Neoadjuvant PD-1 Monoclonal Antibody in Cisplatin-ineligible High Risk Upper Tract Urothelial Carcinoma

A Phase II Study of Tislelizumab(T) as Neoadjuvant Treatment for Cisplatin-ineligible High Risk Upper Tract Urothelial Carcinoma (UTUC)

Neoadjuvant therapy of cisplatin-based chemotherapy has been proved to improve prognosis of muscle invasive UTUC patients in several studies. This study is designed to investigate the safety and efficacy of neoadjuvant PD-1 monoclonal antibody in patients with locally advanced upper urinary tract urothelial carcinoma (UTUC) which are ineligible for cisplatin. Tislelizumab, an anti-programmed death protein-1 (PD-1) monoclonal antibody, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. The safety, tolerability, and efficacy of tislelizumab in patients with PD-L1 positive urothelial carcinoma who progressed during/following platinum-containing therapy was proved in a phase 2 trial (CTR20170071). This trial focuses on the efficacy of Tislelizumab to induce pathological down-staging of locally advanced UTUC in neoadjuvant setting.

Study Overview

• Status: Completed
• Conditions: Neoadjuvant Immunotherapy of Cisplatin-ineligible High Risk Upper Urinary Tract Urothelial Carcinoma
• Intervention / Treatment: Drug: Tislelizumab

Detailed Description

Neoadjuvant therapy of cisplatin-based chemotherapy has been proved to improve prognosis of muscle invasive UTUC patients in several studies. This study is designed to investigate the safety and efficacy of neoadjuvant PD-1 monoclonal antibody in patients with locally advanced upper urinary tract urothelial carcinoma (UTUC) which are ineligible for cisplatin. Tislelizumab, an anti-programmed death protein-1 (PD-1) monoclonal antibody, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. The safety, tolerability, and efficacy of tislelizumab in patients with PD-L1 positive urothelial carcinoma who progressed during/following platinum-containing therapy was proved in a phase 2 trial (CTR20170071). This trial focuses on the efficacy of Tislelizumab to induce pathological down-staging of locally advanced UTUC in neoadjuvant setting.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200127
      • Shanghai Renji Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. had non-metastatic high risk UTUC and planed to receive surgery(defined as high grade UTUC either by endoscopic biopsy or urinary cytology and/or any invasive aspect on radiological examination and/or hydronephrosis );
• 2. were ineligible for cisplatin-based chemotherapy(defined as meeting at least one of the following criteria: Eastern Cooperative Oncology Group [ECOG] performance status 2, creatinine clearance 30-60 mL/min, grade ≥2 audiometric hearing loss, grade ≥2 peripheral neuropathy, or New York Heart Association Class III heart failure);
• 3. had not received any systemic anti-tumor therapy;
• 4. Adequate organ function defined by study-specified laboratory tests; Hemoglobin ≥90 g/L; Hematological Absolute neutrophil count (ANC) ≥1.5×109 /L; Platelets ≥100×109 /L
• 5. No functional organic disease: T-BIL≤1.5×upper limit of normal (ULN); ALT andAST≤2.5×ULN; Serum creatinine≤2×ULN; endogenous creatinine clearance rate>30ml/min
• 6. Agree to comply with scheduled visits, treatment plans, lab tests and any other required study procedures;

Exclusion Criteria:

• 1. Patients who have received prior therapy of an anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody;
• 2. Patients who are allergic to monoclonal antibodies or any of its excipients;
• 3. Patients who have received other systems for anti-tumor treatment (e. g., Steroid therapy, immunotherapy) within 4 weeks or enrolled in other clinical trials;
• 4. Patients who are pregnant or breastfeeding, or expecting to conceive;
• 5. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies);
• 6. Patients who have known active Hepatitis B or Hepatitis C;
• 7. Patients who have active autoimmune disease that has required systemic treatment in the past 2 years;
• 8. Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment;
• 9. Patients who have received prior radiation therapy to the bladder;
• 10.Patients who have muscle invasive bladder cancer;
• 11.Patients who have received allogeneic hematopoietic stem cell transplantation or solid organ transplantation;
• 12.Patients who have a history of substance abuse or with a history of mental disorders;
• 13.Patients who had other malignant tumors in the past five years that have not recovered except for curable tumors that have been cured including basal or squamous skin cancer, localized carcinoma in situ of the cervix or the breast and low-risk prostate cancer, etc.
• 14.Patients who have active tuberculosis;
• 15.Patients who have other serious and uncontrollable accompanying diseases that may affect compliance or interfere with the interpretation of results including active opportunistic infections or advanced (severe) infections, uncontrollable diabetes, cardiovascular disease (grade III or IV heart failure defined by the New York Heart Association classification, II degree atrioventricular block and above, myocardial infarction in the past 6 months, unstable arrhythmia or instability angina, cerebral infarction within 3 months, etc.) or lung disease (interstitial pneumonia, history of obstructive lung disease and symptomatic bronchospasm);

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: Neoadjuvant arm; Patients will receive 2-4 cycles of Tislelizumab (200mg per cycle) prior to surgery（radical nephroureterectomy, segmental ureteral resection, endoscopic ablation） Drug: Tislelizumab 200 mg per cycle, IV on day 1 of every 3-week cycle, for 2-4 cycles prior to surgery	Drug: Tislelizumab; Patients will receive 2-4 cycles of Tislelizumab (200mg per cycle) before surgery（radical nephroureterectomy, segmental ureteral resection, endoscopic ablation）; Other Names: anti-PD-1 monoclonal antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pathological reponse rate	ypT0N0 at surgical specimen，in the intention-to-treat population	30 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
perioperative complication rate	the rate of perioperative complications are determined according to Clavien classification	30 days after surgery
objective response rate	the proportion of patients with a confirmed complete response or partial response based on radiological examination before surgery per RECIST version 1.1	12 months after drug treatment
disease free survival	from surgery to any kind of recurrence including tumour bed, first metastasis, or death from any cause	5 years after surgery or treatment
overall survival	time from enrollment to death for any cause	5 years after enrollment
pathological response rate	ypT0 and ypT1 at surgical specimen，in the intention-to-treat population	30 days after surgery

Collaborators and Investigators

• Sponsor: RenJi Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Actual): January 25, 2023
• Study Completion (Actual): November 25, 2023

Study Registration Dates

• First Submitted: December 12, 2020
• First Submitted That Met QC Criteria: December 12, 2020
• First Posted (Actual): December 17, 2020

Study Record Updates

• Last Update Posted (Actual): January 9, 2024
• Last Update Submitted That Met QC Criteria: January 7, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: neoadjuvant therapy; Tislelizumab; radical nephroureterectomy; Cisplatin-ineligible
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Antineoplastic Agents; Antineoplastic Agents, Immunological; Tislelizumab
• Other Study ID Numbers: NEO-IO

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