Clinical trial NCT05139017: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: DLBCL
Diffuse Large B-Cell Lymphoma
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2021-12-01
Enrollment: 290
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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

Brief summary: 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.


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.

Primary outcomes:
measure: Number of participants who experienced dose-limiting toxicities (DLTs) in Part 1
timeFrame: Up to ~6 weeks
measure: Number of participants who experienced an adverse event (AE)
timeFrame: Up to ~68 months
measure: Number of participants who discontinued study treatment due to an AE
timeFrame: Up to ~68months
measure: Overall survival (OS)
timeFrame: Up to ~35 months
measure: Progression-free survival (PFS)
timeFrame: Up to ~26 months
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: Up to ~26 months
measure: Duration of response (DOR)
timeFrame: Up to ~26 months
Other outcomes:
Locations:
city: Walnut Creek
country: United States
facility: Bass Medical Group ( Site 0166)
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute ( Site 0122)
state: California
city: Boca Raton
country: United States
facility: Boca Raton Regional Hospital- Lynn Cancer Institute ( Site 0163)
state: Florida
city: Edgewood
country: United States
facility: Saint Elizabeth Medical Center Edgewood ( Site 0165)
state: Kentucky
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center ( Site 0158)
state: Kentucky
city: Louisville
country: United States
facility: Norton Women's and Children's Hospital-Norton Cancer Institute - St. Matthews ( Site 0133)
state: Kentucky
city: New Orleans
country: United States
facility: Louisiana State University Health Sciences Center New Orleans ( Site 0134)
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland ( Site 0123)
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute-Lymphoma ( Site 0111)
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School ( Site 0119)
state: Massachusetts
city: Billings
country: United States
facility: St. Vincent Frontier Cancer Center-Research ( Site 0108)
state: Montana
city: Morristown
country: United States
facility: Atlantic Health System ( Site 0116)
state: New Jersey
city: Valhalla
country: United States
facility: New York Medical College ( Site 0113)
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center-Vanderbilt-Ingram Cancer Center ( Site 0156)
state: Tennessee
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires ( Site 2203)
state: Buenos Aires
city: Mar del Plata.
country: Argentina
facility: Instituto de Investigaciones Clínicas Mar del Plata ( Site 2205)
state: Buenos Aires
city: Buenos Aites
country: Argentina
facility: Hospital Aleman ( Site 2200)
state: Caba
city: Caba
country: Argentina
facility: Instituto Alexander Fleming ( Site 2201)
city: Cordoba
country: Argentina
facility: Hospital Privado Universitario de Córdoba ( Site 2202)
city: Douglas
country: Australia
facility: Townsville University Hospital ( Site 1800)
state: Queensland
city: Ballarat
country: Australia
facility: Grampians Health ( Site 1802)
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital-Haematology ( Site 1801)
state: Western Australia
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner ( Site 2302)
state: Parana
city: Natal
country: Brazil
facility: Liga Norte Riograndense Contra o Câncer ( Site 2305)
state: Rio Grande Do Norte
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0200)
state: Ontario
city: Concepcion.
country: Chile
facility: Biocenter ( Site 2401)
state: Biobio
city: La Serena
country: Chile
facility: IC La Serena Research ( Site 2405)
state: Coquimbo
city: Valdivia.
country: Chile
facility: Oncocentro Valdivia ( Site 2407)
state: Los Rios
city: Santiago.
