Surveillance of the Genetic Signature in Circulating Tumor DNA for Guiding Adjuvant Chemotherapy in Urothelial Carcinoma

Surveillance of the Genetic Signature in Circulating Tumor DNA for Guiding Adjuvant Chemotherapy in Urothelial Carcinoma: A Pilot Randomized Controlled Trial

Urothelial carcinomas are one of the most commonly diagnosed cancers worldwide. Postoperative patients carry a poor prognosis with an estimated five-year disease-specific survival rate of 50%. To improve overall survival and reduce the recurrent risk, chemotherapy is recommended as a standard of care. However, currently in Hong Kong, neoadjuvant (preoperational) chemotherapy and adjuvant (postoperative) chemotherapy are not commonly or regularly provided due to the concern of the potential harm from both physicians and patients. Recently, genetic signature from circulating tumor DNA (ctDNA) is emerging as a pivotal biomarker for detecting caner in early stage and molecular residual disease (MRD). With strengths of non-invasive and superior sensitivity, ctDNA is hopefully to serve as a cancer-agnostic surrogate analyte for risk stratification of tumor recurrence, thereby guiding individually tailored treatment. Therefore, this study is proposed to exploratively assess the benefit of ctDNA-guided approach for postoperative adjuvant therapy.

Study Overview

• Status: Recruiting
• Conditions: Muscle-Invasive Bladder Carcinoma; Muscle Invasive Bladder Urothelial Carcinoma
• Intervention / Treatment: Drug: gemcitabine; Drug: Cisplatin

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Research Assistant; Phone Number: 22554852; Email: stac@hku.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Queen Mary Hospital
    • Contact: Research Assistant; Phone Number: 22554852; Email: stac@hku.hk
    • Contact: Yung Na, PHD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. aged 18-70 years old;
2. a score of ≤1 for the Eastern Cooperative Oncology Group (ECOG) Performance Status;
3. receiving radical cystectomy (with lymph node dissection) or nephroureterectomy;
4. histologically confirmed (surgical specimen) muscle invasive urothelial carcinoma, and the major histological type should be transitional cell carcinoma;
5. Classification of tumour, node and metastasis (TNM): pT2-4a N0-2M0;
6. absence of microscopic (i.e., positive margin) or gross residual of the tumor (R0 resection) and absence of metastasis, confirmed by a negative CT or MRI scan of pelvis, abdomen and chest within 4 weeks prior to enrolment;

7. adequate hematologic and end-organ function, defined by the following laboratory results obtained within 28 days prior to the first study treatment:

   • ANC≥1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
   • WBC counts > 2500 cells/μL
   • Lymphocyte count ≥ 300 cells/μL
   • Platelet count ≥ 100,000 cells/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
   • Hemoglobin ≥ 9.0 g/dL
   • AST, ALT, and alkaline phosphatase ≤ 2.5 × the upper limit of normal (ULN),
   • PTT ≤ 1.5 × ULN
   • PT ≤ 1.5 × ULN or INR < 1.7
   • Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula)
8. able to understand and provide written informed consent, and agree to receive the treatment arrangement and study procedures stated in the informed consent

Exclusion Criteria:

1. receiving any approved anti-cancer treatment within 3 weeks prior to study enrolment;
2. participation in another clinical trial with therapeutic intent within 28 days prior to enrolment;
3. suffering from malignancies other than urothelial carcinoma within 5 years prior to study enrolment;
4. conditions that contraindicate chemotherapy, such as renal impairment with creatinine clearance rate (CCr) <50 mL/min, hearing impairment, and inadequate marrow function;
5. anaphylactic or hypersensitivity reactions or other contraindication to cisplatin and gemcitabine;
6. active or uncontrolled infections, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or tuberculosis;
7. pregnancy or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gemcitabine plus cisplatin chemotherapy arm (GC arm); Patients in this group will receive adjuvant chemotherapy of gemcitabine and cisplatin, prior to radiological progression	Drug: gemcitabine; 1,000 mg/m2 intravenous gemcitabine on day 1 and day 8; Drug: Cisplatin; 70 mg/m2 intravenous cisplatin (split into 2 doses on day 1 and day 8)
Other: Standard management arm (SM arm); Patients in this group will receive chemotherapy of gemcitabine and cisplatin only after radiological progression is observed	Drug: gemcitabine; 1,000 mg/m2 intravenous gemcitabine on day 1 and day 8; Drug: Cisplatin; 70 mg/m2 intravenous cisplatin (split into 2 doses on day 1 and day 8)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
the radiational disease-free survival (rDFS)	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	time to recurrence	1 year
Overall Survival (OS)		5 year
ctDNA clearance rate in ctDNA(+) patients		1 year

Collaborators and Investigators

• Sponsor: Yung NA
• Collaborators: Queen Mary Hospital, Hong Kong; Pamela Youde Nethersole Eastern Hospital
• Investigators: Principal Investigator: Yung Na, PHD, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2024
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: February 5, 2024
• First Submitted That Met QC Criteria: February 5, 2024
• First Posted (Actual): February 13, 2024

Study Record Updates

• Last Update Posted (Actual): April 4, 2025
• Last Update Submitted That Met QC Criteria: April 1, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: ctDNA; circulating tumor DNA; molecular residual disease
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Urologic Neoplasms; Urinary Bladder Diseases; Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Gemcitabine
• Other Study ID Numbers: HKURO202401

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
• product manufactured in and exported from the U.S.: No