A Phase 3, Randomized, Double-blind, Study of Belzutifan + Zanzalintinib Versus Belzutifan + Placebo in Participants With Advanced RCC Who Have Progressed on or After Both PD-1/L1 and VEGF-TKI Therapies in Sequence or in Combination (LITESPARK-034)

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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: April 9, 2026

Planned enrollment: 758

Trial ID: NCT07489495
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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 adding zanzalintinib to belzutifan improves progression-free survival and overall survival compared with belzutifan alone in advanced renal cell carcinoma previously treated with both PD-1/PD-L1 and VEGF-targeted tyrosine kinase inhibitor therapy.

Patients: Participants have unresectable stage IV renal cell carcinoma with a clear-cell component, with or without sarcomatoid features, measurable disease by RECIST 1.1, and progression on or after both PD-1/PD-L1 and VEGF-TKI therapy given sequentially or in combination. No more than three prior systemic regimens are permitted, including only one prior anti-PD-1/PD-L1 therapy. Important exclusions include resting oxygen saturation below 92% or supplemental oxygen use, current pneumonitis/interstitial lung disease, clinically significant cardiovascular disease, left ventricular ejection fraction of 50% or lower, recent major surgery or deep-vein thrombosis, active hepatitis B or C, HIV infection, solid-organ transplantation, and another recently active malignancy.

Design: Phase 3, randomized, double-blind, placebo-controlled treatment study. Participants are assigned to belzutifan plus zanzalintinib or belzutifan plus a matching placebo. Tumor progression and responses are assessed by blinded independent central review using RECIST 1.1.

Treatments: The experimental arm receives oral belzutifan 120 mg plus oral zanzalintinib 60 mg once daily for approximately 24 months. The comparator arm receives oral belzutifan 120 mg plus zanzalintinib-matching placebo once daily for approximately 24 months. Belzutifan is an oral HIF-2α inhibitor and an established targeted treatment option in advanced clear-cell RCC. Zanzalintinib, also called XL092, is an investigational oral multikinase inhibitor targeting VEGFR2, MET, and the TAM kinases TYRO3, AXL, and MER, pathways involved in angiogenesis, tumor growth, and tumor-associated immunosuppression. In an early-phase cohort of 32 heavily pretreated clear-cell RCC patients, 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.

Outcomes: The co-primary outcomes are progression-free survival by blinded independent central review, assessed for up to approximately 30 months, and overall survival, assessed for up to approximately 50 months. Secondary outcomes include confirmed objective response rate, duration of response, adverse events, and treatment discontinuations due to adverse events. Patient-reported outcomes include changes and time to deterioration in global health and quality of life, physical functioning, and role functioning using the EORTC QLQ-C30, as well as kidney cancer symptoms using the FKSI-DRS.

Burden on patient: Estimated burden is moderate. Both regimens are once-daily oral therapies, avoiding routine infusion visits, but treatment may continue for approximately two years and requires regular clinic assessments, laboratory monitoring, safety evaluations, and serial imaging for RECIST-based disease assessment. Participants must also complete repeated quality-of-life and symptom questionnaires. No mandatory research biopsy or intensive pharmacokinetic blood-draw schedule is described, so the procedural burden appears broadly comparable to that of a closely monitored oral systemic therapy trial, although travel and follow-up may continue for survival assessment for about four years.

Last updated: Sep 2026

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COE (Centro Oncológico de Excelencia) ( Site 0259)

San Juan, J5402BGA, Argentina

No email / +54 2644229585

Status: Recruiting

Centro Oncológico Riojano Integral ( Site 0256)

La Rioja, X5004BAL, Argentina

No email / +543804436443X108

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Instituto Alexander Fleming ( Site 0252)

CABA, C1426ANZ, Argentina

No email / +541132218900

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Centro Oncologico Korben ( Site 0254)

CABA, Buenos Aires, C1426AHB, Argentina

No email / +541159507952

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Hospital Italiano de Buenos Aires ( Site 0253)

Ciudad de Buenos Aires, Buenos Aires, 1181, Argentina

No email / +541149590200

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Instituto de Investigaciones Clinicas Mar del Plata ( Site 0250)

