Zilovertamab Vedotin + Standard of Care for Diffuse Large B-Cell Lymphoma

Recruiting at 138 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Corticosteroids, others

Disqualifiers: Solid organ transplant, Cardiovascular disease, Peripheral neuropathy, 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: 2

290 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option, zilovertamab vedotin (an experimental treatment), combined with other standard drugs to determine its effectiveness for people with diffuse large B-cell lymphoma, a type of blood cancer that has recurred or not responded to treatment. The trial aims to discover if this combination can help patients live longer without disease progression. The study seeks participants who have tried other treatments without success and are not eligible for certain transplants. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have ongoing corticosteroid therapy or have received certain treatments like systemic anticancer therapy or radiotherapy within 4 weeks before starting the study.

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

Earlier studies found that zilovertamab vedotin has a manageable safety profile, meaning side effects were usually not severe and could be controlled. When combined with R-GemOx—a mix of rituximab, gemcitabine, and oxaliplatin—it showed promising results for patients with relapsed or hard-to-treat diffuse large B-cell lymphoma (DLBCL). The recommended dose of zilovertamab vedotin was 1.75 mg/kg, which most patients tolerated well. Common side effects included tiredness and low blood cell counts, but these were expected and generally manageable.

The treatment's presence in a Phase 2/3 trial indicates prior human testing with some success. Researchers have gathered enough data to confidently test it on a larger scale. For those considering joining a trial with zilovertamab vedotin, it's important to know that it has been extensively studied and is considered relatively safe based on current evidence. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Zilovertamab vedotin (ZV) for treating Diffuse Large B-Cell Lymphoma because it offers a novel approach by targeting specific proteins on cancer cells. Unlike standard treatments like Rituximab, Bendamustine, Gemcitabine, and Oxaliplatin, which focus on killing fast-growing cells generally, ZV is designed to deliver a drug directly to the cancer cells, sparing more healthy cells. This targeted method could potentially improve effectiveness and reduce side effects, making the treatment process more tolerable for patients.

What evidence suggests that this trial's treatments could be effective for diffuse large B-cell lymphoma?

Research has shown that zilovertamab vedotin (ZV) could be a promising treatment for relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL). In this trial, some participants will receive ZV combined with the standard R-GemOx treatment. Studies have shown that 56.3% of patients experienced their cancer shrinking or disappearing with this combination. ZV targets a protein called ROR1, often found on cancer cells, delivering the treatment directly to the tumor. This targeted method has demonstrated significant antitumor activity, offering hope for those whose previous treatments have failed. Early evidence suggests it could be effective and has a manageable safety profile. ^{1 3 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

Adults with relapsed or refractory Diffuse Large B-Cell Lymphoma (rrDLBCL) who have measurable disease, an ECOG status of 0 to 2, and adequate organ function. They must have failed previous therapies and be able to provide a tumor tissue sample. Exclusions include those with certain medical conditions, recent treatments or vaccinations, active infections like HIV or Hepatitis C, significant heart issues, CNS lymphoma involvement, ongoing corticosteroid therapy, and other specific health concerns.

Inclusion Criteria

I can provide a new or stored tumor sample that hasn't been exposed to radiation.

My previous CAR-T cell therapy did not work, or I am not eligible for it.

My DLBCL is measurable by scans according to Lugano criteria.

Exclusion Criteria

I have an active Hepatitis C infection.

My slow-growing cancer has changed into aggressive large B-cell lymphoma.

I have a type of Charcot-Marie-Tooth disease that affects the nerve covering.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Confirmation (Part 1)

Participants receive ZV in combination with R-GemOx or BR to confirm the dose

Up to 6 cycles of 21 days each

1 visit per cycle (in-person)

Efficacy Expansion (Part 2)

Participants receive the recommended Phase 2 dose of ZV in combination with R-GemOx or BR to evaluate efficacy

Up to 6 cycles of 21 days each

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 26 months

What Are the Treatments Tested in This Trial?

Interventions

• Bendamustine
• Gemcitabine
• Oxaliplatin
• Rituximab
• Zilovertamab vedotin

Trial Overview The trial is testing Zilovertamab Vedotin (ZV) combined with standard care options against just the standard care for rrDLBCL treatment. It's in two parts: first confirming the dose of ZV and then expanding to test its effectiveness. The goal is to see if adding ZV improves progression-free survival compared to the current treatments alone.

How Is the Trial Designed?

