A Phase 3, Randomized, Open-label Study of Belzutifan + Zanzalintinib Versus Cabozantinib in Participants With Advanced RCC Who Experienced Disease Recurrence During or After Prior Adjuvant Anti-PD-1/L1 Therapy (LITESPARK-033)

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Investigational drug late phase More information Active drug More information Moderate burden on patient More information

Trial Details

Sponsor: Merck Sharp & Dohme LLC (industry)

Phase: 3

Start date: Nov. 26, 2025

Planned enrollment: 904

Trial ID: NCT07227402
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More trial details at ClinicalTrials.gov More info

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Investigational Drug AI Analysis

chevron Show for: Zanzalintinib (XL092)

TrialFetch AI Analysis

Goal: To determine whether belzutifan plus zanzalintinib improves progression-free survival and overall survival compared with cabozantinib in recurrent advanced clear-cell renal cell carcinoma after adjuvant anti-PD-1/L1 therapy.

Patients: Patients have histologically confirmed unresectable stage IV RCC with a clear-cell component, measurable disease by RECIST 1.1, and recurrence during adjuvant anti-PD-1/L1 therapy or within 24 months after its last dose. No prior systemic RCC therapy other than adjuvant anti-PD-1/L1 treatment is permitted. Key exclusions include significant recent cardiovascular or thromboembolic disease, left ventricular ejection fraction of 50% or lower, current pneumonitis/interstitial lung disease, dialysis, active hepatitis B or C, HIV infection, high-risk gastrointestinal disorders, and recent major surgery.

Design: Randomized, open-label, active-controlled phase 3 trial. Participants receive treatment until a protocol-defined reason for discontinuation, with efficacy followed for up to approximately 73 months. Tumor responses and progression are assessed by blinded independent central review using RECIST 1.1.

Treatments: The experimental arm receives oral belzutifan plus oral zanzalintinib once daily. Belzutifan is a HIF-2α inhibitor with established antitumor activity in RCC. Zanzalintinib, also known as XL092, is an investigational multikinase inhibitor targeting VEGFR2, MET, and the TAM kinases TYRO3, AXL, and MER, thereby affecting angiogenesis, tumor growth, and tumor-associated immunosuppression. In an early study of 32 heavily pretreated patients with clear-cell RCC, zanzalintinib produced a 38% objective response rate, an 88% disease-control rate, and median progression-free survival of 9 months; grade 3 treatment-related adverse events occurred in 44%, with no grade 4 or 5 treatment-related events reported. The comparator arm receives oral cabozantinib once daily, an established multikinase inhibitor used in advanced RCC.

Outcomes: The co-primary endpoints are progression-free survival by blinded independent central review and overall survival, assessed for up to approximately 73 months. Secondary endpoints include objective response rate, duration of response, adverse events, and treatment discontinuations due to adverse events. Patient-reported outcomes assess global health and quality of life, physical and role functioning, and kidney cancer symptoms using the EORTC QLQ-C30 and FKSI-DRS, including changes from baseline and time to clinically meaningful deterioration, for up to approximately 25 months.

Burden on patient: Estimated burden is moderate. Both regimens are taken orally once daily, avoiding routine infusion visits, and the protocol information does not specify mandatory research biopsies or intensive pharmacokinetic sampling. However, patients will require repeated clinic visits, laboratory and safety monitoring, cardiovascular assessment as appropriate, serial imaging for RECIST evaluation, adverse-event management, and regular quality-of-life questionnaires. The potentially prolonged treatment and follow-up period, along with toxicities associated with HIF-2α and multikinase inhibition, may create meaningful cumulative travel and monitoring demands.

Last updated: Jul 2026

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Hospital Privado Universitario de Córdoba ( Site 0207)

Córdoba, X5016KEH, Argentina

No email / +543514688200

Status: Recruiting

Asociación de Beneficencia Hospital Sirio Libanés ( Site 0205)

Caba, Buenos Aires, C1419AHN, Argentina

No email / +541145740870

Status: Recruiting

Hospital Aleman ( Site 0204)

CABA, Buenos Aires, C1118AAT, Argentina

No email / +5448277000

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Hospital Italiano de Buenos Aires. ( Site 0203)

Caba, Buenos Aires, C1199ABB, Argentina

No email / +541149590200

Status: Recruiting

Hospital Universitario Austral ( Site 0212)