Mar del Plata, Buenos Aires, B7600FZO, Argentina

No email / +542234963224

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Centro Privado de RMI Río Cuarto S.A. II ( Site 0255)

Río Cuarto, Córdoba Province, X5800ALB, Argentina

No email / +543584620273

Status: Recruiting

Instituto de Oncología de Rosario ( Site 0257)

Rosario, Santa Fe Province, S2000KZE, Argentina

No email / +543414484830

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Sanatorio Parque ( Site 0251)

Rosario, Santa Fe Province, S2000DSV, Argentina

No email / +5493416955611

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CEDOES ( Site 0303)

Vitória, Espírito Santo, 29055-450, Brazil

No email / +552721250202

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Instituto do Câncer e Transplante de Curitiba ( Site 0300)

Curitiba, Paraná, 80510-130, Brazil

No email / +55 41 99205-7755

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Liga Norte Riograndense Contra o Câncer ( Site 0307)

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

No email / +55 84 4009-5595

Status: Recruiting

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 / +55 17 3201-5054

Status: Recruiting

Hope - Humanizacao Em Oncologia, Pesquisa E Ensino ( Site 0306)

Ribeirão Preto, São Paulo, 14026-610, Brazil

No email / +55 16 3913-8181

Status: Recruiting

The Ottawa Hospital Cancer Centre ( Site 0003)

Ottawa, Ontario, K1H 8L6, Canada

No email / 613-737-7700

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IC La Serena Research ( Site 0405)

La Serena, Coquimbo Region, 1720430, Chile

No email / 56958646664

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Clínica Puerto Montt ( Site 0404)

Port Montt, Los Lagos Region, 5500243, Chile

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Bradfordhill ( Site 0400)

Santiago, Region M. de Santiago, 8420383, Chile

No email / 56229490970

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Fundacion Arturo Lopez Perez ( Site 0401)

Santiago, Region M. de Santiago, 7500921, Chile

No email / 56224205098

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ONCOCENTRO APYS ( Site 0403)

Viña del Mar, Valparaiso, 2520598, Chile

No email / 56323320850

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Fakulti poliklinika ( Site 0906)

Prague, 128 08, Czechia

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Fakultni nemocnice Hradec Kralove ( Site 0902)

Hradec Králové, 500 05, Czechia

No email / +420727854666

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Fakultni nemocnice Olomouc ( Site 0901)

Olomouc, 779 00, Czechia

No email / +420588445923

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Fakultni nemocnice v Motole ( Site 0900)

Prague, 150 06, Czechia

No email / +420734236410

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Masarykuv onkologicky ustav ( Site 0903)

Brno, Brno-mesto, 656 53, Czechia

No email / +420543132216

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Fakultni nemocnice Ostrava ( Site 0904)

Ostrava, Ostrava Mesto, 708 52, Czechia

No email / +420597374322

Status: Recruiting

Herlev Hospital ( Site 1002)

Herlev, Capital Region, 2730, Denmark

No email / 00 45 38689191

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Aarhus Universitetshospital, Skejby ( Site 1001)

Aarhus, Central Jutland, 8200, Denmark

No email / +4591167472

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Centre Antoine Lacassagne ( Site 1209)

Nice, Alpes-Maritimes, 06189, France

No email / +33492031538

Status: Recruiting

Hopital Europeen Marseille ( Site 1216)

Marseille, Bouches-du-Rhone, 13003, France

No email / +33413427427

Status: Recruiting

LBM ONCOPOLE CLAUDIUS REGAUD ( Site 1215)

Toulouse, Haute-Garonne, 31059, France

No email / +33531155050

Status: Recruiting

CHU Angers ( Site 1204)

Angers, Maine-et-Loire, 49933, France

No email / +33241354694

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CHU de Saint-Etienne ( Site 1202)

Saint Priest En Jarez, Pays de la Loire Region, 42271, France

No email / +33477917082

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Clinique Victor Hugo Le Mans-Oncology-Radiotherapy ( Site 1203)

Le Mans, Pays de la Loire Region, 72000, France

No email / +33 243297908

Status: Recruiting

Charité Universitaetsmedizin Berlin - Campus Mitte ( Site 1312)

Berlin, 10117, Germany

No email / +4930450515288

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Universitaetsklinikum Augsburg ( Site 1316)

