Disitamab Vedotin Combined With BCG Therapy in HER2-expressing High-risk Non-muscle Invasive Bladder Cancer

A Prospective, Open, Single-center Clinical Study of Disitamab Vedotin Combined With BCG Therapy in HER2-expressing High-risk Non-muscle Invasive Bladder Cancer

This is a prospective, open, single-center clinical study of the anti-HER2(Human epidermal growth factor receptor-2) ADC(antibody-drug conjugate) drug Disitamab Vedotin in combination with BCG(bacillus Calmette-Guerin) therapy in very high-risk NMIBC(Non-muscle invasive bladder cancer) patients with HER2 expression (IHC 1+/2+/3+), which is being conducted in accordance with the Good Clinical Practice for Pharmaceutical Trials (GCP). Approximately 20 subjects will be enrolled in this study to evaluate the efficacy and safety of Disitamab Vedotin (2.0 mg/kg, administered intravenously every three weeks) in combination with BCG therapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-muscle Invasive Bladder Cancer; HER-2 Protein Overexpression
• Intervention / Treatment: Drug: Disitamab vedotin; Drug: Bacillus Calmette Guerin Vaccine

Detailed Description

The study will include patients with very high risk NMIBC with HER2 expression (IHC 1+/2+/3+) who refuse to undergo cystectomy or do not meet the requirements for cystectomy. Reasons for unsuitability or refusal of cystectomy will be documented on an electronic case report form (eCRF).

Subjects will receive 6 months of Disitamab Vedotin therapy and at least 1 year of BCG therapy. EFS(Event free survival) and CR(Complete response) rates will be evaluated after treatment by cystoscopy, pathologic histology, urine cytology, laboratory tests, and imaging. Cystoscopy and urine cytology every three months for two years, and radiography every six months. Cystoscopy and urine cytology were done every six months and radiography once a year after two years.

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

Contacts and Locations

• Study Contact: Name: Dingwei Ye, Doctor; Phone Number: 64175590-82800; Email: dwyeli@163.com
• Study Contact Backup: Name: Yijun Shen, Doctor; Phone Number: 64175590-82800

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age≥18 years;
2. Histologically confirmed non-muscle-invasive urothelial cell carcinoma (UCC) of the bladder; A.Histopathology: any variant of UCC, The presence of any lymphovascular infiltration (LVI) was considered evidence of high risk. B. Confined to the mucosal (Ta, Tis) and lamina propria layers (T1) of the bladder. In addition, subjects had all visible tumors removed as completely as possible prior to the first dose of study drug and documented at baseline cystoscopy. C. CIS(Carcinoma in situ) does not require complete resection, but coexisting papillary carcinoma must be removed as completely as possible prior to enrollment and documented at baseline cystoscopy. Negative urine cytology results against malignant tumor cells are not required.
3. Presence of HER2 expression (IHC 1+/2+/3+) by IHC in our pathology department;
4. VHR(Very high risk) NMIBC, defined as having at least 1 of the following: Multiple and/or large (greater than [>] 3 centimeters [cm]) T1, (HG/G3) tumors; T1, (HG/G3) tumor with concurrent CIS; T1, G3 with CIS in prostatic urethra; Micropapillary variant of non-muscle invasive urothelial carcinoma;
5. Received first dose of medication ≤ 12 weeks from first TURBT;
6. Refusal or unsuitability for radical cystectomy;
7. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (</=) 1;
8. Adequate hematologic and end-organ function, Creatinine clearance >/=30 milliliters per minute (mL/min) (calculated using the Cockcroft-Gault formula);
9. Subjects (or their legal representatives) must sign an informed consent form (ICF);
10. Females of childbearing potential must have a negative pregnancy test result (beta-hCG) (urine or serum) within 7 days prior to the first dose of study drug.

Exclusion Criteria:

1. Evidence of locally advanced, metastatic, muscle-invasive, and/or extravesical bladder cancer;
2. Upper urinary tract urothelial carcinoma(UTIC), except 2 years without recurrence after previous radical UTUC;
3. Histopathologic examination reveals any small cell component of the bladder, simple adenocarcinoma, simple squamous cell carcinoma or simple squamous CIS;
4. Previously received other anti-HER-2 therapy;
5. Active malignancy outside of the disease being treated by the study (i.e., disease progression or need for change in therapy within the past 24 months);Only the following special cases are allowed: a. Skin cancer treated within the last 24 months and completely cured; b. Adequately treated lobular carcinoma in situ (LCIS) and ductal CIS; c. History of localized breast cancer and receiving anti-hormonal drugs or history of localized prostate cancer (N0M0) and receiving androgen blockade therapy.
6. History of uncontrolled cardiovascular disease, Included: 1) presence of any of the following in the past 3 months: unstable angina, myocardial infarction, ventricular fibrillation, torsional ventricular tachycardia, cardiac arrest or known congestive New York Heart Association class III-IV heart failure, cerebrovascular accident, or transient ischemic attack. 2) Prolonged QTc intervals confirmed by ECG evaluation during screening(Fridericia; QTc>480 ms). 3) Pulmonary embolism or other venous thromboembolism within the past 2 months.
7. Pregnant or lactating women;
8. Known infection with human immunodeficiency virus (HIV), unless the subject has been on stable antiretroviral therapy for the past 6 months or longer and has not had an opportunistic infection in the past 6 months and has had a CD4 count >350 in the past 6 months;
9. Evidence of active hepatitis B or C infection (e.g., subjects with hepatitis B who have a history of hepatitis C but have a normal polymerase chain reaction test result for hepatitis C virus and who are positive for antibodies to hepatitis B surface antigen may be enrolled in the study);
10. Have not recovered from toxic effects of previous anticancer therapy (except for toxic effects of no clinical significance, such as alopecia, skin discoloration, neuropathy and hearing impairment).
11. Delayed wound healing, defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or non-healing incisions;
12. Major surgery within 4 weeks prior to day 1 of cycle 1 (TURBT not considered major surgery);
13. Other patients assessed by the investigator to be unsuitable for participation in this 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: RC48+BCG; Disitamab Vedotin (2.0 mg/kg, administered intravenously every three weeks); BCG therapy: Induction therapy, i.e., intravesical therapy once a week for 6 weeks. maintenance therapy, i.e., one course of maintenance therapy at three, six and twelve months after surgery, each course once a week for 3 weeks.	Drug: Disitamab vedotin; 2.0 mg/kg, administered intravenously every three weeks; Other Names: RC48; Drug: Bacillus Calmette Guerin Vaccine; Induction therapy, i.e., intravesical therapy once a week for 6 weeks. maintenance therapy, i.e., one course of maintenance therapy at three, six and twelve months after surgery, each course once a week for 3 weeks.; Other Names: BCG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With CR as Assessed by the Investigator according to Cystoscopy and Urine Cytology at Month 3	CR at the 3-month disease assessment, evaluated by both cystoscopy and cytology.	up to 3 months
Event-Free Survival (EFS) rate, as Assessed according to Cystoscopy and Urine Cytology	Percentage of Participants With Event-Free Survival (EFS), as assessed according to Cystoscopy and Urine Cytology ( patients who are alive and free of persistent/recurrent high-grade NMIBC.)	up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With CR as Assessed by the Investigator according to Cystoscopy and Urine Cytology at Month 6, 12	CR at the 6, 12-month disease assessment, evaluated by both cystoscopy and cytology.	up to 12 months from the date of randomization as assessed by the investigator according to cystoscopic assessment and urine cytology
Duration of CR will be defined for participants with a CR as the time from the first occurrence of a documented complete response to recurrence of high-grade NMIBC or death from any cause.	Duration of CR will be defined for participants with a CR as the time from the first occurrence of a documented complete response to recurrence of high-grade NMIBC or death from any cause.	From first occurence of a documented CR until the time of recurrence of NMIBC or death from any cause, whichever came first, assessed up to 24 months
Percentage of Participants With Event-Free Survival (EFS), as Assessed according to Cystoscopy and Urine Cytology	EFS rate at 12, 24 months, defined as the proportion of patients who are alive and free of persistent/recurrent high-grade NMIBC.	up to 24 months
Progression-Free Survival (PFS), as Assessed according to Cystoscopy and Urine Cytology	PFS, defined as the time from the first study treatment to the first occurrence of progression to muscle-invasive disease based on cystoscopy and urine cytology or death from any cause.	Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Overall Survival	defined as the time from first study treatment to death from any cause	Time from date of randomization to death from any cause, assessed up to 60 months
Percentage of Participants With Adverse Events	Percentage of participants with at least one adverse event during the study	up to 24 months

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Dingwei Ye, Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: December 28, 2023
• First Posted (Estimated): January 1, 2024

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 28, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Immunoconjugates; BCG Vaccine; Disitamab vedotin
• Other Study ID Numbers: RC48C066

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