Perioperative Trial With IO/TKI for Multi-stage Clear Cell Renal Cell Carcinoma (TRIPLE-PATH)

A Prospective, Open-label, Phase II Clinical Trial of Perioperative Toripalimab Plus Lenvatinib for Multi-stage Clear Cell Renal Cell Carcinoma (ccRCC)

The IO/TKI regimens which combines Immune checkpoint inhibitors (IO) with Tyrosine Kinase Inhibitors (TKI) have become the standard first-line option for advanced ccRCC. Currently, IO/TKI regimens are serving as neoadjuvant treatment in arising clinical trials for ccRCC. Although anatomical change reflected by radiological response is reported in most neoadjuvant trials, only few studies focus on evaluation for pathological response in ccRCC.

The TRIPLE-PATH trial is an investigator initiated prospective, open-label phase II trial with the main objective to evaluate the clinical activity of preoperative/neoadjuvant therapy of toripalimab plus lenvatinib as mesured by pathological response of resected primary lesion in multi-stage ccRCC. Patients with ccRCC will be enrolled into 3 different cohorts based on their clinical TNM at the time of screening: localized ccRCC (cT1-2N0M0), locally advanced ccRCC (cT3-4N0M0 or cTanyN1M0), and metastatic ccRCC (cTanyNanyM1). Toripalimab (240mg Q3W) will be administered intravenously on the 1st day, and lenvatinib (20mg QD) will be administered orally once daily of each 3 weeks cycle. Patients in all cohorts will receive 4 cycles of preopertive/neoadjuvant toripalimab (240mg Q3W IV) plus lenvatinib (20mg QD PO), and a subsequent partial/radical nephrectomy 7-10 days after the last cycle. For adjuvant/postoperative treatment, patients who undergo R0 resection presented with cT1-2aN0M0G4/cT2bN0M0G3-4/cT3-4N0M0Gany/cTanyN1M0Gany will receive adjuvant doses of toripalimab (240mg Q3W IV) for 17 cycles; patients who undergo simultaneous resection of all oligometastases considered as "no evidence of disease" (M1 NED) will also receive adjuvant doses of toripalimab (240mg Q3W IV) for 17 cycles; patients who undergo R1 resection or presented with M1 disease cannot be definitely resected will receive postoperative doses of toripalimab (240mg Q3W IV) plus lenvatinib (20mg QD PO) for 17 cycles.

Specific follow-up for the enrolled patients is required in the TRIPLE-PATH trial. Longitudinal CT/MRI is utilized to assess the radiological response. Tissues and body fluid samples collected from the patients will be utilized for biomarker and multi-omic analysis.

The primary endpoint of the TRIPLE-PATH trial is major pathological response (MPR) in the primary lesion according to the pathological response reporting guidelines by the International Neoadjuvant Kidney Cancer Consortium (INKCC). Simon's two-stage minimax design is adopted by TRIPLE-PATH. An initial of 12 patients per cohort (36 in total) will be recruited, following an interim analysis. Recruitment to any cohort will be suspended if MPR is not observed in any patient at the interim analysis. If MPR is observed in at least 1 patient, additional 9 patients will be recruited in each cohort to at most 21 patients. Considering potential 15% dropout rate in each cohort, an anticipation of 25 patients will be recruited for each cohort (75 in total) in this study.

Study Overview

• Status: Recruiting
• Conditions: Clear Cell RCC
• Intervention / Treatment: Drug: Toripalimab; Drug: Lenvatinib

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Le Qu, M.D.; Phone Number: +86 15720625951; Email: septsoul@hotmail.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Recruiting
      • Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University
      • Contact: Le Qu, M.D.; Phone Number: +86 15720625952; Email: septsoul@hotmail.com
      • Contact: Junfu Huang; Phone Number: +86 15123894157; Email: junfuh810@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients have fully understood and give written informed consent prior to receive neoadjuvant therapy. Patients with history of major psychiatric disease must be judged able to fully understand the trial, and the explicit consent of family members is required;
• Patients with the ages range from 18 to 80 years old (at the time of signing informed consent);
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1;
• Patients have at least 1 measurable target lesion according to RECIST v1.1. The target lesion can be biopsied as per protocol.
• Histologically confirmed clear cell RCC;