Augsburg, Bavaria, 86156, Germany

No email / +498214002348

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klinikum rechts der isar der technischen universität münchen ( Site 1315)

Munich, Bavaria, 81675, Germany

No email / 00498941402522

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Universitätsklinikum Jena ( Site 1313)

Jena, Thuringia, 07747, Germany

No email / +4936419329970

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ATTIKON GENERAL UNIVERSITY HOSPITAL ( Site 1401)

Athens, Attica, 124 62, Greece

No email / +302105832549

Status: Recruiting

Alexandra General Hospital of Athens ( Site 1400)

Athens, Attica, 115 28, Greece

No email / +302132162543

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Metropolitan Hospital ( Site 1402)

Athens, Attica, 185 47, Greece

No email / +302104809667

Status: Recruiting

Meir Medical Center. ( Site 1603)

Kfar Saba, 4428164, Israel

No email / +97297472555

Status: Recruiting

Rabin Medical Center ( Site 1602)

Petah Tikva, 4941492, Israel

No email / 97239378074

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Rambam Health Care Campus ( Site 1600)

Haifa, 3109601, Israel

No email / +97247772688

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Sheba Medical Center ( Site 1601)

Ramat Gan, 5265601, Israel

No email / 97235303030

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A.O.U.C. Policlinico di Bari ( Site 1802)

Bari, 70124, Italy

No email / 00390805593767

Status: Recruiting

AO Santa Maria della Misericordia ( Site 1805)

Perugia, 06132, Italy

No email / +39 0755784188

Status: Recruiting

Fondazione IRCCS Istituto Nazionale dei Tumori ( Site 1800)

Milan, 20133, Italy

No email / 02 2390 3028

Status: Recruiting

Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore ( Site 1801)

Roma, 00168, Italy

No email / 00390630155202

Status: Recruiting

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola ( Site 1803)

Bologna, 40138, Italy

No email / +390512142204

Status: Recruiting

Istituto Nazionale Tumori Regina Elena ( Site 1804)

Roma, 00144, Italy

No email / +39 0652666919

Status: Recruiting

IRCCS - Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori" ( Site 1809)

Meldola, Emilia-Romagna, 47014, Italy

No email / +390543739100

Status: Recruiting

Istituto Clinico Humanitas ( Site 1808)

Rozzano, Milano, 20089, Italy

No email / 0282244061

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Istituto Oncologico Veneto IRCCS ( Site 1806)

Catselfranco Veneto, Padova, 31033, Italy

No email / +39 0423732336

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Azienda Ospedaliera Universitaria Careggi ( Site 1807)

Florence, Tuscany, 50134, Italy

No email / +390557949648

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Maastricht UMC+ ( Site 1901)

Maastricht, Limburg, 6229 HX, Netherlands

No email / +31433877025

Status: Recruiting

Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI AVL) ( Site 1900)

Amsterdam, North Holland, 1066 CX, Netherlands

No email / +3120 512 9111

Status: Recruiting

Haga Ziekenhuis locatie Leyweg ( Site 1906)

The Hague, South Holland, 2545 AA, Netherlands

No email / +3170 210 2143

Status: Recruiting

AIDPORT Sp. z o.o. ( Site 2118)

Skórzewo, Greater Poland Voivodeship, 60-185, Poland

No email / +48570783100

Status: Recruiting

Pratia MCM Krakow ( Site 2115)

Krakow, Lesser Poland Voivodeship, 30-727, Poland

No email / +48122958160

Status: Recruiting

MTZ Clinical Research Powered by Pratia ( Site 2107)

Warsaw, Masovian Voivodeship, 02-172, Poland

No email / +48225725959

Status: Recruiting

Mazowiecki Szpital Wojewódzki w Siedlcach-Siedleckie Centrum Onkologii ( Site 2102)

Siedlce, Masovian Voivodeship, 08-110, Poland

No email / +48256403300

Status: Recruiting

Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Klinika Nowotworów Układu Moczowego ( Site 2100)

Warsaw, Masovian Voivodeship, 02-781, Poland

No email / +48225462331

Status: Recruiting

Narodowy Instytut Onkologii - Oddzial w Gliwicach ( Site 2106)