country: Chile
facility: FALP-UIDO ( Site 2400)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Clínica Inmunocel ( Site 2404)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Clínica RedSalud Vitacura ( Site 2409)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Bradfordhill ( Site 2403)
state: Region M. De Santiago
city: Beijing
country: China
facility: Beijing Cancer hospital ( Site 3000)
state: Beijing
city: Chongqing
country: China
facility: Chongqing University Cancer Hospital-Medical Oncology ( Site 3025)
state: Chongqing
city: Chongqing
country: China
facility: Chongqing University Three Gorges Hospital ( Site 3026)
state: Chongqing
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center-Internal Medicine ( Site 3001)
state: Guangdong
city: Guangzhou
country: China
facility: Zhujiang Hospital ( Site 3002)
state: Guangdong
city: Luoyang
country: China
facility: The First Affiliated Hospital of Henan University of Science &Technology ( Site 3029)
state: Henan
city: Zhengzhou
country: China
facility: Henan Cancer Hospital-hematology department ( Site 3013)
state: Henan
city: Wuhan
country: China
facility: Union Hospital Tongji Medical College Huazhong University of Science and Technology ( Site 3017)
state: Hubei
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University ( Site 3004)
state: Jiangxi
city: Nanchang
country: China
facility: Jiangxi Provincial Cancer Hospital ( Site 3005)
state: Jiangxi
city: Changchun
country: China
facility: The First Hospital of Jilin University-Hematology ( Site 3012)
state: Jilin
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center ( Site 3009)
state: Shanghai
city: Cheng Du
country: China
facility: West China Hospital of Sichuan University-Head and Neck Oncology ( Site 3016)
state: Sichuan
city: Chengdu
country: China
facility: Sichuan Cancer hospital-Oncology ( Site 3021)
state: Sichuan
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital ( Site 3014)
state: Zhejiang
city: Hangzhou
country: China
facility: The First Affiliated Hospital Zhejiang University School of Medicine ( Site 3027)
state: Zhejiang
city: Medellin
country: Colombia
facility: Hospital Pablo Tobon Uribe ( Site 0804)
state: Antioquia
city: Monteria
country: Colombia
facility: Instituto Médico de Alta Tecnologia S.A.S ( Site 0803)
state: Cordoba
city: Bogota
country: Colombia
facility: FUNDACION CTIC CENTRO DE TRATAMIENTO E INVESTIGACION SOBRE CANCER LUIS CARLOS SARMIENTO ANGULO ( Site 0801)
state: Distrito Capital De Bogota
city: Pereira.
country: Colombia
facility: Oncologos del Occidente ( Site 0800)
state: Risaralda
city: Cali
country: Colombia
facility: Fundacion Valle del Lili ( Site 0802)
state: Valle Del Cauca
city: Santa Ana
country: Costa Rica
facility: Hospital Metropolitano - Sede Lindora ( Site 2500)
state: San Jose
city: San Jose
country: Costa Rica
facility: CIMCA ( Site 2501)
city: Pierre-Bénite
country: France
facility: centre hospitalier lyon sud-Service Hématologie ( Site 0702)
state: Rhone
city: Paris
country: France
facility: Pitie Salpetriere University Hospital-Clinical haematology ( Site 0700)
city: Alexandroupolis
country: Greece
facility: University Hospital of Alexandroupolis ( Site 0903)
state: Anatoliki Makedonia Kai Thraki
city: Athens
country: Greece
facility: Evangelismos General Hospital of Athens ( Site 0900)
state: Attiki
city: Athens
country: Greece
facility: Regional General Hospital of Athens "Laiko" ( Site 0901)
state: Attiki
city: Guatemala
country: Guatemala
facility: MEDI-K ( Site 2602)
city: Guatemala
country: Guatemala
facility: Private Practice- Dr. Rixci Augusto Lenin Ramírez ( Site 2601)
city: Guatemala
country: Guatemala
facility: CELAN,S.A ( Site 2603)
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital ( Site 3100)
city: Hong Kong
country: Hong Kong
facility: Princess Margaret Hospital ( Site 3101)
city: Afula
country: Israel
facility: Emek Medical Center-Hematology Unit ( Site 1102)
city: Haifa
country: Israel
facility: Carmel Hospital ( Site 1103)
