Perioperative Trial With IO/TKI for Multi-stage Clear Cell Renal Cell Carcinoma
ConditionClear Cell RCC
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18-80
SponsorJinling Hospital, China
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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;
Trial design
Design model
Single group
Treatments tested in this trial
Toripalimab
DrugPatients 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.
Lenvatinib
DrugPatients 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.
Treatment groups
75 Participants
are divided into 1 treatment groupGroup A: Experimental: Perioperative toripalimab + lenvatinib followed by a partial/radical nephrectomyExperimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
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.
Time frame
Within 1 week after nephrectomySecondary outcomes
1
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).
Time frame
From baseline to 12 weeks after last dose2
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.
Time frame
Up to 4 weeks after nephrectomy3
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.
Time frame
From baseline to 12 weeks4
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.
Time frame
From baseline to 12 weeksOther outcomes
1
Tissue-based Biomarker Analysis
Biopsied and resected tumor specimens will be collected for revealing changes in the tumor microenvironment.
Time frame
Up to 2 years after treatment2
Peripheral Plasma-based Biomarker Analysis
Baseline, during-treatment, pre-operative, and postoperative peripheral plasma will be collected for revealing potential cycling biomarkers.
Time frame
Up to 2 years after treatment3
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.
Time frame
Up to 2 years after treatmentSponsors and contacts
Click on the lead sponsor to view all of their trials.
Source ClinicalTrials.gov