A Study of Zilovertamab Vedotin (MK-2140) in Combination With Standard of Care in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (rrDLBCL) (MK-2140-003)

Merck Sharp & Dohme (MSD)

Status and phase: Enrolling; Phase 3; Phase 2

Conditions: DLBCL; Diffuse Large B-Cell Lymphoma

Treatments: Drug: Bendamustine; Biological: Zilovertamab vedotin; Drug: Gemcitabine; Biological: Rituximab; Drug: Oxaliplatin; Drug: Granulocyte Colony-Stimulating Factor (G-CSF)

Study type: Interventional

Funder types: Industry

Identifiers

NCT05139017

waveLINE-003 (Other Identifier)

2140-003

MK-2140-003 (Other Identifier)

VLS-101 (Other Identifier)

U1111-1285-0898 (Other Identifier)

2022-502646-27-00 (Registry Identifier)

Details and patient eligibility

About

The purpose of this Phase 2/3, randomized, multisite, open-label, dose confirmation, and expansion study is to evaluate the safety, and efficacy of zilovertamab vedotin (ZV) in combination with standard of care options for the treatment of rrDLBCL. This study will be divided into 2 parts: Dose Confirmation (Part 1) and Efficacy Expansion (Part 2) and will enroll participants who are at least 18 years of age with rrDLBCL. The hypotheses are: ZV in combination with rituximab, gemcitabine, and oxaliplatin (R-GemOx) is superior to R-GemOx with respect to progression-free survival (PFS) per Lugano response criteria by blinded independent review committee (BICR); and that ZV in combination with bendamustine rituximab (BR) is superior to BR with respect to PFS per Lugano response criteria by BICR.

With protocol amendment 4 (effective: 04-April-2024), enrollment in Cohort B (study arms Bendamustine Rituximab [BR] and ZV + BR) is discontinued. No efficacy outcome analysis and hypothesis testing will be conducted for Cohort B.

Enrollment: 290 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Has a histologically confirmed diagnosis of Diffuse Large B-Cell Lymphoma (DLBCL).
• Has radiographically measurable DLBCL per the Lugano Response Criteria, as assessed locally by the investigator.
• Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 within 7 days prior to study treatment initiation.
• Has adequate organ function.
• Is able to provide new or archival tumor tissue sample not previously irradiated.

Zilovertamab vedotin plus R-GemOx, or R-GemOx study arms:

• Has relapsed or refractory DLBCL and is ineligible for or have failed autologous stem-cell transplant (ASCT) and have failed at least 1 line of prior therapy.
• Has post-chimeric antigen receptor T (post-CAR-T) cell therapy failure or is ineligible for CAR-T cell therapy.

Not applicable with protocol amendment 4: Zilovertamab vedotin plus Bendamustine Rituximab (BR), and Bendamustine Rituximab study arms:

• Has relapsed or refractory DLBCL and is ineligible for or have failed ASCT and have failed at least 2 lines of prior therapy.
• Has post-CAR-T therapy failure or is ineligible for CAR-T cell therapy.

Exclusion criteria

• Not applicable with protocol amendment 4: Has history of transformation of indolent disease to DLBCL
• Has received solid organ transplant at any time.
• Has received a diagnosis of primary mediastinal B-cell lymphoma (PMBCL).
• Has clinically significant (ie, active) cardiovascular disease or serious cardiac arrhythmia requiring medication.
• Has ongoing graft-versus-host disease (GVHD) of any grade, or is receiving treatment for their GVHD.
• Has clinically significant pericardial or pleural effusion.
• Has ongoing Grade >1 peripheral neuropathy.
• Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
• Has a demyelinating form of Charcot-Marie-Tooth disease.
• Has contraindication to any of the study intervention components including but not limited to prior anaphylactic reaction.
• Has received prior systemic anticancer therapy, including investigational agents within 4 weeks prior to the first dose of study intervention.
• Has received prior radiotherapy within 4 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
• Has ongoing corticosteroid therapy.
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
• Has known active central nervous system (CNS) lymphoma involvement or active CNS involvement by lymphoma. Participants with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for cerebrospinal fluid disease), and clinical remission.
• Has an active infection requiring systemic therapy.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has a known active Hepatitis C virus infection.
• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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290 participants in 6 patient groups

ZV + R-GemOx (Part 1)

Experimental group

Description:

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.

Treatment:

Drug: Granulocyte Colony-Stimulating Factor (G-CSF)

Drug: Oxaliplatin

Biological: Rituximab

Drug: Gemcitabine

Biological: Zilovertamab vedotin

ZV + R-GemOx (Part 2)

Experimental group

Description:

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.

Treatment:

Drug: Granulocyte Colony-Stimulating Factor (G-CSF)

Drug: Oxaliplatin

Biological: Rituximab

Drug: Gemcitabine

Biological: Zilovertamab vedotin

R-GemOx (active control for Part 2)

Active Comparator group

Description:

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.

Treatment:

Drug: Oxaliplatin

Biological: Rituximab

Drug: Gemcitabine

ZV + BR (Part 2)

Experimental group

Description:

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.

Treatment:

Drug: Granulocyte Colony-Stimulating Factor (G-CSF)

Biological: Rituximab

Drug: Bendamustine

Biological: Zilovertamab vedotin

Bendamustine Rituximab (BR)

Active Comparator group

Description:

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.

Treatment:

Biological: Rituximab

Drug: Bendamustine

ZV + BR (Part 1)

Experimental group

Description:

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.

Treatment:

Drug: Granulocyte Colony-Stimulating Factor (G-CSF)

Biological: Rituximab

Drug: Bendamustine

Biological: Zilovertamab vedotin