Substudy 01A: Zilovertamab Vedotin in Pediatric and Young Adult Participants With Hematologic Malignancies or Solid Tumors (MK-9999-01A/LIGHTBEAM-U01)
- Conditions
- B-cell Acute Lymphoblastic LeukemiaDiffuse Large B-cell LymphomaBurkitt LymphomaNeuroblastomaEwing Sarcoma
- Interventions
- Registration Number
- NCT06395103
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
Substudy 01A is part of a platform study. The purpose of this study is to assess the efficacy and safety of zilovertamab vedotin in pediatric participants with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, or neuroblastoma and in pediatric and young adult participants with Ewing sarcoma.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 90
- For hematological malignancies: Confirmed diagnosis of B-precursor B-ALL or DLBCL/Burkitt lymphoma according to World Health Organization (WHO) classification of neoplasms of the lymphoid tissues.
- For solid tumor malignancies: Histologically confirmed diagnosis of neuroblastoma or Ewing sarcoma.
- History of solid organ transplant.
- Clinically significant (ie, active) cardiovascular disease.
- Known history of liver cirrhosis.
- Ongoing Grade >1 peripheral neuropathy.
- Demyelinating form of Charcot-Marie-Tooth disease.
- Diagnosed with Down syndrome.
- Ongoing graft-versus-host disease (GVHD) of any grade or receiving systemic GVHD treatment or prophylaxis.
- History of human immunodeficiency virus (HIV) infection.
- Contraindication or hypersensitivity to any of the study intervention components.
- Received prior radiotherapy within 4 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities.
- Ongoing, chronic corticosteroid therapy (exceeding 10 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 4 weeks before Cycle 1 Day 1 (C1D1).
- Received a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 7 days or a strong CYP3A4 inducer within 14 days before the start of study intervention or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer during the study intervention period and for 30 days after the last dose of study intervention
- Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention (except for prophylactic intrathecal chemotherapy and/or cytoreductive therapy with steroids/hydroxyurea.
- Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
- Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
- Known additional malignancy that is progressing or has required active treatment within the past 1 year.
- Active infection requiring systemic therapy.
- Known history of Hepatitis B or known active Hepatitis C virus infection.
- Participants who have not adequately recovered from major surgery or have ongoing surgical complications.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Zilovertamab vedotin Zilovertamab vedotin Participants receive escalating doses of zilovertamab vedotin via intravenous (IV) infusion on Day 1 of each 21-day cycle (every 3 weeks).
- Primary Outcome Measures
Name Time Method Part 1: Number of Participants from 1 to <18 years of Age Who Receive Dose Modification Due to AEs Up to approximately 60 months An AE is defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. The number of participants in Part 1 who receive a dose modification due to an AE will be presented.
Part 1 and Part 2: Objective Response (OR) for Participants with B-Cell Acute Lymphoblastic Leukemia (B-ALL) Up to approximately 60 months OR for participants with B-ALL is defined as complete response (CR) or complete response with incomplete hematologic recovery (CRi) based on investigator's assessment per Ponte-di-Legno Consortium criteria. For Part 1 and Part 2, the OR for participants with B-ALL as assessed by investigator will be presented.
Part 1: Number of Participants from 1 to <18 years of Age Who Experience a Dose-Limiting Toxicity (DLT) Up to 42 days Number of participants experiencing toxicities that are possibly, probably, or definitely related to study therapy; that meet pre-defined severity criteria; and result in a change in the given dose.
Part 1: Number of Participants from 1 to <18 years of Age Who Experience One or More Adverse Events (AEs) Up to approximately 60 months An AE is defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. The number of participants in Part 1 who experience at least 1 AE will be presented.
Part 1: Number of Participants from 1 to <18 years of Age Who Discontinue Study Treatment Due to AEs Up to approximately 60 months An AE is defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. The number of participants in Part 1 who discontinue study treatment due to an AE will be presented.
Part 1 and Part 2: OR for Participants with Diffuse Large B-Cell Lymphoma (DLBCL)/Burkitt Lymphoma, Neuroblastoma, and Ewing Sarcoma Up to approximately 60 months OR for participants with DLBCL/Burkitt lymphoma, neuroblastoma, and Ewing sarcoma is defined as complete response (CR) or partial response (PR) based on investigator's assessment per International Pediatric Non-Hodgkin Lymphoma (IPNHL) Response Criteria for participants with DLBCL/Burkitt lymphoma, per International Neuroblastoma Response Criteria (INRC) for neuroblastoma, and per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for Ewing sarcoma. For Part 1 and Part 2, the OR for participants with DLBCL/Burkitt lymphoma, neuroblastoma, and Ewing sarcoma as assessed by investigator will be presented.
- Secondary Outcome Measures
Name Time Method Part 1 and Part 2: Maximum Plasma Concentration (Cmax) of Total Antibody Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the Cmax of total antibody.
Part 1 and Part 2: Plasma Trough Concentration (Ctrough) of Total Antibody Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the Ctrough of total antibody.
