Zilovertamab Vedotin + R-CHP for Diffuse Large B-Cell Lymphoma

(waveLINE-007 Trial)

Recruiting at 21 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Cardiovascular disease, CNS lymphoma, 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

Compensation: Varies

Number of Visits: 16

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain medications like strong CYP3A4 inhibitors or inducers within 7 days before starting the study. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Zilovertamab Vedotin + R-CHP for treating Diffuse Large B-Cell Lymphoma?

Research shows that rituximab, a component of the R-CHP regimen, has improved outcomes in diffuse large B-cell lymphoma (DLBCL) when added to chemotherapy. Additionally, a study demonstrated that a rituximab biosimilar combined with chemotherapy had similar effectiveness to the original rituximab in treating DLBCL, suggesting the potential effectiveness of the R-CHP regimen. ^{1 2 3 4 5}

Is the combination of Zilovertamab Vedotin and R-CHP safe for treating diffuse large B-cell lymphoma?

The safety of rituximab and its biosimilars, when combined with chemotherapy for diffuse large B-cell lymphoma, has been well-studied, showing similar safety profiles and adverse event rates. However, specific safety data for Zilovertamab Vedotin in combination with R-CHP is not provided in the available research. ^{4 6 7 8 9}

What makes the drug Zilovertamab Vedotin + R-CHP unique for treating diffuse large B-cell lymphoma?

Zilovertamab Vedotin + R-CHP is unique because it combines a novel antibody-drug conjugate, Zilovertamab Vedotin, with the standard R-CHP regimen, potentially offering a new mechanism of action by targeting specific proteins on cancer cells, which may improve outcomes for patients not fully cured by traditional treatments like R-CHOP. ^{10 11 12 13 14}

What is the purpose of this trial?

This trial tests a new drug called zilovertamab vedotin combined with standard chemotherapy in patients with DLBCL who haven't been treated before. The drug targets and kills cancer cells like a guided missile, while the chemotherapy helps to further attack the cancer.

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with a confirmed diagnosis of Diffuse Large B-Cell Lymphoma (DLBCL) who haven't been treated before. They should have PET-positive disease and be in good physical condition, meaning they can carry out daily activities with ease or with some limitation. People with certain heart conditions, other cancers within the last 2 years, recent radiotherapy, ongoing high-dose steroids, live vaccines taken recently, strong drug interactions or active infections are excluded.

Inclusion Criteria

Has positron emission tomography (PET)-positive disease verified by blinded independent central review (BICR) at screening, defined as 4-5 on the Lugano response criteria 5-point scale

My diagnosis of DLBCL was confirmed through a biopsy.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I have been diagnosed with primary mediastinal B-cell lymphoma.

I had another cancer but have been cancer-free for 2 years, except for certain skin cancers or in situ cancers.

I haven't taken strong CYP3A4 inhibitors like itraconazole within the last week.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation/Confirmation

Participants receive a dose level of zilovertamab vedotin plus R-CHP to determine safety and tolerability and establish a preliminary recommended Phase 2 dose

5.5 months

8 visits (in-person, every 21 days)

Efficacy Expansion

Participants receive the RP2D of zilovertamab vedotin plus R-CHP to determine efficacy

5.5 months

8 visits (in-person, every 21 days)

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 months

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin
• Prednisone
• Rituximab
• Rituximab Biosimilar
• Zilovertamab Vedotin

Trial Overview The study tests Zilovertamab Vedotin combined with R-CHP (Cyclophosphamide, Doxorubicin, Prednisone plus Rituximab or its biosimilar). It has two parts: first to find a safe dose and then to see how effective this combination is at that dose for treating people newly diagnosed with DLBCL.

Participant Groups

Group I: Zilovertamab Vedotin + R-CHP: Efficacy Expansion Experimental Treatment 7 Interventions

Participants in the efficacy expansion phase receive the RP2D of zilovertamab vedotin plus 750 mg/m\^2 cyclophosphamide, 50 mg/m\^2 doxorubicin, and 375 mg/m\^2 rituximab or rituximab biosimilar (truxima) administered by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 8 cycles (up to approximately 5.5 months). Participants also receive 100 mg prednisone or prednisolone per day during Days 1-5 of each 21-day cycle for up to 8 cycles (up to approximately 5.5 months).

Group II: Zilovertamab Vedotin + R-CHP: Dose Escalation/Confirmation Experimental Treatment 7 Interventions

Participants in the dose escalation/confirmation phase receive a dose level of zilovertamab vedotin (from 1.5 mg/Kg up to 2.5 mg/Kg) plus 750 mg/m\^2 cyclophosphamide, 50 mg/m\^2 doxorubicin, and 375 mg/m\^2 rituximab or rituximab biosimilar (truxima) administered by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 8 cycles (up to approximately 5.5 months). Participants also receive 100 mg prednisone or prednisolone per day during Days 1-5 of each 21-day cycle for up to 8 cycles (up to approximately 5.5 months).

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a study of 348 patients with diffuse large B-cell lymphoma treated with various chemotherapy regimens, those receiving more than 90% of the average relative dose intensity (ARDI) had a median survival of 7.08 years, significantly better than those with lower ARDI.

The findings suggest that maintaining optimal chemotherapy intensity is crucial for improving patient outcomes, as dose reductions due to hematological toxicities negatively impacted treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Bosly, A., Bron, D., Van Hoof, A., et al.[2022]

In a study of 134 patients with diffuse large B-cell lymphoma (DLBCL) involving the testis, the addition of rituximab to standard chemotherapy (R-CHOP) significantly improved progression-free survival and overall survival, with hazard ratios of 0.42 and 0.39 respectively, indicating a strong protective effect.

Despite the benefits of rituximab in reducing lymphoma recurrence, the risk of central nervous system (CNS) relapse remained high, suggesting that additional strategies for CNS prophylaxis are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era. Kridel, R., Telio, D., Villa, D., et al.[2017]

A phase 3 study involving 407 treatment-naïve patients with diffuse large B-cell lymphoma demonstrated that HLX01, a biosimilar to rituximab, has comparable efficacy to the reference drug, with overall response rates of 94.1% for HLX01 and 92.8% for rituximab, falling within the pre-defined equivalence margin.

The safety profiles of HLX01 and rituximab were similar, with nearly identical rates of treatment-emergent adverse events (99.5% vs. 99.0%) and serious adverse events (34.0% vs. 32.5%), confirming that HLX01 is a safe alternative to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. Shi, Y., Song, Y., Qin, Y., et al.[2021]

Rituximab (RTX) is a widely used monoclonal antibody for treating diffuse large B-cell lymphoma, often combined with other drugs in the R-CHOP regimen, but some patients experience suboptimal responses or resistance.

New developments in CD20-targeting monoclonal antibodies, including second- and third-generation agents like ofatumumab and obinutumumab, are being actively researched to improve treatment outcomes for B-cell non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel CD20 monoclonal antibodies for lymphoma therapy. Cang, S., Mukhi, N., Wang, K., et al.[2022]

In a study of 83 patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia, switching between the reference rituximab and its biosimilars (TRUXIMA and RIXATHON) did not lead to any new safety concerns, with adverse events being similar to those reported in existing literature.

Out of 465 rituximab infusions, 84.5% of patients experienced at least one adverse event, but only 5.9% had serious grade 3-4 events, indicating that the biosimilars are as safe as the reference product when switching is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of switching between rituximab biosimilars in onco-hematology. Urru, SAM., Spila Alegiani, S., Guella, A., et al.[2021]

In a phase 3 trial involving 879 patients with untreated intermediate-risk or high-risk diffuse large B-cell lymphoma (DLBCL), the modified regimen pola-R-CHP (which replaces vincristine with polatuzumab vedotin) showed a significantly higher progression-free survival rate at 2 years (76.7%) compared to the standard R-CHOP regimen (70.2%).

The overall survival rates at 2 years were similar between the pola-R-CHP and R-CHOP groups (88.7% vs. 88.6%), indicating that while pola-R-CHP may reduce the risk of disease progression, it does not significantly improve overall survival compared to the standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. Tilly, H., Morschhauser, F., Sehn, LH., et al.[2022]

Brentuximab vedotin (BV) is an effective treatment for relapsed or refractory Hodgkin lymphoma (HL) and anaplastic large-cell lymphoma (ALCL), and it has recently been approved for use as a consolidation therapy after autologous stem cell transplantation in high-risk HL patients.

BV is being investigated in various new treatment settings, including as a single agent or in combination with other therapies for first-salvage HL and frontline treatment in DLBCL, showing promising results that could lead to first-line approvals if ongoing trials are successful.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New uses for brentuximab vedotin and novel antibody drug conjugates in lymphoma. Merli, M., Ferrario, A., Maffioli, M., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14). [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era. [2017]

4. England pubmed.ncbi.nlm.nih.gov

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Novel CD20 monoclonal antibodies for lymphoma therapy. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Rituximab biosimilar for the treatment of diffuse large B-cell lymphoma: a phase 3 randomized study in India. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Safety of switching between rituximab biosimilars in onco-hematology. [2021]

8. India pubmed.ncbi.nlm.nih.gov

Comparison of the Efficacy of Innovator Rituximab and its Biosimilars in Diffuse Large B Cell Lymphoma Patients: A Retrospective Analysis. [2021]

9. Turkey pubmed.ncbi.nlm.nih.gov

Biosimilar Rituximab (Redditux) Added to CHOP Chemotherapy for De Novo Diffuse Large B-Cell Lymphoma Patients: Real-Life Single-Center Experience [2022]

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

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. [2022]

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

Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes. [2022]

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

New uses for brentuximab vedotin and novel antibody drug conjugates in lymphoma. [2019]

14. Japan pubmed.ncbi.nlm.nih.gov

Classical Hodgkin lymphoma primary refractory to brentuximab vedotin, with transformation to CD30-positive diffuse large B-cell lymphoma. [2019]