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)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2/3 Multicenter, Open-label, Randomized, Active-Control Study of Zilovertamab Vedotin (MK-2140) in Combination With Standard of Care in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (waveLINE-003)

Conditions
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DLBCL, Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Biological: Zilovertamab vedotin
* Biological: Rituximab
* Drug: Gemcitabine
* Drug: Oxaliplatin
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically confirmed diagnosis of 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. 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: 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 pericardial effusion or clinically significant 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: In Part 1, Dose Confirmation will be determined by modified toxicity probability interval (mTPI) design, where participants will be assigned to two treatment groups, cohort: A (zilovertamab vedotin in combinatio with R-GemOx) in parallel with cohort B (zilovertamab vedotin in combination with BR). Part 2 will be an Efficacy Expansion (cohorts A & B) where all participants in each cohort will be assigned to 2 treatment groups for the duration of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZV + R-GemOx (Part 1)<br>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. | Biological: Zilovertamab vedotin<br>* Intravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg<br>* Other names: VLS-101;Biological: Rituximab<br>* IV Infusion 375 mg/m^2<br>* Other names: RUXIENCE®);Drug: Gemcitabine<br>* IV Infusion 1000 mg/m^2<br>* Other names: Gemzar®;Drug: Oxaliplatin<br>* IV Infusion 100 mg/m^2<br>* Other names: Eloxatin®;|
| Experimental: ZV + R-GemOx (Part 2)<br>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. | Biological: Zilovertamab vedotin<br>* Intravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg<br>* Other names: VLS-101;Biological: Rituximab<br>* IV Infusion 375 mg/m^2<br>* Other names: RUXIENCE®);Drug: Gemcitabine<br>* IV Infusion 1000 mg/m^2<br>* Other names: Gemzar®;Drug: Oxaliplatin<br>* IV Infusion 100 mg/m^2<br>* Other names: Eloxatin®;|
| Active Comparator: R-GemOx (active control for Part 2)<br>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. | Biological: Rituximab<br>* IV Infusion 375 mg/m^2<br>* Other names: RUXIENCE®);Drug: Gemcitabine<br>* IV Infusion 1000 mg/m^2<br>* Other names: Gemzar®;Drug: Oxaliplatin<br>* IV Infusion 100 mg/m^2<br>* Other names: Eloxatin®;|
| Experimental: ZV + BR (Part 2)<br>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. | Biological: Zilovertamab vedotin<br>* Intravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg<br>* Other names: VLS-101;Biological: Rituximab<br>* IV Infusion 375 mg/m^2<br>* Other names: RUXIENCE®);Drug: Bendamustine<br>* IV Infusion 90 mg/m^2<br>* Other names: Belrapzo®;|
| Active Comparator: Bendamustine Rituximab (BR)<br>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. | Biological: Rituximab<br>* IV Infusion 375 mg/m^2<br>* Other names: RUXIENCE®);Drug: Bendamustine<br>* IV Infusion 90 mg/m^2<br>* Other names: Belrapzo®;|
| Experimental: ZV + BR (Part 1)<br>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. | Biological: Zilovertamab vedotin<br>* Intravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg<br>* Other names: VLS-101;Biological: Rituximab<br>* IV Infusion 375 mg/m^2<br>* Other names: RUXIENCE®);Drug: Bendamustine<br>* IV Infusion 90 mg/m^2<br>* Other names: Belrapzo®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who experienced dose-limiting toxicities (DLTs) in Part 1 | The CTCAE, Version 5.0 will be used to grade the severity of AEs in this study. DLTs will be reported for Part 1 of this study. | Up to  2 cycles (6 weeks) | 
| Number of participants who experienced an adverse event (AE) | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who experienced an AE will be reported. | Up to  6 months | 
| Number of participants who discontinued study treatment due to an AE | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who discontinued study treatment due to an AE will be reported. | Up to  6 months | 
| PFS | PFS, defined as the time from randomization to the first documented disease progression per Lugano response criteria as assessed by BICR or death due to any cause, whichever occurs first will be presented. | Up to  36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS, defined as the time from randomization to death due to any cause will be reported. | Up to  36 months | 
| Objective response rate (ORR) | ORR, defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) per Lugano criteria as assessed by BICR will be presented. | Up to  36 months | 
| Duration of response (DOR) | DOR, defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first, will be reported. | Up to  36 months |