Pilar, Buenos Aires, B1629AHJ, Argentina

No email / +542304387649

Status: Recruiting

Instituto Alexander Fleming ( Site 0202)

CABA, Buenos Aires, C1426ANZ, Argentina

No email / +541132218900

Status: Recruiting

Centro de Educación Médica e Investigaciones clínicas "Dr. Norberto Quirno" (CEMIC) ( Site 0208)

Caba., Buenos Aires F.D., C1431FWO, Argentina

No email / +541152990000

Status: Recruiting

Instituto de Oncología de Rosario ( Site 0209)

Rosario, Santa Fe Province, S2000KZE, Argentina

No email / +5493414218909

Status: Recruiting

Sanatorio Parque ( Site 0201)

Rosario, Santa Fe Province, S2000DSV, Argentina

No email / +5493416955611

Status: Recruiting

Macquarie University-MQ Health Clinical Trials Unit ( Site 2100)

Sydney, New South Wales, 2109, Australia

No email / +61 2 9812 3526

Status: Recruiting

Medizinische Universitat Wien ( Site 0601)

Vienna, 1090, Austria

No email / +43 1 40400 60430

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Ordensklinikum Linz GmbH Elisabethinen-Urologie ( Site 0600)

Linz, Upper Austria, 4020, Austria

No email / +43 732 7676 4641

Status: Recruiting

Cliniques Universitaires Saint-Luc ( Site 0703)

Brussels, Bruxelles-Capitale, Region de, 1200, Belgium

No email / +3227643546

Status: Recruiting

Ziekenhuis Oost-Limburg, Campus St.-Jan ( Site 0701)

Genk, Limburg, 3600, Belgium

No email / +32 89 80 40 40

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UZ Gent ( Site 0702)

Ghent, Oost-Vlaanderen, 9000, Belgium

No email / +32 (0)9 332 62 18

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UZ Leuven ( Site 0700)

Leuven, Vlaams-Brabant, 3000, Belgium

No email / +32 (0)16 34 69 12

Status: Recruiting

IPC - MT Instituto de Pesquisas Clínicas do Mato Grosso ( Site 0305)

Cuiabá, Mato Grosso, 78020-500, Brazil

No email / +5565999470522

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Liga Norte Riograndense Contra o Câncer ( Site 0307)

Natal, Rio Grande do Norte, 59062-000, Brazil

No email / +558440095595

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Hospital Moinhos de Vento ( Site 0309)

Porto Alegre, Rio Grande do Sul, 90560-032, Brazil

No email / +5551980609999

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Fundação Faculdade Regional de Medicina de São José do Rio Preto ( Site 0302)

São José do Rio Preto, São Paulo, 15090-000, Brazil

No email / +551732015000

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Hospital Alemao Oswaldo Cruz ( Site 0311)

São Paulo, São Paulo, 01327-001, Brazil

No email / +551135490391

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Klinički bolnički centar Sestre milosrdnice ( Site 0801)

Zagreb, City of Zagreb, 10000, Croatia

No email / +38513787421

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Klinički bolnički centar Zagreb ( Site 0800)

Zagreb, City of Zagreb, 10000, Croatia

No email / +38512388575

Status: Recruiting

Klinički Bolnički Centar Split ( Site 0802)

Split, Split-Dalmatia County, 21000, Croatia

No email / +385915297299

Status: Recruiting

Fakultni nemocnice Hradec Kralove ( Site 0902)

Hradec Králové, 500 05, Czechia

No email / +420 607 192 913

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Fakultni nemocnice Olomouc ( Site 0901)

Olomouc, 779 00, Czechia

No email / +420588444295

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Fakultni nemocnice v Motole ( Site 0900)

Prague, 150 06, Czechia

No email / +420224439427

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Nemocnice České Budějovice ( Site 0905)

České Budějovice, 370 01, Czechia

No email / +420387871111

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Vseobecna fakultni nemocnice v Praze ( Site 0906)

Prague, 128 08, Czechia

No email / +420 224 966 405

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Masarykuv onkologicky ustav ( Site 0903)

Brno, Brno-mesto, 656 53, Czechia

No email / +420543136831

Status: Recruiting

Fakultni nemocnice Ostrava ( Site 0904)

Ostrava, Ostrava Mesto, 708 52, Czechia

No email / +420597374322

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Herlev Hospital ( Site 1002)

Herlev, Capital Region, 2730, Denmark

No email / +45 38688798

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Aarhus University Hospital Skejby ( Site 1001)

Aarhus, Central Jutland, 8200, Denmark

No email / +45 91167192

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Odense Universitetshospital ( Site 1000)

Odense, Region Syddanmark, 9000, Denmark

No email / +45 65411516

Status: Recruiting

CHU de Bordeaux Hop St ANDRE ( Site 1115)

Bordeaux, Gironde, 33075, France

No email / +33556795679

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Hôpital Foch ( Site 1118)

Suresnes, Hauts-de-Seine, 92150, France

No email / +33146253671

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Centre de Cancérologie du Grand Montpellier ( Site 1112)

Montpellier, Herault, 34070, France

No email / +33467926155

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CHU GRENOBLE ALPES ( Site 1101)

La Tronche, Isere, 38700, France

No email / +33476765451

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Centre d'Oncologie de Gentilly ( Site 1117)

Nancy, Lorraine, 54100, France

No email / +33355685518

Status: Recruiting

Centre Hospitalier Universitaire d'Angers-Urology ( Site 1104)

Angers, Pays de la Loire Region, 49933, France

No email / +33665807200

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Centre Hospitalier de la Côte Basque ( Site 1113)

Bayonne, Pyrenees-Atlantiques, 64109, France

No email / +33559443535

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centre hospitalier lyon sud ( Site 1102)

Pierre-Bénite, Rhone, 69310, France

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CHU de Rouen ( Site 1108)

Rouen, Seine-Maritime, 76031, France

No email / +33232881315

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HENRI MONDOR HOSPITAL ( Site 1116)

Créteil, Val-de-Marne, 94010, France

No email / +33145178243

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CHD Vendee ( Site 1103)

La Roche-sur-Yon, Vendee, 85000, France

No email / +33251446173

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Charité Universitaetsmedizin Berlin - Campus Mitte ( Site 1203)

Berlin, 10117, Germany

No email / +49 30 45050

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Universitaetsklinikum Hamburg-Eppendorf ( Site 1214)

Hamburg, 20246, Germany

No email / +4915222823094

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Klinikum Stuttgart - Katharinenhospital ( Site 1201)

Stuttgart, Baden-Wurttemberg, 70174, Germany

No email / +49 7071 278 54564

Status: Recruiting

UniversitaetsklInikum Tuebingen ( Site 1207)

Tübingen, Baden-Wurttemberg, 72076, Germany

No email / 004970712987235

Status: Recruiting

Universitätsmedizin Göttingen - Georg-August-Universität ( Site 1211)

Göttingen, Lower Saxony, 37075, Germany

No email / +4955139 68145

Status: Recruiting

Helios Kliniken Schwerin GmbH ( Site 1206)

Schwerin, Mecklenburg-Vorpommern, 19055, Germany

No email / +493855202120

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Marienhospital Herne ( Site 1215)

Herne, North Rhine-Westphalia, 44625, Germany

No email / +492323 4990

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Universitaetsklinikum Muenster ( Site 1202)

Münster, North Rhine-Westphalia, 70174, Germany

No email / +492518344658

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Universitaetsklinikum Carl Gustav Carus Dresden ( Site 1213)

Dresden, Saxony, 01307, Germany

No email / +493514584425

Status: Recruiting

HELIOS Klinikum Erfurt ( Site 1208)

Erfurt, Thuringia, 99089, Germany

No email / +493617810

Status: Recruiting

Universitätsklinikum Jena ( Site 1204)

Jena, Thuringia, 07747, Germany

No email / +4936419329901

Status: Recruiting

Alexandra General Hospital of Athens ( Site 1300)

Athens, Attica, 115 28, Greece

No email / +302132162543

Status: Recruiting

Metropolitan Hospital ( Site 1302)

Athens, Attica, 185 47, Greece

No email / +302104809667

Status: Recruiting

University General Hospital ''Attikon'' - General Hospital of West Attica "H AGIA VARVARA" ( Site 1301)

Chaïdári, Attica, 124 62, Greece

No email / +302105832549

Status: Recruiting

Prince of Wales Hospital ( Site 2200)

Hong Kong, Hong Kong

No email / +85235051042

Status: Recruiting

Queen Mary Hospital ( Site 2201)

Hong Kong, Hong Kong

No email / +85222554361

Status: Recruiting

Cork University Hospital ( Site 1501)

Cork, T12 YK23, Ireland

No email / +353214234802

Status: Recruiting

Tallaght University Hospital ( Site 1500)

Dublin, D24 NR0A, Ireland

No email / +35314144000

Status: Recruiting

A.O.U.C. Policlinico di Bari ( Site 1602)

Bari, 70124, Italy

No email / +390805592909

Status: Recruiting

Azienda USL 8 di Arezzo ( Site 1605)

Arezzo, 52100, Italy

No email / +390575255446

Status: Recruiting

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola ( Site 1604)

Bologna, 40138, Italy

No email / +390512142575

Status: Recruiting

Ospedale San Martino ( Site 1606)

Genova, 16132, Italy

No email / 003901015553303

Status: Recruiting

Azienda Ospedaliera Di Rilievo Nazionale A. Cardarelli ( Site 1609)

Naples, Campania, 80131, Italy

No email / 00390817472223

Status: Recruiting

Istituto Nazionale Tumori Regina Elena ( Site 1611)

Rome, Lazio, 00144, Italy

No email / +39 0652666919

Status: Recruiting

Fondazione IRCCS Istituto Nazionale dei Tumori ( Site 1600)

Milan, Milano, 20133, Italy

No email / 00390223903028

Status: Recruiting

Istituto Clinico Humanitas ( Site 1613)

Rozzano, Milano, 20089, Italy

No email / 00390282244061

Status: Recruiting

Azienda Ospedaliera S. Luigi Gonzaga ( Site 1607)

Orbassano, Piedmont, 10043, Italy

No email / 00390119026534

Status: Recruiting

Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore ( Site 1601)

Rome, Roma, 00618, Italy

No email / 00390630155202

Status: Recruiting

Azienda Ospedaliera Universitaria Careggi ( Site 1608)

Florence, Tuscany, 50134, Italy

No email / +390557949648

Status: Recruiting

Casa di Cura Dott. Pederzoli - UO Oncologia ( Site 1610)

Peschiera del Garda, Veneto, 37019, Italy

No email / +390456444193

Status: Recruiting

Clinica Integral Internacional de Oncología ( Site 0506)

Puebla City, 72530, Mexico

No email / +522229525806

Status: Recruiting

Higiea Oncologia ( Site 0504)

Mexico City, 11810, Mexico

No email / +525652731712

Status: Recruiting

CIO - Centro de Inmuno-Oncología de Occidente ( Site 0503)

Guadalajara, Jalisco, 44630, Mexico

No email / 3331721132

Status: Recruiting

I CAN ONCOLOGY CENTER S.A. DE C.V. ( Site 0507)

Monterrey, Nuevo León, 64710, Mexico

No email / 8125558165 Ext. 1005

Status: Recruiting

Centro de Investigacion Clinica de Oaxaca ( Site 0502)

Oaxaca City, Oaxaca, 68020, Mexico

No email / +529516035559

Status: Recruiting

AIDPORT Sp. z o.o. ( Site 1716)

Skórzewo, Greater Poland Voivodeship, 60-185, Poland

No email / +48570783100

Status: Recruiting

Zakład Diagnostyki Laboratoryjnej, Centrum Onkologii ( Site 1707)

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-796, Poland

No email / +48523743883

Status: Recruiting

Pratia MCM Krakow ( Site 1713)

Krakow, Lesser Poland Voivodeship, 30-727, Poland

No email / +48122958160

Status: Recruiting

Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 1703)

Krakow, Lesser Poland Voivodeship, 31-826, Poland

No email / +48126468251

Status: Recruiting

MTZ Clinical Research Powered by Pratia ( Site 1705)

Warsaw, Masovian Voivodeship, 02-172, Poland

No email / +48225725959

Status: Recruiting

Mazowiecki Szpital Wojewódzki w Siedlcach-Siedleckie Centrum Onkologii ( Site 1702)

Siedlce, Masovian Voivodeship, 08-110, Poland

No email / +48256403300

Status: Recruiting

Wojewodzki Szpital im. Sw. Ojca Pio w Przemyslu ( Site 1710)

Przemyśl, Podkarpackie Voivodeship, 37-700, Poland

No email / +48166775511

Status: Recruiting

Szpital Wojewodzki im. Mikolaja Kopernika w Koszalinie ( Site 1701)

Koszalin, West Pomeranian Voivodeship, 75-581, Poland

No email / 943488930

Status: Recruiting

National Cancer Centre Singapore ( Site 2401)

Singapore, Central Singapore, 168583, Singapore

No email / +6564368000

Status: Recruiting

National University Hospital ( Site 2400)

Singapore, Central Singapore, 119074, Singapore

No email / 6908 2222

Status: Recruiting

Asan Medical Center ( Site 2501)

Seoul, 05505, South Korea

No email / +82230105977

Status: Recruiting

Samsung Medical Center ( Site 2502)

Seoul, 06351, South Korea

No email / +82234101767

Status: Recruiting

Severance Hospital, Yonsei University Health System ( Site 2503)

Seoul, 03722, South Korea

No email / +82222280430

Status: Recruiting

Chonnam National University Hwasun Hospital ( Site 2505)

Hwasun-gun, Jeonranamdo, 58128, South Korea

No email / +82613797623

Status: Recruiting

Seoul National University Bundang Hospital ( Site 2504)

Seongnam, Kyonggi-do, 13620, South Korea

No email / +82317877039

Status: Recruiting

Chungnam National University Hospital ( Site 2506)

Taejŏn, Taejon-Kwangyokshi, 35015, South Korea

No email / +82422808369

Status: Recruiting

Hospital Clinic de Barcelona ( Site 1810)

Barcelona, 08036, Spain

No email / +34932275402

Status: Recruiting

Hospital Clinico San Carlos ( Site 1802)

Madrid, 28040, Spain

No email / +34 91 330 35 46

Status: Recruiting

Hospital Universitari Vall d'Hebron ( Site 1804)

Barcelona, 08035, Spain

No email / +34934894350

Status: Recruiting

Hospital Universitario 12 de Octubre ( Site 1800)

Madrid, 28041, Spain

No email / +34 91 390 83 39

Status: Recruiting

Hospital Universitario Fundacion Jimenez Diaz ( Site 1803)

Madrid, 28040, Spain

No email / +34915504800-2869

Status: Recruiting

Hospital Universitario Reina Sofia ( Site 1809)

Córdoba, 14004, Spain

No email / +34957011464

Status: Recruiting

Institut Català d'Oncologia - L'Hospitalet ( Site 1805)

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

No email / +34932607744

Status: Recruiting

Hospital Universitario Marqués de Valdecilla ( Site 1807)

Santander, Cantabria, 39008, Spain

No email / +34 942 20 25 25

Status: Recruiting

Institut Català d'Oncologia (ICO) - Girona ( Site 1806)

Girona, Gerona, 17007, Spain

No email / +34972225832

Status: Recruiting

Hospital Universitario Ramón y Cajal ( Site 1801)

Madrid, Madrid, Comunidad de, 28034, Spain

No email / +34 913368263

Status: Recruiting

Fundación Instituto Valenciano de Oncología ( Site 1808)

Valencia, Valenciana, Comunitat, 46009, Spain

No email / +34 961114605

Status: Recruiting

Chang Gung Memorial Hospital - Linkou Branch ( Site 2604)

Taoyuan, 333, Taiwan

No email / +88633281200

Status: Recruiting

China Medical University Hospital ( Site 2603)

Taichung, 40447, Taiwan

No email / +886422052121

Status: Recruiting

Taichung Veterans General Hospital ( Site 2602)

Taichung, 40705, Taiwan

No email / +886423592525x5121

Status: Recruiting

Taipei Veterans General Hospital ( Site 2600)

Taipei, 11217, Taiwan

No email / +886218712121x86334

Status: Recruiting

Alaska Oncology and Hematology ( Site 0133)

Anchorage, Alaska, 99508, United States

No email / 907-257-9851

Status: Recruiting

Providence Medical Foundation ( Site 0141)

Fullerton, California, 92835, United States

No email / 714-446-5900

Status: Recruiting

New England Cancer Specialists ( Site 0132)

Westbrook, Maine, 04092, United States

No email / 207-303-3300

Status: Recruiting

Greater Baltimore Medical Center ( Site 0145)

Baltimore, Maryland, 21204, United States

No email / 443-849-8136

Status: Recruiting

Metro-Minnesota Community Clinical Oncology ( Site 0144)

Saint Louis Park, Minnesota, 55426, United States

No email / 952-993-1555

Status: Recruiting

Oncology Hematology West P.C. dba Nebraska Cancer Specialists ( Site 0131)

Omaha, Nebraska, 68130-2042, United States

No email / 402-691-6971

Status: Recruiting

Carolina Oncology Specialists, PA ( Site 9002)

Charlotte, North Carolina, 28207, United States

No email / 704-342-1900

Status: Recruiting

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