A clinical study of combination therapies in people with kidney cancer (MK-3475-03C)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Aug 2025 → ongoing

Decision date (initial)

2025-08-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme LLC · Exelixis

External identifiers

EU CT number

2024-516437-12-00

WHO UTN

U1111-1310-6076

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Pharmacodynamic, Therapy, Pharmacokinetic, Pharmacogenetic, Safety, Efficacy

1. Safety Lead-in Phase: To assess the safety and tolerability, and to establish a recommended Phase 2 dose (RP2D) if applicable, of treatment combinations that have not been evaluated in a separate study
2. Efficacy Phase: To assess the safety and tolerability based on the proportion of participants with adverse events (AEs).
3. Efficacy Phase: To evaluate objective response (OR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)

Secondary objectives 4

1. Efficacy Phase: To evaluate durability of response (DOR) per RECIST 1.1
2. Efficacy Phase: To evaluate progression-free survival (PFS) per RECIST 1.1
3. Efficacy Phase: To evaluate overall survival (OS)
4. Efficacy Phase: To evaluate clinical benefit rate (CBR) per RECIST 1.1

Conditions and MedDRA coding

Clear cell renal cell carcinoma

Regulatory references

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Has a histologically confirmed diagnosis of unresectable locally advanced/metastatic renal cell carcinoma (RCC) with clear cell component (with or without sarcomatoid features),
2. Has received no other prior systemic therapy for treatment of advanced/metastatic clear cell RCC (ccRCC) except for adjuvant anti- programmed cell death 1/programmed cell death ligand 1 (PD-(L)1) therapy.
3. Has disease recurrence during adjuvant anti- PD-(L)1 therapy or ≤24 months following the last dose of adjuvant anti-PD-(L)1 therapy.
4. Has measurable disease per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as assessed by investigator and verified by blinded independent central review (BICR).
5. Is able to swallow oral medication.
6. Submits an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
7. Participants receiving bone resorptive therapy(must have therapy initiated at least 2 weeks before allocation/randomization.
8. Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤140/90 mm Hg with no change in antihypertensive medications within 1 week before allocation/randomization.
9. Has adequate organ function
10. Is an individual of any sex/gender, from 18 years to 120 years of age inclusive,
11. A participant assigned male sex at birth, capable of producing sperm, continues contraception at least 7 days after the last dose of Belzutifan, and at least 96 days after the last dose of Zanzalintinib. Refrains from donating sperm and abstains from penile-vaginal intercourse and remains abstinent, or uses external condom or contraceptives consistent with local regulations.
12. A participant assigned female sex at birth is not breast feeding at least 96 days after the last dose of study intervention. A participant of childbearing potential (POCBP) is not pregnant and has a negative highly sensitive pregnancy test before the first dose of study intervention. A POCBP uses a highly effective contraceptive method, and continues using contraception at least 30 days after the last dose of Belzutifan, and at least 186 days after the last dose of Zanzalintinib.

Exclusion criteria 25

1. Has clinically significant hematuria, hematemesis, or hemoptysis of (>2.5 mL) of red blood, or other history of significant bleeding.
2. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention,
3. Has deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization.
4. Has deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization.
5. Has history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis.
6. Has a left ventricular ejection fraction (LVEF) ≤50% or below the institutional (or local laboratory) normal range.
7. Has serious wound, ulcer or bone fracture or has had major surgery within 8 weeks before first dose of study intervention.
8. Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage in the last 4 weeks before allocation/randomization.
9. Has gastrointestinal (GI) disorders, including those associated with a high risk of perforation or fistula formation.
10. Has malabsorption due to prior GI surgery or GI disease.
11. Has moderate to severe hepatic impairment (Child-Pugh B or C).
12. Has received colony-stimulating factors within 28 days prior to intervention allocation/randomization.
13. Has received prior treatment with Hypoxia-Inducible Factor-2α (HIF-2α) and/or Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitor (VEGF/TKI) inhibitors.
14. Ha recibido radioterapia previa dentro de las 2 semanas del comienzo de la intervención del estudio o tiene toxicidades relacionadas con la radiación que requieren corticoesteroides.
15. Is currently receiving strong inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study.
16. Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention.
17. Is currently receiving anticoagulants or platelet inhibitors that cannot be discontinued for the duration of the study,
18. Have been previously allocated/randomized to study intervention in any substudy of protocol MK-3475-U03.
19. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
20. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
21. Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation.
22. Has active autoimmune disease that has required systemic treatment in the past 2 years.
23. Has an active infection requiring systemic therapy.
24. Has history of human immunodeficiency virus (HIV) infection.
25. Has hepatitis B or hepatitis C virus infection.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Safety Lead In Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)
2. Safety Lead In Phase: Number of participants who experience one or more adverse events (AEs)
3. Safety Lead In Phase: Number of participants who discontinue study treatment due to an AE
4. Efficacy Phase: Number of participants who experience one or more DLTs
5. Efficacy Phase: Number of participants who experience one or more AEs
6. Efficacy Phase: Number of participants who discontinue study treatment due to an AE
7. Efficacy Phase: Objective Response (OR)

Secondary endpoints 4

1. Efficacy Phase: Duration of response (DOR)
2. Efficacy Phase: Progression-free survival (PFS)
3. Efficacy Phase: Overall survival (OS)
4. Efficacy Phase: Clinical benefit rate (CBR)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue, P. O. Box 2000 P. O. Box 2000

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Manish Sharma

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Manish Sharma

Third parties 4

Locations

3 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications