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)

Official title

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)

Overview

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.

Interventions

• 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
• Biological Rituximab
  IV Infusion 375 mg/m\^2
• Drug Gemcitabine
  IV Infusion 1000 mg/m\^2
• Drug Oxaliplatin
  IV Infusion 100 mg/m\^2
• Drug Bendamustine
  IV Infusion 90 mg/m\^2
• Drug Granulocyte Colony-Stimulating Factor (G-CSF)
  Prophylactic G-CSF will be administered at each cycle of zilovertamab vedotin as per the institutional guidelines.

Primary outcome measures

• Number of participants who experienced dose-limiting toxicities (DLTs) in Part 1 [Time frame: Up to ~6 weeks]
• Number of participants who experienced an adverse event (AE) [Time frame: Up to ~68 months]
• Number of participants who discontinued study treatment due to an AE [Time frame: Up to ~68 months]
• Overall survival (OS) [Time frame: Up to ~35 months]
• Progression-free survival (PFS) [Time frame: Up to ~35 months]

Secondary outcome measures (2)

• Objective response rate (ORR) [Time frame: Up to ~35 months]
• Duration of response (DOR) [Time frame: Up to ~35 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 26 centers

• Palo Verde Hematology/ Oncology Center, Ltd. ( Site 0175) — Glendale
• Beverly Hills Cancer Center ( Site 0184) — Beverly Hills
• Bass Medical Group ( Site 0166) — Walnut Creek
• Innovative Clinical Research Institute ( Site 0122) — Whittier
• Boca Raton Regional Hospital- Lynn Cancer Institute ( Site 0163) — Boca Raton
• Clermont Oncology Center ( Site 0174) — Clermont
• BRP-Hialeah Hospital ( Site 0182) — Hialeah
• Illinois Cancer Specialists ( Site 8000) — Niles
• … and 18 more centers

China · 16 centers

• Beijing Cancer hospital ( Site 3000) — Beijing
• Chongqing University Cancer Hospital-Medical Oncology ( Site 3025) — Chongqing
• Chongqing University Three Gorges Hospital ( Site 3026) — Chongqing
• Sun Yat-sen University Cancer Center-Internal Medicine ( Site 3001) — Guangzhou
• Zhujiang Hospital ( Site 3002) — Guangzhou
• The First Affiliated Hospital of Henan University of Science &Technology ( Site 3029) — Luoyang
• Henan Cancer Hospital-hematology department ( Site 3013) — Zhengzhou
• Union Hospital Tongji Medical College Huazhong University of Science and Technology ( Site — Wuhan
• … and 8 more centers

Japan · 13 centers

Center list to be confirmed — check the primary protocol.

Poland · 8 centers

Center list to be confirmed — check the primary protocol.

Chile · 7 centers

• Biocenter ( Site 2401) — Concepción
• IC La Serena Research ( Site 2405) — La Serena
• Oncocentro Valdivia ( Site 2407) — Valdivia
• FALP-UIDO ( Site 2400) — Santiago
• Clínica Inmunocel ( Site 2404) — Santiago
• Clínica RedSalud Vitacura ( Site 2409) — Santiago
• Bradfordhill ( Site 2403) — Santiago

Turkey (Türkiye) · 6 centers

Center list to be confirmed — check the primary protocol.

Argentina · 5 centers

• Hospital Italiano de Buenos Aires ( Site 2203) — Ciudad Autonoma de Buenos Aires
• Instituto de Investigaciones Clínicas Mar del Plata ( Site 2205) — Mar del Plata
• Hospital Aleman ( Site 2200) — Buenos Aites
• Hospital Privado Universitario de Córdoba ( Site 2202) — Córdoba
• Instituto Alexander Fleming ( Site 2201) — CABA

Colombia · 5 centers

• Hospital Pablo Tobon Uribe ( Site 0804) — Medellín
• FUNDACION CTIC CENTRO DE TRATAMIENTO E INVESTIGACION SOBRE CANCER LUIS CARLOS SARMIENTO AN — Bogotá
• Instituto Médico de Alta Tecnologia S.A.S ( Site 0803) — Montería
• Oncologos del Occidente ( Site 0800) — Pereira
• Fundacion Valle del Lili ( Site 0802) — Cali

Peru · 5 centers

Center list to be confirmed — check the primary protocol.

Ukraine · 5 centers

Center list to be confirmed — check the primary protocol.

Italy · 4 centers

Center list to be confirmed — check the primary protocol.

Australia · 3 centers

• Townsville University Hospital ( Site 1800) — Townsville
• Grampians Health ( Site 1802) — Ballarat
• Royal Perth Hospital-Haematology ( Site 1801) — Perth

Brazil · 3 centers

• Hospital Erasto Gaertner ( Site 2302) — Curitiba
• Liga Norte Riograndense Contra o Câncer ( Site 2305) — Natal
• Hospital Paulistano ( Site 2300) — São Paulo

Greece · 3 centers

• Evangelismos General Hospital of Athens ( Site 0900) — Athens
• Regional General Hospital of Athens "Laiko" ( Site 0901) — Athens
• University Hospital of Alexandroupolis ( Site 0903) — Alexandroupoli

Guatemala · 3 centers

• MEDI-K ( Site 2602) — Guatemala City
• Private Practice- Dr. Rixci Augusto Lenin Ramírez ( Site 2601) — Guatemala City
• CELAN,S.A ( Site 2603) — Guatemala City

Israel · 3 centers

• Emek Medical Center-Hematology Unit ( Site 1102) — Afula
• … and 2 more centers

Mexico · 3 centers

Center list to be confirmed — check the primary protocol.

Thailand · 3 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 3 centers

Center list to be confirmed — check the primary protocol.

Costa Rica · 2 centers

• Hospital Metropolitano - Sede Lindora ( Site 2500) — Santa Ana
• CIMCA ( Site 2501) — San José

France · 2 centers

• centre hospitalier lyon sud-Service Hématologie ( Site 0702) — Pierre-Bénite
• Pitie Salpetriere University Hospital-Clinical haematology ( Site 0700) — Paris

Hong Kong · 2 centers

• Queen Mary Hospital ( Site 3100) — Hong Kong
• Princess Margaret Hospital ( Site 3101) — Hong Kong

South Korea · 2 centers

Center list to be confirmed — check the primary protocol.

Canada · 1 center

• Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0200) — Toronto

Denmark · 1 center

• Aarhus Universitetshospital, Skejby ( Site 1701) — Aarhus

New Zealand · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT05139017 · 2140-003 · VLS-101 · MK-2140-003 · waveLINE-003 · 2022-502646-27-00 · U1111-1285-0898 · jRCT2011250068

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