• Patients will be enrolled into 3 separate cohorts based on their clinical TNM at the time of baseline screening:

  1. Cohort 1: localized ccRCC (cT1-2N0M0): the primary tumor in this cohort must meet the subsequent criteria:

     • The cT1a primary tumor should have ≥10 R.E.N.A.L. score, or locate in renal hilum close to renal artery or its main branch;

       • Patients with cT1b-2b primary tumors can be directly enrolled;

         • In case of necessary, patients will undergo dual radiological examinations using contrast-enhanced CT and MRI to rule out potential invasion of the renal pelvis or perirenal fat as per protocol.
  2. Cohort 2: locally advanced ccRCC (cT3-4N0M0 or cTanyN1M0);

  3. Cohort 3: metastatic ccRCC (cTanyNanyM1): the patients should be evaluated as suitable for cytoreductive nephrectomy.

     • Patient have no symptomatic metastatic lesions requiring urgent intervention;

       • The sum of the diameters of the other target lesions (excluding the primary tumor) does not exceed the longest diameter of the primary tumor.
• The patients who are treatment-naive, and have not received systemic therapy for any tumor;

• Adequate main organ function. The screening laboratory indicators must meet the following criteria:

  1. Hemoglobin ≥ 90 g/L (Without blood transfusion);
  2. Platelets count ≥ 100 x 109/L;
  3. Absolute neutrophil count ≥ 1.5 x 109/L;
  4. Serum creatinine ≤ 1.5 x ULN, or eGFR > 60 mL/min/1.73m2;
  5. Total bilirubin ≤ 1.5 mg/dL;
  6. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 x ULN for patients without evidence of liver metastases; AST and/or ALT ≤ 5 x ULN for patients with liver metastases;
  7. Normal CK;
  8. Normal Troponin T;
  9. Normal LDH.
• Willingness and ability to comply with planned visits, therapeutic laboratory testing, and other procedures.

Exclusion Criteria:

• Signs of tumor metastasis involving the central nervous system, or radiological evidence of brain metastasis;
• History of malignant tumors other than ccRCC within the previous 5 years, with the exception of malignant tumors that can be expected to be cured with treatment (including but not limited to adequately treated thyroid cancer, carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated with radical surgery);
• Prior to participating in the study, patients have received prior immune checkpoint inhibitors, investigational drugs or device therapy;
• History of undergoing major surgery (judged by the investigator) within 4 weeks before the first trial dose, are recovering, or are unable to undergo baseline puncture;
• History of severe drug allergy, including but not limited to antibody drugs;

• Patients with contraindications to immunotherapy restart, including but not limited to:

  1. Grade 2-4 immune myocarditis;
  2. Severe grade 4 proteinuria;
  3. Severe or life-threatening grade 4 immune hepatitis;
  4. Severe grade 3-4 immune pneumonitis;
  5. Severe inflammatory arthritis that significantly affects daily life or quality of life;
  6. Severe neurological toxicity:
  7. Myasthenia gravis grade 2-4;
  8. Guillain-Barre syndrome (GBS) or transverse myelitis of any grade;
  9. Grade 2-4 encephalitis;
  10. Severe or life-threatening grade 3-4 pancreatitis;
  11. Severe or life-threatening bullous disease (grade 3-4);
  12. Severe grade 3-4 uveitis or episcleritis.
• Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation or long-term corticosteroid therapy.
• Non-resolution of toxicity after previous antineoplastic therapy, i.e., resolution to baseline, CTCAE v5.0 grade 0-1 (excluding alopecia), or inclusion/exclusion criteria. Irreversible toxicities (e.g., hearing loss) that would not reasonably be expected to be exacerbated by the study drug can be included in the study;
• Known history of clinically significant liver disease, including active viral hepatitis (hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HbcAb) positive, HBV DNA>10000 copies /mL or >2000 IU/mL; Hepatitis C virus (HCV) antibody positive and HCV RNA positive), or other active hepatitis, clinically significant moderate to severe cirrhosis;
• Patients with uncontrolled third space effusion requiring repeated drainage, such as pleural effusion, ascites, pericardial effusion, etc. (Patients who do not need drainage of effusion or stop drainage for 3 days without significant increase in effusion can be enrolled);
• Receiving a systemic corticosteroid (prednisone > 10mg/ day or equivalent) or other immunosuppressive medication within 14 days before the first study medication;