city: Jerusalem
country: Israel
facility: Hadassah Medical Center ( Site 1100)
city: Rozzano
country: Italy
facility: Humanitas-U.O di Oncologia medica ed Ematologia ( Site 1203)
state: Milano
city: Bologna
country: Italy
facility: IRCCS - AOU di Bologna-Istituto di Ematologia "L. e A. Seragnoli" ( Site 1200)
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 1202)
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS -ISTITUTO DI EMATOLOGIA ( Site 1204)
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital-Oncology ( Site 0302)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 0300)
city: Auckland
country: New Zealand
facility: Aotearoa Clinical Trials ( Site 0501)
city: Chiclayo
country: Peru
facility: Clínicas AUNA Sede Chiclayo ( Site 2803)
state: Lambayeque
city: Lima
country: Peru
facility: Clínica San Felipe ( Site 2805)
city: Walbrzych
country: Poland
facility: Specjalistyczny Szpital im. Dr Alfreda Sokolowskiego w Walbrzychu ( Site 1305)
state: Dolnoslaskie
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny-Klinika Hematologii, Nowotworow Krwi i Transplantacji Szpiku ( Site 1301)
state: Dolnoslaskie
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej-Oddzial Hematologii i Transplantacji Szpiku ( Site 1304)
state: Lubelskie
city: Krakow
country: Poland
facility: Pratia MCM Krakow ( Site 1303)
state: Malopolskie
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Klinika Nowotworów Układu Chłonnego ( Site 1300)
state: Mazowieckie
city: Gdynia
country: Poland
facility: Szpitale Pomorskie Sp. z o. o.-Hematology and Bone Marrow Transplantation Department ( Site 1302)
state: Pomorskie
city: Słupsk
country: Poland
facility: Wojewódzki Szpital Specjalistyczny im. J. Korczaka w Słupsku ( Site 1309)
state: Pomorskie
city: Katowice
country: Poland
facility: Pratia Onkologia Katowice ( Site 1306)
state: Slaskie
city: Bangkok
country: Thailand
facility: Faculty of Medicine Siriraj Hospital-Division of Hematology, Department of Medicine ( Site 0400)
state: Krung Thep Maha Nakhon
city: Pathumwan
country: Thailand
facility: Chulalongkorn University ( Site 0402)
state: Krung Thep Maha Nakhon
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital ( Site 0401)
city: Yenimahalle
country: Turkey
facility: Dr. Abdurrahman Yurtaslan Ankara Onkoloji Egitim ve Arastırma Hastanesi ( Site 1912)
state: Ankara
city: Bornova
country: Turkey
facility: Ege University Medicine of Faculty ( Site 1902)
state: Izmir
city: Ankara
country: Turkey
facility: Ankara University Hospital Cebeci-hematology ( Site 1901)
city: Istanbul
country: Turkey
facility: Mega Medipol-Hematology ( Site 1909)
city: Izmir
country: Turkey
facility: Dokuz Eylül Üniversitesi-Hematology ( Site 1905)
city: Samsun
country: Turkey
facility: Ondokuz Mayıs Universitesi ( Site 1907)
city: Cherkasy
country: Ukraine
facility: MNPE ClinCenter of Oncology,Hematology,Transplantology and Palliative Care of CherkasyRegCouncil ( Site 2000)
state: Cherkaska Oblast
city: Ivano-Frankivsk
country: Ukraine
facility: Communal non-profit enterprise "Regional clinical hospital of Ivano-Frankivsk Regional Council" ( Site 2004)
state: Ivano-Frankivska Oblast
city: Lviv
country: Ukraine
facility: Institute of Blood Pathology and Transfusion Medicine AMS Ukraine ( Site 2002)
state: Lvivska Oblast
city: Kyiv
country: Ukraine
facility: State non-profit enterprise National Cancer Institute ( Site 2001)
city: Kyiv
country: Ukraine
facility: National Research Center for Radiation Medicine of National Academy of Medical Sciences of Ukraine ( Site 2005)
city: Kyiv
country: Ukraine
facility: Public Non-Profit Enterprise Kyiv City Clinical Hospital #9 under the Executive Body of Kyiv City Co ( Site 2003)
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary ( Site 2104)
state: Aberdeen City
city: London-Camden
country: United Kingdom
facility: University College London Hospital-Cancer Clinical Trials Unit ( Site 2100)
state: London, City Of
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: