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.
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.
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.
Sequential
Zilovertamab vedotin
Biological/VaccineIntravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg
Rituximab
Biological/VaccineIV Infusion 375 mg/m\^2
Gemcitabine
DrugIV Infusion 1000 mg/m\^2
Oxaliplatin
DrugIV Infusion 100 mg/m\^2
Bendamustine
DrugIV Infusion 90 mg/m\^2
Granulocyte Colony-Stimulating Factor (G-CSF)
DrugProphylactic G-CSF will be administered at each cycle of zilovertamab vedotin as per the institutional guidelines.
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Treatment groupsSee each treatment group below.
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.
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.
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.
Overall survival (OS)
OS, defined as the time from randomization to death due to any cause will be reported.
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.
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.
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