Pembrolizumab Plus Belzutifan With or Without Lenvatinib in Localized Renal Cell Carcinoma

NCT07593040 | Not Yet Recruiting Phase 2

• 2 other identifiers: VHIO240022024-519673-18-00
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 14

Brief Summary

This study is designed to evaluate the efficacy of belzutifan in combination with pembrolizumab with or without lenvatinib in the neoadjuvant setting, followed by adjuvant pembrolizumab versus adjuvant pembrolizumab alone, as treatment for participants with intermediate-high and high risk clear cell renal cell carcinoma (ccRCC).

Conditions

Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Response Rate

  Radiographic response defined as a decrease of initial tumour size ≥30% from baseline to week 12 CT scan

  At 12 weeks from start of treatment

Study Arms (3)

Cohort A

EXPERIMENTAL

Neoadjuvant therapy with Pembrolizumab (400mg q6w) + Lenvatinib (20mg daily for 12w) + Belzutifan (120mg daily for 12w). Followed by nephrectomy and pembrolizumab (400mg q6w for 9 months)

Drug: Neoadjuvant Pembrolizumab; Drug: Belzutifan; Drug: Lenvatinb

Cohort B

EXPERIMENTAL

Neoadjuvant therapy with Pembrolizumab (400mg q6w) + Belzutifan (120mg daily for 12w). Followed by nephrectomy and pembrolizumab (400mg q6w for 9 months)

Drug: Neoadjuvant Pembrolizumab; Drug: Belzutifan

Cohort C

ACTIVE COMPARATOR

Nephrectomy folloewd by pembrolizumab (400mg q6w for 12 months)

Drug: Neoadjuvant Pembrolizumab

Interventions

Neoadjuvant Pembrolizumab DRUG

400mg q6w of Pembrolizumab will be administered before nephrectomy in cohorts A and B

Cohort A; Cohort B; Cohort C

Belzutifan DRUG

120mg daily for 12w of Belzutifan will be administered before nephrectomy in Cohorts A and B

Cohort A; Cohort B

Lenvatinb DRUG

20mg daily for 12 weeks of lenvatinib will be administered before nephrectomy in Cohort A

Cohort A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male/female participants who are at least 18 years of age on the day of signing informed consent.
• \. Willing to provide written informed consent. They may also provide consent for Future Biomedical Research; however, the participant may participate in the main trial without participating in the Future Biomedical Research.
• \. Histologically confirmed diagnosis of RCC with a clear cell component with or without sarcomatoid features. Diagnosis is to be made by the investigator and does not require central histology review.
• \. Tumours must be T2 with grade 4, T3, T4, or any T with N1, M0 on radiographic imaging using TNM staging (8th edition)
• T2 is defined as a tumour \>7cm but limited to the kidney; grade 4 is per the International Society of Urological Pathology (ISUP) grading.
• T3 is defined as tumour extension into major veins or perinephric tissues, but not into ipsilateral adrenal gland or beyond Gerota's fascia.
• T4 is defined as a tumour involving the ipsilateral adrenal gland or invading beyond Gerota's fascia.
• N1 is defined as metastatic involvement of regional lymph nodes. 5. Archival tumour tissue sample or newly obtained core, incisional, or excisional biopsy of a tumour lesion not previously irradiated has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
• \. Have an Eastern Cooperation Oncology Group (ECOG) Performance Status of 0 to 1.
• Evaluation of ECOG is to be performed within 14 days prior to the first dose of study intervention.
• \. Have been considered suitable for curative intent surgery (partial or total nephrectomy), as evaluated by a surgeon. 8. Have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg.
• \. Have adequate organ function as defined in the following table (Table 7). Specimens must be collected within 14 days prior to the start of study intervention.
• Participants agree to the contraception guidelines outlined in section 5.1.3.2.
• Participants who are HBsAg positive are eligible if they have received hepatitis B virus (HBV) anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
• Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.

You may not qualify if:

• \. Has evidence of metastatic disease on screening imaging. 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
• \. Has received prior systemic anti-cancer therapy including investigational agents within 3 years prior to randomization.
• \. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
• Participants with low-risk early-stage prostate cancer either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.
• \. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. COVID-19 and influenza vaccinations are allowed provided they are not live vaccines 6. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• \. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug 8. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, and/or lenvatinib, and/or belzutifan.
• \. Has active autoimmune disease that has required immunosuppressive systemic treatment in the past 2 years except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid).
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease11.Has any of the following:
• A pulse oximeter reading \<92% at rest, or
• Requires intermittent supplemental oxygen, or
• Requires chronic supplemental oxygen. 12.Has an active infection requiring systemic intravenous therapy. 13.Has moderate to severe hepatic impairment (Child-Pugh B or C). 14.Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.
• Note: Hepatitis B and C screening tests are not required unless:
• Known history of HBV and HCV infection
• As mandated by local health authority
• Has urine protein ≥1 g/24 hours.

Sponsors & Collaborators

• Vall d'Hebron Institute of Oncology: lead

Study Sites (14)

Hospital Universitario Reina Sofia

Córdoba, Andalusia, 14004, Spain

Location

Hospital Clinico Universitario Lozano Blesa

Zaragoza, Aragon, 50009, Spain

Location

Hospital Universitario Marques De Valdecilla

Santander, Cantabria, 39008, Spain

Location

Hospital Universitari Vall D Hebron

Barcelona, Catalonia, 08035, Spain

Location

Hospital Clinic De Barcelona

Barcelona, Catalonia, 08036, Spain

Location

Institut Catala D'oncologia

L'Hospitalet de Llobregat, Catalonia, 08908, Spain

Location

Parc Tauli Hospital Universitari

Sabadell, Catalonia, 08208, Spain

Location

Hospital Universitario Lucus Augusti

Lugo, Galicia, 27003, Spain

Location

Complejo Hospitalario Universitario De Ourense

Ourense, Galicia, 32005, Spain

Location

Hospital Universitario Ramon Y Cajal

Madrid, Madrid, 28034, Spain

Location

Hospital Universitario 12 De Octubre

Madrid, Madrid, 28041, Spain

Location

Hospital Universitario De Navarra

Pamplona, Navarre, 31008, Spain

Location

Hospital Universitario Central De Asturias

Oviedo, Principality of Asturias, 33011, Spain

Location

Hospital Universitario Y Politecnico La Fe

Valencia, Valencia, 46026, Spain

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

belzutifan

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Cristina Suárez, Dr

  Hospital Vall d'Hebron

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cristina Suárez, Dr

CONTACT

+34 932543450; csuarez@vhio.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study is a randomized, multi-arm, open label design to evaluate the efficacy of belzutifan in combination with pembrolizumab with or without lenvatinib in the neoadjuvant setting, followed by adjuvant pembrolizumab versus adjuvant pembrolizumab alone, as treatment for participants with intermediate-high and high risk clear cell renal cell carcinoma (ccRCC), defined as T2 with grade 4, T3, T4, or TxN1, M0 disease

Study Record Dates

• First Submitted: May 11, 2026
• First Posted: May 18, 2026
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): June 1, 2031
• Last Updated: May 20, 2026

Record last verified: 2025-11

Locations

ES (14)