An Open-label, Single Arm, Single Center Phase 2 Study of RC48-ADC (IV) in Combination With Gemcitabine(Intravesical) in High Risk NMIBC Subjects (BCG Naïve or BCG Unresponsive) That Expresses HER2 (IHC 1+ and Greater)
In this study, participants with high risk non-muscle-invasive bladder cancer (NMIBC) who are BCG Naïve or BCG Unresponsive and are considered ineligible for or have refused to undergo radical cystectomy, will receive RC48-ADC in combination with gemcitabine.
‣ 1\. Voluntary consent to participate in the study and sign an informed consent form.
‣ 2\. Male or female, age ≥ 18 years. 3. Disease satisfies.
• Diagnosis in accordance with the Chinese Guidelines for the Treatment of Bladder Cancer (2022) high-risk non-muscle invasive bladder cancer (NMIBC) and meeting any of the following ± carcinoma in situ (CIS): 1. stage T1 tumor of any grade; 2. high-grade tumor; 3. multiple and/or recurrent tumors, with recurrent tumors excluding low-grade solitary tumors.
• Histopathological satisfaction of uroepithelial carcinoma predominant by histopathology, confirming the absence of muscular infiltration.
• Completion of TURBT and resection of all visible lesions within 3 weeks prior to study dosing.
• Clinical staging (cTa/T1±CIS, N0, M0) and absence of distant metastases as assessed by imaging (which needs to include at least CTU) within 3 months prior to enrollment.
• 4\. 4. Prior BCG treatment.
⁃ Cohort 1 is high-risk NMIBC patients who have not received prior BCG therapy: high-risk NMIBC patients who have not received prior BCG therapy due to subjective and objective conditions, including one of the following 1. patient refusal to receive BCG therapy; 2. presence of contraindications to BCG therapy; 3. BCG inaccessibility.
⁃ Cohort 2 was high-risk NMIBC patients with BCG non-response, and BCG non-response met any of the following: 1. presence of persistent/recurrent high-risk NMIBC within 12 months (±1 month) of completing adequate BCG therapy; 2. high-grade T1 disease at first assessment after induction phase BCG therapy. Note: Adequate BCG therapy is defined as at least 5 BCG bladder instillations completed within 2 months and at least 2 BCG bladder instillations completed in any 6 consecutive weeks over the next 10 months, i.e., at least 5+2 BCG bladder instillations completed over an approximately 12-month period.
• 5\. Subjects who have been assessed by a urologist to be unsuitable for radical bladder cancer surgery or who have refused radical bladder cancer surgery.
• 6\. Subjects whose tumor tissue obtained by TURBT within 3 weeks meets 1+, 2+ or 3+ HER2 expression by immunohistochemistry (IHC) at the study center.
• 7\. ECOG physical status score of 0-2. 8. Adequate cardiac, bone marrow, liver, and renal function, which should meet the following criteria within 7 days prior to study dosing (normal values are based on the clinical trial center).
• Left ventricular ejection fraction ≥ 50%.
• Hemoglobin ≥ 9 g/dL.
• Absolute neutrophil count (ANC) ≥ 1.5×109/L.
• Platelets ≥ 100×109/L.
• Serum total bilirubin ≤ 1.5 times the upper limit of normal (ULN).
• ALT and AST ≤ 2.5×ULN.
• blood creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 50 mL/min calculated according to the Cockcroft-Gault formula method.
• 9\. Female subjects should be surgically sterilized, post-menopausal, or agree to use at least one medically approved contraceptive (e.g., IUD, pill, or condom) during study treatment and for 6 months after the end of the study treatment period, and must have a negative blood pregnancy test within 7 days prior to study enrollment; false-positive results may be excluded by the investigator after enrollment. Male subjects should agree to use at least one medically approved contraceptive during the study treatment period and for 6 months after the end of the study treatment period.
• 10\. be willing and able to comply with the trial and follow-up procedural arrangements.