LENVATINIB for Localized renal cell carcinoma | Renal clear cell carcinoma

Inclusion criteria

• {"criterion_text":"- Male/female participants who are at least 18 years of age on the day of signing informed consent.\n- Male participants are eligible only if they agree to comply with the contraception/abstinence requirements specified in the protocol during the intervention period and for at least 7 days after the last dose of lenvatinib and belzutifan, i.e., they must either remain abstinent from heterosexual intercourse (if this is their preferred and usual long-term lifestyle) or, unless confirmed to be azoospermic (e.g., vasectomized/medical cause), use effective contraception; when having penile-vaginal intercourse with a woman of childbearing potential who is not pregnant, they must use a male condom and ensure the partner uses an additional contraceptive method, and if the partner is pregnant or breastfeeding they must remain abstinent or use a condom; contraception must comply with local regulations and, where local product information is more stringent, the stricter requirements apply; after stopping lenvatinib and belzutifan, if the participant continues on pembrolizumab only, no male contraception measures are required beyond the 7-day period.\n- A female participant is eligible only if she is not pregnant or breastfeeding and agrees to comply with the contraception and pregnancy-testing requirements specified in the protocol, i.e., she must either not be a woman of childbearing potential (WOCBP) or, if she is a WOCBP, use a highly effective, low user-dependent contraceptive method (failure rate <1% per year) or remain abstinent from heterosexual intercourse as her usual long-term lifestyle during the intervention period and for at least 120 days after the last dose of pembrolizumab or 30 days after the last dose of lenvatinib and belzutifan (whichever occurs first); the investigator should assess the potential for contraceptive method failure in relation to the first dose and contraception must comply with local regulations. WOCBP must have a negative highly sensitive pregnancy test (urine or serum per local requirements) within 24 hours prior to the first dose; if a urine result is ambiguous, a serum test is required and the participant is excluded if the serum test is positive. The investigator must review medical/menstrual history and recent sexual activity to minimize the risk of enrolling a woman with an early undetected pregnancy, and pregnancy testing during and after treatment should follow the protocol schedule.\n- The participant (or legally acceptable representative if applicable) provides written informed consent for the study.\n- 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.\n- Have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤ 150/90 mmHg.\n- Has adequate organ function as defined in Table 5 of the protocol. All screening laboratory tests must be performed within 14 days prior to the first dose of study intervention.\n- Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have an undetectable HBV viral load prior to randomization; they should remain on antiviral therapy throughout study intervention and follow local guidelines after completion. HBV screening is only required for participants with a known history of HBV infection or if mandated by the local health authority.\n- Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening and they have completed curative antiviral therapy at least 4 weeks prior to randomization; HCV screening is only required for participants with a known history of HCV infection or if mandated by the local health authority.\n- HIV-infected participants are eligible only if they have well-controlled HIV on antiretroviral therapy (ART): participants must have a CD4+ T-cell count ≥350 cells/mm³ at screening, must have confirmed virologic suppression (HIV RNA <50 copies/mL or below the assay LLOQ) at screening and maintained for at least 12 weeks prior to screening, and must have been on a stable ART regimen without drug or dose changes for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study; it is advised that participants should have had no AIDS-defining opportunistic infections within the past 12 months.\n- 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.\n- Tumours must be T2 with grade 4, T3, T4, or any T with N1, M0 on radiographic imaging using TNM staging (8th edition)\n- Has measurable disease per RECIST 1.1.\n- 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.\n- Have been considered suitable for curative intent surgery (partial or total nephrectomy), as evaluated by a surgeon.\n- Has recovered from all AEs due to previous therapies to ≤Grade 1 or baseline, with the exception of ≤Grade 2 neuropathy or endocrine-related AEs ≤Grade 2 requiring treatment or hormone replacement.\n- Have an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1. Evaluation of ECOG is to be performed within 14 days prior to the first dose of study intervention.\n- KPS score of at least 70% within 10 days before allocation/randomization."}

Exclusion criteria

• {"criterion_text":"- Has evidence of metastatic disease on screening imaging.\n- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.\n- Has any of the following: a resting pulse oximeter reading <92%, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen.\n- Has an active infection requiring systemic intravenous therapy.\n- Has moderate to severe hepatic impairment (Child-Pugh B or C).\n- Concurrent active hepatitis B (HBsAg positive and/or detectable HBV DNA) and active hepatitis C (anti-HCV antibody positive with detectable HCV RNA). Hepatitis B and C screening is only required for participants with a known history of HBV/HCV infection or if mandated by the local health authority.\n- Has urine protein ≥1 g/24 hours; participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing (preferred) or urinalysis (if dipsticks are not feasible) will undergo a 24-hour urine collection for quantitative assessment of proteinuria.\n- Has had major surgery within 3 weeks prior to the first dose of study intervention; adequate wound healing after major surgery must be clinically assessed for eligibility regardless of time since surgery.\n- Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.\n- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.\n- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.\n- 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).\n- Has had an allogenic tissue/solid organ transplant.\n- Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.\n- Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO).\n- Prolongation of QTcF interval to >480 ms.\n- Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted.\n- Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.\n- Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib.\n- Is currently receiving strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin/rifabutin/rifapentine, carbamazepine, nevirapine, St John’s Wort) or moderate (e.g., bosentan, efavirenz, modafinil) CYP3A4 inducers that cannot be discontinued for the duration of the study.\n- Has received prior systemic anti-cancer therapy including investigational agents within 3 years prior to randomization.\n- 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.\n- 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.\n- Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.\n- 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.\n- Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, and/or lenvatinib, and/or belzutifan.\n- 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)."}

Primary endpoints

• {"endpoint_text":"- Radiographic response defined as a decrease of initial tumour size ≥30% from baseline to the week 12 CT scan, as assessed by the investigator per RECIST v1.1 criteria.","definition_or_measurement_approach":"Radiographic response measured as ≥30% decrease from baseline to week 12 CT scan, assessed by investigator using RECIST v1.1."}

Secondary endpoints

• {"endpoint_text":"- Adverse event (AE) rate, study intervention discontinuation due to AEs, rates of surgery delayed >4 weeks due to AEs from neoadjuvant treatment.","definition_or_measurement_approach":"Measured as AE rates, proportions discontinuing study intervention due to AEs, and proportion of surgeries delayed >4 weeks due to AEs."}
• {"endpoint_text":"- 30-day mortality and Clavien-Dindo classification.","definition_or_measurement_approach":"30-day postoperative mortality and surgical complications graded by Clavien-Dindo classification."}
• {"endpoint_text":"- Patient reported outcomes (PRO) scores for the following domains: EORTC QLQ-C30 global health status/HRQoL (Items 29-30); EORTC QLQ-C30 physical functioning (Items 1-5); EORTC QLQ-C30 role functioning (Items 6-7); FKSI-DRS Subscale (Items 1-9)","definition_or_measurement_approach":"PRO instruments: EORTC QLQ-C30 domains and FKSI-DRS subscale as specified (items listed); scores per validated instrument scoring rules."}

Spain

Earliest CTIS Part Ii Submission Date

05-02-2026

Latest Decision Or Authorization Date

24-04-2026

Processing Time Days

78

Number Of Sites

14

Number Of Participants

90

Primary sponsor

Full Name

Vall D Hebron Institute Of Oncology

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

Spain

Third parties

• {"country":"Spain","full_name":"Alcura Health Espana S.A.","duties_or_roles":"14","organisation_type":"Pharmaceutical company"}
• {"country":"","full_name":"MERCK SHARP & DOHME DE ESPAÑA, S.A","duties_or_roles":"Source of monetary support","organisation_type":""}