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

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.

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.