Gliwice, Silesian Voivodeship, 44-102, Poland

No email / +48322788237

Status: Recruiting

Asan Medical Center ( Site 2901)

Seoul, 05505, South Korea

No email / +82-2-3010-5977

Status: Recruiting

Samsung Medical Center ( Site 2902)

Seoul, 06351, South Korea

No email / +82-2-3410-1767

Status: Recruiting

Severance Hospital, Yonsei University Health System ( Site 2903)

Seoul, 03722, South Korea

No email / +82-2-2228-8138

Status: Recruiting

Fundación Instituto Valenciano de Oncología ( Site 2307)

Valencia, 46009, Spain

No email / +34961114229

Status: Recruiting

Hospital Insular de Gran Canaria ( Site 2308)

Las Palmas, 35016, Spain

No email / +34928441738

Status: Recruiting

Hospital Universitari Vall d'Hebron ( Site 2303)

Barcelona, 08035, Spain

No email / +34934894350

Status: Recruiting

Hospital Universitario 12 de Octubre ( Site 2300)

Madrid, 28041, Spain

No email / +34913908339

Status: Recruiting

Hospital Universitario Virgen del Rocio ( Site 2306)

Seville, Andalusia, 41013, Spain

No email / +34955013068

Status: Recruiting

Institut Català d'Oncologia - L'Hospitalet ( Site 2305)

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

No email / +34932607744

Status: Recruiting

HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 2301)

Madrid, Madrid, Comunidad de, 28007, Spain

No email / +34914269393

Status: Recruiting

Adana Medical Park Seyhan Hastanesi ( Site 2505)

Adana, 01140, Turkey (Türkiye)

No email / +905372688986

Status: Recruiting

Ankara University Health Practice and Research Hospitals ( Site 2506)

Ankara, 06620, Turkey (Türkiye)

No email / +90 312 595 71 12

Status: Recruiting

Koc Universitesi Hastanesi ( Site 2501)

Istanbul, 34010, Turkey (Türkiye)

No email / 0090 850 250 8 250

Status: Recruiting

Trakya University Medical Faculty Hospital ( Site 2502)

Edirne, 22030, Turkey (Türkiye)

No email / +9005378528123

Status: Recruiting

Hacettepe Universite Hastaneleri ( Site 2500)

Sıhhiye, Ankara, 06230, Turkey (Türkiye)

No email / +905439340493

Status: Recruiting

University Hospitals Birmingham NHS Foundation Trust ( Site 2610)

Birmingham, B15 2GW, United Kingdom

No email / +4407789651543

Status: Recruiting

Western General Hospital ( Site 2608)

Edinburgh, Edinburgh, City of, EH4 2XU, United Kingdom

No email / +441315371398

Status: Recruiting

Leicester Royal Infirmary ( Site 2604)

Leicester, Leicestershire, LE1 5WW, United Kingdom

No email / 0300 303 1573

Status: Recruiting

The Christie Hospital NHS Foundation Trust ( Site 2601)

Withington, Manchester, M20 4BX, United Kingdom

No email / 0161 918 2546

Status: Recruiting

Northwest Georgia Oncology Centers, a Service of Wellstar Cobb Hospital ( Site 0102)

Marietta, Georgia, 30060, United States

No email / 770-281-5124

Status: Recruiting

Washington University School of Medicine ( Site 0114)

St Louis, Missouri, 63110, United States

No email / 314-362-7355

Status: Recruiting

Memorial Sloan Kettering Cancer Center ( Site 0126)

New York, New York, 10065, United States

No email / 347-798-9213

Status: Recruiting

The West Clinic, P.C. ( Site 0115)

Germantown, Tennessee, 38138, United States

No email / 901-683-0055

Status: Recruiting

Macquarie University ( Site 2700)

Macquarie University, New South Wales, 2109, Australia

No email / No phone

Status: SUSPENDED

Princess Alexandra Hospital ( Site 2703)

Woolloongabba, Queensland, 4102, Australia

No email / No phone

Status: SUSPENDED

Peter MacCallum Cancer Centre ( Site 2702)

Melbourne, Victoria, 3000, Australia

No email / No phone

Status: SUSPENDED

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