A Phase 2 Multicenter Single-Arm Clinical Trial of Zanzalintinib and Pembrolizumab in Subjects With Resectable Clear Cell Renal Cell Carcinoma

This is a multicenter, single-arm, phase 2 clinical trial designed to evaluate the clinical efficacy of combination therapy with zanzalintinib and pembrolizumab in patients with locally advanced intermediate- to high-risk, high-risk, or resectable metastatic clear cell renal cell carcinoma.

The neoadjuvant treatment period consists of a total of 6 cycles; pembrolizumab is administered every 3 weeks, and zanzalintinib is administered orally once daily. A drug washout period of at least 21 days is required prior to the last dose before surgery.

Surgery will be performed after completion of the neoadjuvant treatment and following a drug washout period of at least 21 days.

The adjuvant treatment period begins at least 28 days after surgery, and pembrolizumab is administered every 3 weeks for a total of 11 cycles.

Radiologic response assessments are conducted at predefined time points during the neoadjuvant period, and pathologic response is evaluated using resected tissue obtained at the time of surgery.

• Study duration: Approximately 30 months (18 months for enrollment + 12 months for treatment and follow-up)
• Planned sample size: 48 patients (including an estimated 10% dropout rate) Tumor size and disease stage will be assessed using baseline imaging performed prior to treatment, and tumor response will be evaluated through predefined scheduled imaging assessments conducted during treatment. Tumor response will be evaluated during treatment via imaging at regular intervals per cycle. Surgery will be scheduled after the completion of 6 cycles, following a minimum 21-day washout period (±7 days at the investigator's discretion). If postoperative recovery is adequate (at least 28 days, ±14 days at the investigator's discretion), adjuvant Pembrolizumab treatment will commence.

Study Overview

• Status: Not yet recruiting
• Conditions: Patients With Locally Advanced or Metastatic But Resectable Clear Cell Renal Cell Carcinoma
• Intervention / Treatment: Drug: Zanzalintinib and Pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sang Joon Shin, Professor; Phone Number: 02-2228-8138; Email: ssj338@yuhs.ac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects with clear cell renal cell carcinoma (clear cell RCC) confirmed by pathological or cytological diagnosis.

   meeting one or more of the following criteria:

   • Locally advanced disease or resectable metastatic disease.
   • Resectable intermediate- to high-risk or high-risk patients are eligible for enrollment.
   • Resectability is determined by multidisciplinary Resectability will be determined based on multidisciplinary evaluation. Resectable metastatic disease is defined as cases in which, in the presence of a primary tumor, complete resection of both the primary tumor and all identifiable metastatic lesions is deemed feasible by multidisciplinary assessment. All metastatic lesions must be amenable to complete resection within the planned surgical schedule. Subjects will be excluded from enrollment if metastatic lesions have already been completely resected prior to study entry, are deemed unresectable, or are expected to have residual disease after attempted resection.

   Intermediate-High Risk Group cT2· Grade 4· or· Sarcomatoid cT3, any Grade, N0 High Risk Group cT4, any Grade, N0 any cT, any Grade, N+ Resectable Metastatic Disease any cT, any cN, any Grade, M1

2. Age 19 years or older on the day of consent
3. ECOG performance status 0~1
4. Female subjects of childbearing potential must have a negative result on a serum or urine pregnancy test conducted during the clinical trial screening period. If the urine test result is positive or cannot be confirmed as negative, a serum pregnancy test must be performed.

5. Sexually active fertile subjects and their partners must agree to use highly effective method of contraception (defined in Appendix E) during the course of the study and for a specified period after the last dose of treatment, as defined below. Subjects and their partners must consistently use highly effective contraception, and an additional contraceptive method (e.g., condom) is required.

   • Male subjects: Must use a condom during the treatment period and for 120 days after the last dose and must agree not to donate sperm during this period.
   • Female subjects: Women of childbearing potential (WOCBP) must comply with protocol-specified contraceptive methods during the treatment period and for 186 days after the last dose.

   The durations reflect the longer washout period between Zanzalintinib and Pembrolizumab.

6. Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 as determined by the Investigator.
7. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
8. Adequate organ and marrow function as defined by the table below.