• Patients with any severe and/or uncontrolled disease, including:

  1. Hypertension that is not well controlled by antihypertensive medication;
  2. Unstable angina pectoris or myocardial infarction, coronary artery bypass grafting or stent implantation within 6 months before study medication;
  3. Grade I or above myocardial ischemia or myocardial infarction, arrhythmia (including QTc≥480ms) and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification); Degree II or above heart block; Left ventricular ejection fraction (LVEF) < 50%;
  4. Poorly controlled diabetes (fasting blood glucose > 10 mmol/L);
  5. Patients with urinary protein ≥++ and confirmed 24-hour urinary protein > 1.0g;
  6. Severe active or uncontrolled infection.
• Patients with or suspected to have active autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, etc.;
• Renal failure requiring hemodialysis or peritoneal dialysis;
• Patients with a history of immunodeficiency, including HIV positive patients, other acquired immunodeficiency diseases, congenital immunodeficiency diseases, or organ transplantation history;
• History of live attenuated vaccine inoculation within 4 weeks before the first study drug or the expected vaccination during the study period;
• History of psychiatric drug abuse and can not quit or have a history of mental disorders;
• Women who are of childbearing potential. Women of childbearing potential must have a negative serum or urine pregnancy test, and must use appropriate methods of contraception.
• The presence of any other severe, acute or chronic medical disease or mental illness or laboratory abnormality, as judged by the investigator, that may increase the risk associated with participation in the study or that may interfere with the interpretation of the results of the study.

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: Experimental: Perioperative toripalimab + lenvatinib followed by a partial/radical nephrectomy; Toripalimab (240mg Q3W) will be administered intravenously on the 1st day of each 3 weeks cycle, and lenvatinib (20mg QD) will be administered orally once daily of each 3 weeks cycle. The patients will receive preoperative/neoadjuvant 4 cycles of toripalimab (240mg Q3W IV) plus lenvatinb (20mg QD PO) followed by a partial/radical nephrectomy 7-10 days after the last cycle. Adjuvant 17 cycles of toripalimab (240mg Q3W IV) will start at 4-8 weeks after surgery, for patients who undergo R0 resection but presented with cT1-2aN0M0G4/cT2bN0M0G3-4/cT3-4N0M0Gany/cTanyN1M0Gany, or undergo simultaneous resection of all oligometastases considered as "no evidence of disease" (M1 NED). Postoperative 17 cycles of toripalimab (240mg Q3W IV) plus lenvatinb (20mg QD PO) will start at 4-8 weeks after surgery, for patients who undergo R1 resection or presented with M1 disease cannot be definitely resected.

