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Purpose

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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 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 due 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.

Study Design

Phase
Phase 2/Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Sequential Assignment
Intervention 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.
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
ZV + R-GemOx (Part 1) 		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
    Intravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg
    Other names:
    • MK-2140
    • VLS-101
  • Biological: Rituximab
    IV Infusion 375 mg/m^2
    Other names:
    • Rituxan®/mabthera
    • Truxima® (rituximab-abbs)
    • RUXIENCE®)
  • Drug: Gemcitabine
    IV Infusion 1000 mg/m^2
    Other names:
    • Gemzar®
  • Drug: Oxaliplatin
    IV Infusion 100 mg/m^2
    Other names:
    • Eloxatin®
Experimental
ZV + R-GemOx (Part 2) 		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
    Intravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg
    Other names:
    • MK-2140
    • VLS-101
  • Biological: Rituximab
    IV Infusion 375 mg/m^2
    Other names:
    • Rituxan®/mabthera
    • Truxima® (rituximab-abbs)
    • RUXIENCE®)
  • Drug: Gemcitabine
    IV Infusion 1000 mg/m^2
    Other names:
    • Gemzar®
  • Drug: Oxaliplatin
    IV Infusion 100 mg/m^2
    Other names:
    • Eloxatin®
Active Comparator
R-GemOx (active control for Part 2) 		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
    IV Infusion 375 mg/m^2
    Other names:
    • Rituxan®/mabthera
    • Truxima® (rituximab-abbs)
    • RUXIENCE®)
  • Drug: Gemcitabine
    IV Infusion 1000 mg/m^2
    Other names:
    • Gemzar®
  • Drug: Oxaliplatin
    IV Infusion 100 mg/m^2
    Other names:
    • Eloxatin®
Experimental
ZV + BR (Part 2) 		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
    Intravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg
    Other names:
    • MK-2140
    • VLS-101
  • Biological: Rituximab
    IV Infusion 375 mg/m^2
    Other names:
    • Rituxan®/mabthera
    • Truxima® (rituximab-abbs)
    • RUXIENCE®)
  • Drug: Bendamustine
    IV Infusion 90 mg/m^2
    Other names:
    • Bendeka®
    • Treanda®
    • Belrapzo®
Active Comparator
Bendamustine Rituximab (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
    IV Infusion 375 mg/m^2
    Other names:
    • Rituxan®/mabthera
    • Truxima® (rituximab-abbs)
    • RUXIENCE®)
  • Drug: Bendamustine
    IV Infusion 90 mg/m^2
    Other names:
    • Bendeka®
    • Treanda®
    • Belrapzo®
Experimental
ZV + BR (Part 1) 		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
    Intravenous (IV) Infusion 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.5 mg/kg
    Other names:
    • MK-2140
    • VLS-101
  • Biological: Rituximab
    IV Infusion 375 mg/m^2
    Other names:
    • Rituxan®/mabthera
    • Truxima® (rituximab-abbs)
    • RUXIENCE®)
  • Drug: Bendamustine
    IV Infusion 90 mg/m^2
    Other names:
    • Bendeka®
    • Treanda®
    • Belrapzo®

Recruiting Locations

Vanderbilt University Medical Center-Vanderbilt-Ingram Cancer Center ( Site 0156)
Nashville, Tennessee 37232
Contact:
Study Coordinator
615-936-8422

More Details

Status
Recruiting
Sponsor
Merck Sharp & Dohme LLC

Study Contact

Toll Free Number
1-888-577-8839
Trialsites@merck.com

Notice

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