Group I: ZV + R-GemOx (Part 2) Experimental Treatment 5 Interventions

Using the recommended Phase 2 dose (RP2D) dose of ZV plus R-GemOx from Part 1, participants will receive ZV plus R-GemOx given intravenously on Day 1 of repeated 21-day cycles. Treatment will continue for up to 6 cycles or until progressive disease or discontinuation.

Group II: ZV + R-GemOx (Part 1) Experimental Treatment 5 Interventions

Participants in this arm will receive doses of ZV (from 1.5 mg/Kg up to 2.5 mg/Kg) plus Rituximab 375 mg/m\^2, Gemcitabine 1000 mg/m\^2 and Oxaliplatin 100 mg/m\^2 (R-GemOx) given intravenously on Day 1 of repeated 21-day cycles. Treatment will continue for up to 6 cycles.

Group III: ZV + BR (Part 2) Experimental Treatment 4 Interventions

Using RP2D from Part 1, participants will receive ZV plus Rituximab 375 mg/m\^2, given intravenously on Day 1 and Bendamustine 90 mg/m\^2 given intravenously on Day 1 and 2, of repeated 21-day cycles. Treatment will continue for up to 6 cycles or until progressive disease or discontinuation.

Group IV: ZV + BR (Part 1) Experimental Treatment 4 Interventions

Participants in this arm will receive doses of ZV (from 1.5 mg/Kg up to 2.5 mg/Kg) plus Rituximab 375 mg/m\^2, Bendamustine 90 mg/m\^2 (BR) given intravenously on Day 1 and 2 of repeated 21-day cycles. Treatment will continue for up to 6 cycles.

Group V: R-GemOx (active control for Part 2) Active Control 3 Interventions

Participants will receive R-GemOx given intravenously on Day 1 of repeated 21-day cycles. Treatment will continue for up to 6 cycles or until progressive disease or discontinuation.

Group VI: Bendamustine Rituximab (BR) Active Control 2 Interventions

Participants will receive Rituximab 375 mg/m\^2, given intravenously on Day 1 Bendamustine 90 mg/m\^2 given intravenously on Day 1 and 2 of repeated 21-day cycles. Treatment will continue for up to 6 cycles or until progressive disease or discontinuation.

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

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in European Union as Ribomustin for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma

Approved in Canada as Levact for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in Japan as Bendamustine hydrochloride for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

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

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

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

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

Rituximab plus bendamustine (R-B) is less toxic and achieves similar complete remission rates compared to R-CHOP in patients with follicular lymphoma grade 3A, with 97% vs. 96% complete remissions respectively.

Patients treated with R-B experienced significantly lower relapse rates (16% vs. 41%) and longer progression-free survival (15 years vs. 11.7 years) compared to those treated with R-CHOP, making R-B a more effective first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine plus Rituximab Versus R-CHOP as First-Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study. Mondello, P., Steiner, N., Willenbacher, W., et al.[2019]

Polatuzumab vedotin (PoV) combined with chemotherapy showed a 52.5% overall response rate in 40 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), indicating it is an effective treatment option.

The median overall survival for patients receiving PoV was 8.5 months, but those who underwent subsequent hematopoietic stem cell transplantation had a significantly improved survival of 24 months, highlighting the importance of this treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin-based salvage immunochemotherapy as third-line or beyond treatment for patients with diffuse large B-cell lymphoma: a real-world experience. Wang, YW., Tsai, XC., Hou, HA., et al.[2022]

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]

In pivotal study GO29365 involving patients with relapsed/refractory diffuse large B-cell lymphoma, polatuzumab vedotin (1.8 mg/kg) combined with bendamustine-rituximab showed a favorable risk/benefit profile, supporting its use for six cycles.

Supportive studies indicated that higher exposure to polatuzumab vedotin increased response rates but also raised the risk of side effects like peripheral neuropathy and anemia, suggesting that dosing should not fall below 1.8 mg/kg to maintain efficacy while managing safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-safety and exposure-efficacy analyses of polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma. Lu, T., Gibiansky, L., Li, X., et al.[2021]

In a dose-escalation study involving 9 patients with relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma, the combination of bendamustine (120 mg/m²) and rituximab (375 mg/m²) was found to be feasible and well tolerated, with no dose-limiting toxicities observed.