Table 2. Organ function requirements for eligibility evaluation Organ System Laboratory Test Criteria Hematological Absolute neutrophil count (ANC) ≥1,500/μL Platelets ≥100,000/μL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L Renal Creatinine OR creatinine clearance (CrCl) (If CrCl is used, estimated GFR may also be acceptable) ≤1.5 × ULN OR CrCl ≥60 mL/min (if applicable to the study population)

Urine protein-to-creatinine ratio (UPCR) ≤1.5 mg/mg Hepatic

Total bilirubin ≤1.5 × ULN OR, if subject has known Gilbert's syndrome:

direct bilirubin ≤1.5 × ULN (Subjects with other causes of hyperbilirubinemia: total bilirubin ≤3 × ULN and ALT <3 × ULN) AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (or ≤5 × ULN for subjects with liver metastasis) Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤1.5 × ULN, or if the subject is receiving anticoagulant therapy within the treatment range, no restrictions apply.

Exclusion Criteria:

1. Concurrent anticancer treatments other than the investigational therapy, including chemotherapy, curative radiotherapy, surgery, immunotherapy, biological therapy, or tumor embolization.
2. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
3. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment.
4. History of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 therapies, or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors.
5. Any complementary medicine within 2 weeks prior to first dose of treatment.
6. History of another malignancy within the 2 years prior to the first dose of study treatment, except for basal cell carcinoma or squamous cell carcinoma treated solely by local excision, cervical carcinoma in situ, or completely resected papillary thyroid carcinoma.
7. Diagnosis of immunodeficiency or is receiving systemic steroid therapy (> 10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment. Inhaled, intranasal, intraarticular, and topical corticosteroids and mineralocorticoids are allowed
8. Presence of untreated fistulas, irrespective of cancer status.
9. Presence of uncontrolled concomitant diseases, including but not limited to ongoing or active infections, symptomatic congestive heart failure, unstable angina, cardiac arrhythmias, immunosuppressive conditions, autoimmune diseases, underlying pulmonary disorders, or psychiatric or social conditions that may limit compliance with clinical trial requirements.
10. Active autoimmune diseases requiring systemic treatment (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years before the treatment of trial. Physiologic corticosteroid replacement for thyroid hormone, insulin, or adrenal/pituitary insufficiency is excluded from this criterion.
11. Thrombotic, embolic, venous, or arterial events (e.g., cerebrovascular accident including transient ischemic attack, deep vein thrombosis, pulmonary embolism) within 6 months before the treatment of trial.
12. Concomitant anticoagulation with oral anticoagulants and platelet inhibitors. Only low-dose aspirin and LMWH are permitted.
13. Subjects must have discontinued anticoagulant within 3 days or 5 half-lives prior to the first dose of treatment (whichever is longer)
14. History of non-infectious pneumonitis requiring corticosteroid therapy or presence of current pneumonitis.
15. Uncontrolled hypertension (>140 mmHg systolic or >90 mmHg diastolic despite optimal antihypertensive treatment
16. Prior history of myocarditis
17. Known gastric or esophageal varices
18. Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks
19. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 tsp of red blood, or other history of significant bleeding within 12 weeks before first dose of study treatment
20. Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed)
21. Lesions invading or encasing any major blood vessels
22. Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions
23. Malabsorption syndrome
24. Pharmacologically uncompensated, symptomatic hypothyroidism
25. Moderate to severe hepatic impairment (Child-Pugh B-C)
26. Requirement for hemodialysis or peritoneal dialysis
27. History of solid organ or allogeneic stem cell transplant

28. Major surgery within 8 weeks or minor surgery within 14 days prior to study treatment. Subjects must have complete wound healing following major or minor surgery prior to the first dose of study treatment.

    If a tumor biopsy is performed prior to treatment initiation, study treatment may only be initiated after at least 14 days have elapsed from the date of the biopsy and complete wound healing at the biopsy site has been clinically confirmed.

    Complete wound healing is defined as closure of the biopsy site without the need for dressing, and absence of active bleeding, hematoma, infection, erythema, drainage, worsening pain, or wound dehiscence.

