of the Art Updates and Next Questions: Targeted therapies and emerging novel treatment approaches for Waldenström Macroglobulinemia. [2022]