Part 1 and Part 2: Area Under the Curve (AUC) of Total Antibody Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the AUC of total antibody.
Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Total Antibody Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the t1/2 of total antibody.
Part 1 and Part 2: AUC of Antibody-Drug Conjugate (ADC) Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the AUC of ADC.
Part 1 and Part 2: Ctrough of Antibody-Drug Conjugate (ADC) Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the Ctrough of ADC.
Part 1 and Part 2: t1/2 of Antibody-Drug Conjugate (ADC) Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the t1/2 of ADC.
Part 1 and Part 2: AUC of Monomethyl Auristatin E (MMAE) Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the AUC of MMAE.
Part 1 and Part 2: Cmax of Monomethyl Auristatin E (MMAE) Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the Cmax of MMAE.
Part 2: Number of Participants Who Receive Dose Modification Due to AEs Up to approximately 60 months An AE is defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. The number of participants in Part 2 who receive a dose modification due to an AE will be presented.
Part 1 and Part 2: Incidence of Antidrug Antibodies (ADAs) to Zilovertamab Vedotin Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated timepoints will be used to determine the ADA response to zilovertamab vedotin. The incidence of ADAs over time will be presented.
Part 1 and Part 2: Duration of Response (DOR) Up to approximately 60 months DOR is defined as the time from the first documented evidence of CR/CRi for B-ALL or CR/PR for DLBCL/Burkitt lymphoma, Ewing sarcoma, and neuroblastoma until disease progression or death due to any cause, whichever occurs first. For participants under 1-year of age, the time from the first dose will start from the first dose a participant receives during Part 2.
Part 1 and Part 2: Percentage of Participants with B-ALL Who Receive SCT Up to approximately 60 months The percentage of participants with B-ALL who go on to receive SCT will be presented.
Part 1 and Part 2: Percentage of Participants with B-ALL Who Receive Chimeric Antigen Receptor T (CAR-T) Up to approximately 60 months The percentage of participants with B-ALL who go on to receive CAR-T will be presented.
Part 1 and Part 2: Cmax of Antibody-Drug Conjugate (ADC) ose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the Cmax of ADC.
Part 1 and Part 2: Ctrough of Monomethyl Auristatin E (MMAE) Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the Ctrough of MMAE.
Part 1 and Part 2: t1/2 of Monomethyl Auristatin E (MMAE) Predose on Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 4 cycles thereafter, and at end of infusion on Day 1 of Cycles 1 and 3. Each cycle is 21 days. (Up to approximately 60 months) Blood samples collected at designated time points will be used to determine the t1/2 of MMAE.
Part 2: Number of Participants Who Experience One or More Adverse Events (AEs) Up to approximately 60 months An AE is defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. The number of participants in Part 2 who experience at least 1 AE will be presented.
Part 1 and Part 2: Percentage of Participants with DLBCL/Burkitt Lymphoma Who Receive Stem Cell Transplant (SCT) Up to approximately 60 months The percentage of participants with DLBCL/Burkitt Lymphoma who go on to receive SCT will be presented.
Part 2: Number of Participants Who Discontinue Study Treatment Due to AEs Up to approximately 60 months An AE is defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. The number of participants in Part 2 who discontinue study treatment due to an AE will be presented.
Trial Locations
- Locations (53)
Children's Hospital Los Angeles ( Site 1006)
🇺🇸Los Angeles, California, United States
Children's Hospital Colorado-Center for Cancer and Blood Disorders ( Site 1016)
🇺🇸Aurora, Colorado, United States
Yale-New Haven Hospital ( Site 1012)
🇺🇸New Haven, Connecticut, United States
Johns Hopkins All Children's Hospital ( Site 1025)
🇺🇸Saint Petersburg, Florida, United States
University of Iowa-Holden Comprehensive Cancer Center ( Site 1017)
🇺🇸Iowa City, Iowa, United States
Dana-Farber Cancer Institute ( Site 1013)
🇺🇸Boston, Massachusetts, United States
Corewell Health ( Site 1001)
🇺🇸Grand Rapids, Michigan, United States
Children's Mercy Hospital ( Site 1024)
🇺🇸Kansas City, Missouri, United States
Rutgers Cancer Institute of New Jersey ( Site 1008)
🇺🇸New Brunswick, New Jersey, United States
New York Medical College ( Site 1023)
🇺🇸Valhalla, New York, United States
Sanford Fargo Medical Center-Roger Maris Cancer Center ( Site 1003)
🇺🇸Fargo, North Dakota, United States
Oregon Health and Science University ( Site 1004)
🇺🇸Portland, Oregon, United States
Children's Hospital of Philadelphia (CHOP) ( Site 1021)
🇺🇸Philadelphia, Pennsylvania, United States
Sanford Children's Hospital-Sanford Children's Specialty Clinic ( Site 1015)
🇺🇸Sioux Falls, South Dakota, United States
University of Texas MD Anderson Cancer Center ( Site 1007)
🇺🇸Houston, Texas, United States
Intermountain - Primary Children's Hospital ( Site 1014)
🇺🇸Salt Lake City, Utah, United States
Sydney Children's Hospital-Kids Cancer Centre ( Site 1997)
🇦🇺Randwick, New South Wales, Australia
Queensland Children's Hospital-Oncology & Haematology ( Site 1996)
🇦🇺Brisbane, Queensland, Australia
UZ Gent ( Site 1428)
🇧🇪Gent, Oost-Vlaanderen, Belgium
Hospital Erasto Gaertner-CEPEP - Pesquisa Clínica ( Site 1268)
🇧🇷Curitiba, Parana, Brazil
Hospital de Clinicas de Porto Alegre ( Site 1265)
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Fundação Pio XII - Hospital de Câncer de Barretos ( Site 1264)
🇧🇷Barretos, Sao Paulo, Brazil
Fundação Faculdade Regional de Medicina de São José do Rio Preto-Centro Integrado de Pesquisa ( Site 1267)
🇧🇷São José do Rio Preto, Sao Paulo, Brazil
Hospital Carlos Van Buren ( Site 1880)
🇨🇱Valparaíso, Valparaiso, Chile
Hospital Pablo Tobon Uribe ( Site 1923)
🇨🇴Medellin, Antioquia, Colombia
Clinica de la Costa S.A.S.-Clinical Research Oncology & Hematology -Pediatric ( Site 1924)
🇨🇴Barranquilla, Atlantico, Colombia
IMAT S.A.S ( Site 1921)
🇨🇴Monteria, Cordoba, Colombia
Rigshospitalet-Department of paediatrics and adolescent medicine, Section of Paed haem-onc ( Site 1467)
🇩🇰Copenhagen, Hovedstaden, Denmark
CHU de Bordeaux. Hopital Pellegrin ( Site 1105)
🇫🇷Bordeaux, Aquitaine, France
Gustave Roussy ( Site 1103)
🇫🇷Villejuif, Ile-de-France, France
Centre Hospitalier Universitaire de Nantes - Hôpital Femme-Enfant-Adolescent Chu De Nantes ( Site 1104)
🇫🇷Nantes, Pays-de-la-Loire, France
CENTRE LEON BERARD-IHOPE (pediatrric oncology) ( Site 1100)
🇫🇷Lyon, Rhone-Alpes, France
Universitätsklinikum Münster - Albert Schweitzer Campus-Pädiatrische Hämatologie und Onkologie ( Site 1141)
🇩🇪Münster, Nordrhein-Westfalen, Germany
Aghia Sophia Children's Hospital-First Department of Pediatrics, National and Kapodistrian Universi ( Site 1797)
🇬🇷Athens, Attiki, Greece
Semmelweis Egyetem ( Site 1838)
🇭🇺Budapest, Hungary
Rambam Health Care Campus-Pediatric Hemato-Oncology ( Site 1674)
🇮🇱Haifa, Israel
Sheba Medical Center ( Site 1675)
🇮🇱Ramat Gan, Israel
Fondazione IRCCS Istituto Nazionale dei Tumori-Pediatric Oncology ( Site 1552)
🇮🇹Milan, Lombardia, Italy
Ospedale Pediatrico Bambino Gesù IRCCS-Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica ( Site 1553)
🇮🇹Rome, Roma, Italy
Seoul National University Hospital-Pediatrics ( Site 1972)
🇰🇷Seoul, Korea, Republic of
Asan Medical Center-Pediatrics - Pedicatric Oncology ( Site 1973)
🇰🇷Seoul, Korea, Republic of
Prinses Maxima Centrum voor Kinderoncologie ( Site 1510)
🇳🇱Utrecht, Netherlands
Hospital Sant Joan de Déu-Pediatric Oncology Department ( Site 1717)
🇪🇸Esplugas De Llobregat, Barcelona, Spain
Hospital Infantil Universitario Niño Jesús-Servicio de Onco-Hematología Pediátrica ( Site 1715)
🇪🇸Madrid, Madrid, Comunidad De, Spain
Hospital Universitari Vall d'Hebron-Servei de Hematologia i Oncologia Pediatrica ( Site 1716)
🇪🇸Barcelona, Spain
Prövningsenhet barn, Sahlgrenska Universitetssjukhuset ( Site 1634)
🇸🇪Gothenburg, Vastra Gotalands Lan, Sweden
National Taiwan University Hospital ( Site 1983)
🇨🇳Taipei, Taiwan
Hacettepe Universite Hastaneleri ( Site 1961)
🇹🇷Ankara, Turkey
Ankara Bilkent Şehir Hastanesi ( Site 1962)
🇹🇷Ankara, Turkey
Ege Universitesi Hastanesi ( Site 1963)
🇹🇷İzmir, Turkey
Royal Victoria Infirmary-Great North Children's Hospital ( Site 1348)
🇬🇧Newcastle upon Tyne, England, United Kingdom
University College London Hospital ( Site 1350)
🇬🇧London, London, City Of, United Kingdom
University Hospital of Wales ( Site 1346)
🇬🇧Cardiff, United Kingdom