    If complications such as bleeding, hematoma, infection, persistent pain, drainage, wound dehiscence, or any complication requiring additional intervention occur after biopsy, study treatment must not be initiated until such complications have resolved and complete wound healing has been confirmed.

    The investigator may further delay the initiation of study treatment if additional waiting time is considered necessary, taking into account the biopsy location, procedure, and risk of bleeding.

29. History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent.
30. Inability to swallow tablets or ingest a suspension either orally or by a NG or PEG tube
31. Previously identified allergy or hypersensitivity to components of treatment
32. Other conditions, which in the opinion of the investigator, would compromise the safety of the patient or the patient's ability to complete the study
33. Known positive test for tuberculosis infection if supported by clinical or radiographic evidence of disease
34. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field is permitted.
35. Free thyroxine (FT4) outside the laboratory normal reference range. Asymptomatic subjects with FT4 abnormalities can be eligible after Principal Investigator approval.
36. Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.
37. Pregnancy or breastfeeding. Negative serum or urine pregnancy test results must be confirmed within 1 week before the treatment of trial.
38. History of HIV infection or chronic or active hepatitis C requiring antiviral therapy. In cases of hepatitis B, enrollment is permitted if the patient is receiving appropriate antiviral treatment and viral DNA is undetectable.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Combination Therapy of Zanzalintinib and Pembrolizumab; Treatment consists of a neoadjuvant and an adjuvant phase, during which Zanzalintinib and Pembrolizumab are administered. Patients will receive a total of 6 cycles (21 days per cycle) of combination therapy as neoadjuvant treatment, followed by surgery. After srugery, patients will receive 11 additional cycles of adjuvant Pembrolizumab.

Drug: Zanzalintinib and Pembrolizumab; Treatment consists of a neoadjuvant and an adjuvant phase, during which Zanzalintinib and Pembrolizumab are administered. Patients will receive a total of 6 cycles (21 days per cycle) of combination therapy as neoadjuvant treatment, followed by surgery. After srugery, patients will receive 11 additional cycles of adjuvant Pembrolizumab.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Tumor response will be evaluated radiologically in accordance with RECIST version 1.1 and defined as the proportion of complete response (CR) or partial response (PR). As a primary endpoint, the objective response rate will be assessed every 9 weeks (±7 days) during the neoadjuvant treatment period.	Preoperatively, up to 22 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety and tolerability	Incidence of adverse events (AEs) and serious adverse events (SAEs) based on CTCAE version 5.0 criteria.	Perioperatively, up to 59 weeks
major pathologic response	Defined as 10% or less residual viable tumor in the resected specimen.	Major pathological response (MPR) will be assessed during the surgical period.
event-free survival, EFS	Time from treatment initiation to the occurrence of the first event, including relapse, progression, or death.	Up to 5 years
overall survival, OS	Time from treatment initiation to death from any cause.	Up to 5 years
Surgery completion rate	Proportion of subjects who underwent the planned surgery after initiation of neoadjuvant therapy.	From treatment initiation to surgery
Pathologic complete resection rate (R0)	Proportion of subjects with microscopically margin-negative (R0) resection confirmed by pathological assessment.	At the time of surgery
Surgery delay rate (>4 weeks)	Proportion of subjects whose surgery was delayed by more than 4 weeks from the initially planned date due to treatment-related adverse events or medical reasons.	From planned surgery date to actual surgery date (up to 4 weeks after the planned surgery date)
Reoperation rate	Proportion of subjects who required reoperation due to postoperative complications or residual disease.	Within 12 weeks after surgery
Postoperative Complications	Incidence of complications occurring within 12 weeks following surgery.	Within 12 weeks after surgery
Surgery-related mortality	Proportion of subjects who died due to surgery-related causes within 12 weeks after surgery.	Within 12 weeks after surgery

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 31, 2028
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: June 14, 2026
• First Submitted That Met QC Criteria: July 2, 2026
• First Posted (Actual): July 9, 2026

Study Record Updates

• Last Update Posted (Actual): July 9, 2026
• Last Update Submitted That Met QC Criteria: July 2, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: pembrolizumab
• Other Study ID Numbers: 4-2025-1718

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No