Drug: Toripalimab; Patients will receive 4 cycles of preoperative/neoadjuvant toripalimab (240mg Q3W IV) followed by a partial/radical nephrectomy 7-10 days after the last cycle. Patients who undergo R0 resection but presented with cT1-2aN0M0G4/cT2bN0M0G3-4/cT3-4N0M0Gany/cTanyN1M0Gany, or undergo simultaneous resection of all oligometastases considered as "no evidence of disease" (M1 NED), will receive 17 cycles of adjuvant toripalimab (240mg Q3W IV), starting at 4-8 weeks after surgery. Patients who undergo R1 resection or presented with M1 disease cannot be definitely resected will receive 17 cycles of postoperative toripalimab (240mg Q3W IV), starting at 4-8 weeks after surgery. Adjustment of dose: For patients with grade 3 or greater adverse events according to CTCAE v5.0 suspected to be caused by toripalimab, the dose can be postponed. In case of SAE, the dose can be discontinued. Dose de-escalation can be decided in patients who achieve MPR in primary lesions by investigators as per protocol.; Other Names: anti-PD-1 monoclonal antibody; Drug: Lenvatinib; Patients will receive 4 cycles of preoperative/neoadjuvant lenvatinib (20mg QD PO) of each 3 weeks cycle followed by a partial/radical nephrectomy 7-10 days after the last cycle. Patients who undergo R1 resection or presented with M1 disease cannot be definitely resected will receive 17 cycles of postoperative lenvatinib (20mg) orally once daily of each 3 weeks cycle, starting at 4-8 weeks after surgery. Adjustment of dose: For patients with grade 3 or greater adverse events according to CTCAE v5.0 suspected to be caused by lenvatinib, the dosage can be gradually reduced to 16mg, 12mg and a minimal of 8mg. In case of SAE, the dose can be discontinued. Dose de-escalation can be decided in patients who achieve MPR in primary lesions by investigators as per protocol.; Other Names: Lenvatinib mesylate (USAN); Multi-Kinase Inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response Rate	MPR is defined as the total proportion of viable residual tumor cells in the tumor bed via H-E stained sections of the resected tumor according to the guidelines by INKCC. Major pathological response rate is defined as the proportion of patients achieving MPR in their primary lesion.	Within 1 week after nephrectomy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety according to Adverse Events	The frequency and percentage of patients experiencing adverse events (AEs) according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).	From baseline to 12 weeks after last dose
Surgical morbidity	Surgical morbidity or complications rate after neoadjuvant therapy. Intraoperative adverse incidents are defined as adverse events due to surgical intervention occurring between skin incision and closure and are evaluated according to the EAU intraoperative AI classification (EAUiaiC). Postoperative complications are evaluated according to Clavien-Dindo classification system.	Up to 4 weeks after nephrectomy
Best Overall Response	BOR is defined as the best response state among all the longitudinal evaluation according to RECIST v1.1. A modified BOR only focusing on metastases will be specially utilized for patients in cohort 3.	From baseline to 12 weeks
Down-staging Rate of Primary T Stage	The T stage of the primary lesion will be evaluated according to the 8th edition of AJCC at baseline and surgery to reflect the change in T stage of the primary lesion after neoadjuvant therapy.	From baseline to 12 weeks
Change in R.E.N.A.L. Score of Primary Lesion	The R.E.N.A.L. score can reflect the difficulty of the nephrectomy. The R.E.N.A.L. scores of the patients before and after neoadjuvant therapy will be evaluated based on the CT/MRI scan.	From baseline to 12 weeks
Rate of R0 Resection	R0 resection is defined as no visible tumor cells were observed at the surgical margins of the pathological specimens.	Within 1 week after nephrectomy
Change in Tumor Thrombus	For patients with TT at baseline, the change of TT according to Mayo's classification will be recorded.	From baseline to 12 weeks
Change in Renal Function	The change in renal function before and after neoadjuvant therapy,also before and after nephrectomy will be evaluated by eGFR. The eGFR will be calculated using the CKD-EPI formula. Split renal function recovery rate will be report in patients who undergo partial nephrectomy.	Up to 1 year after nephrectomy
Progression Free Survival	PFS is defined as the time from enrollment to progression disease, recurrence, distant metastasis or death from any cause.	Up to 5 years after treatment
Disease Free Survival	DFS is defined as the time from completion of nephrectomy to recurrence, distant metastasis or death from any cause. DFS will only be reported in the cohort 1 and 2.	Up to 5 years after nephrectomy
Overall Survival	OS is defined as the time from enrollment to death from any cause.	Up to 5 years after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tissue-based Biomarker Analysis	Biopsied and resected tumor specimens will be collected for revealing changes in the tumor microenvironment.	Up to 2 years after treatment
Peripheral Plasma-based Biomarker Analysis	Baseline, during-treatment, pre-operative, and postoperative peripheral plasma will be collected for revealing potential cycling biomarkers.	Up to 2 years after treatment
Radiological and Pathological Biomarker Analysis	The radiological and pathological information during the treatment process will be collected. A prediction model related to therapeutic efficacy and prognosis is anticipated to be developed.	Up to 2 years after treatment

Collaborators and Investigators

• Sponsor: Jinling Hospital, China
• Investigators: Principal Investigator: Le Qu, M.D., Jinling Hospital, China

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2032

Study Registration Dates

• First Submitted: April 22, 2026
• First Submitted That Met QC Criteria: April 30, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Perioperative; Immunotherapy; Nephrectomy; ccRCC; Tyrosine Kinase Inhibitors; pathologic response
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Kidney Neoplasms; Carcinoma, Renal Cell; toripalimab; spartalizumab; lenvatinib; multi-kinase inhibitor 108600
• Other Study ID Numbers: DZQH-KYLL-26-05

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes