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

(waveLINE-007 Trial)

Not currently recruiting at 33 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for people with diffuse large B-cell lymphoma (DLBCL), a type of blood cancer. The study aims to find the best dose of zilovertamab vedotin, an experimental drug, when combined with other standard cancer treatments. The trial will assess the effectiveness of this combination for those who haven't received prior treatment for DLBCL. Individuals diagnosed with DLBCL through a biopsy and who have not undergone any previous treatments may be suitable candidates for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that zilovertamab vedotin is promising in terms of safety for patients with certain types of lymphoma. In studies, this treatment, when used with other drugs, has demonstrated a safety profile that patients can generally handle. Specifically, when combined with R-GemOx, it proved effective against tumors and was tolerated by patients with relapsed or hard-to-treat diffuse large B-cell lymphoma (DLBCL).

Participants in these studies experienced various side effects, but they were usually manageable, suggesting the treatment is relatively well-tolerated. However, as with any new treatment, there are risks of side effects, which can vary based on individual health and how the body reacts to the medication.

The current trial is in an early stage, so more information is being collected to fully understand its safety. Nonetheless, existing research offers hope that zilovertamab vedotin could be a viable option with a manageable safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Zilovertamab Vedotin for treating Diffuse Large B-Cell Lymphoma (DLBCL) because it combines a novel mechanism with existing chemotherapy regimens. Unlike the standard treatment, which often involves the R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), Zilovertamab Vedotin targets a specific protein on cancer cells, potentially enhancing the treatment's precision and effectiveness. This targeted approach may improve outcomes by directly attacking cancer cells while sparing more healthy cells, potentially reducing some side effects associated with traditional chemotherapy.

What evidence suggests that this trial's treatments could be effective for Diffuse Large B-Cell Lymphoma?

Research has shown that zilovertamab vedotin yields promising results for treating diffuse large B-cell lymphoma (DLBCL). In studies with patients whose DLBCL returned or was difficult to treat, this treatment demonstrated significant tumor-fighting activity. Specifically, when combined with another treatment, it helped more than half of the patients, achieving a 56.3% positive response rate. In this trial, participants will receive zilovertamab vedotin alongside R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone). Zilovertamab vedotin targets cancer cells specifically, which may enhance its effectiveness and reduce side effects. These early results suggest it could benefit people with DLBCL, especially when other treatments have failed. ^{1 2 3 4 6}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03833180

NCT03833180 | A Study of Zilovertamab Vedotin (MK-2140 ... The purpose of this study is to evaluate the safety, pharmacokinetics, immunogenicity, and efficacy of zilovertamab vedotin given intravenously (IV) across ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7531

Zilovertamab vedotin (MK 2140) in relapsed/refractory (R/R ... Early results show that ZV had clinically meaningful antitumor activity in pts with R/R DLBCL who progressed after or have been ineligible for ASCT and/or CAR- ...

3. merck.com merck.com/news/mercks-investigational-zilovertamab-vedotin-at-1-75-mg-kg-dose-plus-standard-of-care-showed-promising-antitumor-activity-including-complete-response-rate-in-patients-with-relapsed-refractor/

Merck's Investigational Zilovertamab Vedotin at 1.75 mg/kg ... Zilovertamab vedotin 1.75 mg/kg in combination with R-GemOx achieved a 56.3% objective response rate (ORR) in patients with relapsed or refractory DLBCL.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10430974/

PHASE 2 WAVELINE-004 STUDY: ZILOVERTAMAB ... Zilovertamab vedotin is a ROR1-targeting antibody-drug conjugate that had promising antitumor activity and manageable safety in pts with R/R NHL.

5. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1738/532479/Updated-Results-from-the-Phase-2-Waveline-004

Updated Results from the Phase 2 Waveline-004 Study of ... Zilovertamab vedotin is a ROR1-targeting antibody-drug conjugate that has demonstrated clinically meaningful antitumor activity and manageable ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06890884?utm_source=trialradar

A Clinical Study of Zilovertamab Vedotin (MK-2140) Plus ... The goal of this study is to learn if more people who receive zilovertamab vedotin (MK-2140) and R-CHP have the cancer respond (go away) than those who receive ...