The treatment showed promising efficacy, achieving a 100% overall response rate in the higher dose cohort, including five complete responses, indicating that this combination may be effective for aggressive forms of B-NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and pharmacokinetic study of bendamustine hydrochloride in combination with rituximab in relapsed or refractory aggressive B cell non-Hodgkin's lymphoma. Ogura, M., Ando, K., Taniwaki, M., et al.[2015]

Brentuximab vedotin (Bv) combined with bendamustine (B) showed a high overall response rate of 79% and a complete response rate of 49% in 47 patients with relapsed or refractory classic Hodgkin lymphoma, indicating its efficacy as a treatment option.

The treatment resulted in a median progression-free survival of 18 months and a 2-year overall survival rate of 72%, particularly benefiting patients who achieved a major clinical response and those who underwent stem cell transplantation afterward.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin in association with bendamustine in refractory or multiple relapsed Hodgkin lymphoma. A retrospective real-world study. Iannitto, E., Romano, A., Scalzulli, PR., et al.[2021]

In a study of 61 Greek patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), the combination of polatuzumab vedotin and bendamustine-rituximab (Pola-BR) showed a response rate of 43%, with 25% achieving complete remission and 18% partial remission.

The treatment demonstrated an acceptable safety profile, with 55% of patients experiencing grade ≥3 adverse events, primarily hematologic, suggesting that Pola-BR could serve as an effective bridging therapy before further treatments like CAR-T cell therapy or stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-life experience with the combination of polatuzumab vedotin, rituximab, and bendamustine in aggressive B-cell lymphomas. Dimou, M., Papageorgiou, SG., Stavroyianni, N., et al.[2021]

In a study of 71 patients with relapsed/refractory diffuse large B-cell lymphoma, the combination of polatuzumab vedotin with bendamustine and rituximab (Pola-BR) showed an overall response rate of 47.9%, with a complete response rate of 32.4% after a median of 3 treatment cycles.

The treatment demonstrated a manageable safety profile, with the most common severe side effects being grade 3-4 neutropenia and thrombocytopenia, indicating that Pola-BR is a promising and effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin, rituximab, and bendamustine combination in relapsed or refractory diffuse large B-cell lymphoma: a real-world data from Turkey. Dal, MS., Ulu, BU., Uzay, A., et al.[2023]

Bendamustine is an established treatment for chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma, and multiple myeloma, with its use now expanded to include aggressive non-Hodgkin lymphoma and Hodgkin lymphoma.

Recent expert recommendations have been updated to optimize dosing and manage toxicities associated with bendamustine, supporting its safe and effective use in new combination therapies for hematologic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimal use of bendamustine in hematologic disorders: Treatment recommendations from an international consensus panel - an update. Cheson, BD., Brugger, W., Damaj, G., et al.[2019]

In a study of 28 Chinese patients with relapse/refractory diffuse large B-cell lymphoma (R/R DLBCL) who were ineligible for transplantation, the polatuzumab vedotin (pola) combined with rituximab and bendamustine (pola-BR) regimen showed a promising overall response rate of 71.4% and a complete response rate of 25.0%.

The estimated median progression-free survival (PFS) was 200 days, with manageable safety profiles as high-grade peripheral neuropathy was not observed, although common adverse events included thrombocytopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective cohort study of polatuzumab vedotin combined with immunochemotherapy in Chinese patients with relapse/refractory diffuse large B cell lymphoma. Liu, Y., Wuxiao, Z., Kong, F., et al.[2022]

In a study of 59 patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), the combination of bendamustine and rituximab resulted in an objective response rate of 45.8%, with a median duration of response of 17.3 months.

The treatment showed an acceptable safety profile, with significant hematological toxicities such as neutropenia (36%) and leukopenia (29%), indicating that while the therapy is effective, it does carry risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Vacirca, JL., Acs, PI., Tabbara, IA., et al.[2021]

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. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1720/503946/Zilovertamab-Vedotin-MK-2140-in-Relapsed-or

Zilovertamab Vedotin (MK-2140) in Relapsed or Refractory ... Zilovertamab Vedotin (MK-2140) in Relapsed or Refractory Diffuse Large B ... The safety profile of zilovertamab vedotin was manageable, and ...

7. 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 ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.7005

WaveLINE-003: Phase 2/3 trial of zilovertamab vedotin ... Zilovertamab vedotin in combination with R-GemOx demonstrated promising efficacy and acceptable safety in R/R DLBCL at the RP2D of ZV of 1.75 mg/kg plus R- ...