A Clinical Study of Disitamab Vedotin for Injection Combined With Penpulimab Injection in Neoadjuvant Therapy for Patients With HER2-expressing Cisplatin-intolerant cT2-T4aNxM0 Bladder Urothelial Carcinoma

A Clinical Study of Disitamab Vedotin for Injection Combined With Penpulimab Injection in Neoadjuvant Therapy for Patients With HER2-expressing Cisplatin-intolerant cT2-T4aNxM0 Bladder Urothelial Carcinoma

This study is a one-arm exploratory clinical study of Disitamab Vedotin for Injection combined with Penpulimab Injection designed for cisplatin intolerant CT2-T4anxm0 bladder urothelial carcinoma patients.It will confirme the efficacy and safety of Disitamab Vedotin for Injection combined with Penpulimab Injection neoadjuvant treatment for cisplatin intolerant CT2-T4anxm0 bladder urothelial carcinoma patients. Finally, it will provide new evidence-based medical evidence for neoadjuvant therapy for such patients.

This study is a multicenter, open-label, single-arm prospective clinical study to evaluate the neoadjuvant treatment of Disitamab Vedotin for Injection combined with Penpulimab Injection in cisplatin-intolerant cT2-T4aNxM0 bladder urothelial carcinoma Efficacy and safety in patients. If the subject does not withdraw from the trial voluntarily, the toxic and side effects caused by the drug are intolerable, or the investigator believes that the subject is not suitable for further trials, each subject will undergo the following treatment after surgery, and in Efficacy evaluation and follow-up were performed in each cycle.

After completion of all screening activities, patients who are identified as eligible will enter the study and receive the following treatments and visits: Neoadjuvant therapy with Disitamab Vedotin for Injection combined with Penpulimab Injection (administered for a maximum of 4 cycles), every three One week is a medication cycle; patients received radical cystectomy after neoadjuvant chemotherapy; postoperative pathological complete remission rate, downstaging rate, and regular follow-up for two years were evaluated to evaluate the safety of the patients drugs/surgery, and to evaluate the patients new Survival after curative resection with adjuvant immunotherapy combined with chemotherapy.

Neoadjuvant regimen (up to 4 cycles): Disitamab Vedotin for Injection, 2.0 mg/kg, given as an IV infusion on day 1, and Penpulimab Injection, 200 mg, on every 21 days On day 1 of the cycle, it is given as an intravenous infusion. Order of use: Disitamab Vedotin for Injection → Penpulimab Injection.

Surgical plan: radical cystectomy + urinary diversion.

Inclusion Criteria:

1. Voluntarily participate in this trial, be able to sign a written informed consent form, and understand and agree to comply with the requirements of this study and the evaluation schedule.

2. The age on the date of signing the informed consent form is 18 to 75 years old.

3. If it is a patient with cT2-T4aNxM0 bladder urothelial carcinoma with histological diagnosis and imaging evaluation based on AJCC eighth edition bladder cancer TNM staging, if the investigator believes that there is residual disease after TURBT surgery; the histology is mixed type. Oncological patients require urothelial carcinoma predominance (at least 50%).

4. Patients who are intolerant or not receiving cisplatin must be determined by the investigator. Patients who do not tolerate cisplatin chemotherapy must meet at least one of the following criteria:

   1. The performance status of ECOG is >1;
   2. Creatinine clearance rate < 60mL/min;
   3. Hearing loss ≥ grade 2 in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5th edition;
   4. Peripheral neuropathy grade ≥ 2 in NCI-CTCAE 5th edition;
   5. Suffering from New York Heart Association grade 3 or higher heart failure.

5. According to the assessment by the investigator, the need for radical cystectomy after neoadjuvant therapy, and the indications for radical cystectomy are met, and they are willing to undergo the surgery.

6. HER2 testing at local laboratory using pre-treatment tumor specimens: HER2 expression confirmed after IHC results (defined as: IHC 1+ 2+ 3+).

7. ECOG fitness status 0~1.

8. The patient's organ function is good, as measured by the following screening laboratory values ??(obtained ≤14 days prior to enrollment):

   a. Patients should not be on growth factor support ≤ 14 days prior to sample collection when screening for: i. Absolute neutrophil count ≥1.5×109/L; ii. Platelets≥100×109/L; iii. Hemoglobin≥90g/L; b. International normalized ratio or activated partial thromboplastin time ≤ 1.5 upper limit of normal (ULN); c. Serum total bilirubin≤1.5×ULN; d. AST, ALT and alkaline phosphatase≤2.5×ULN; e. The calculated creatinine clearance rate is greater than 30 mL/min;

9. Non-conceptual or fertile women must be willing to use highly effective contraception during the study period and for ≥ 120 days after the last dose of Vidicitumumab or Piamprizumab (whichever occurs later), and Negative urine or serum pregnancy test results within ≤7 days prior to enrollment.

10. Non-sterilized males must be willing to use highly effective contraception during the study period and for ≥ 120 days after the last dose of vildicotumab or pianiprilumab (whichever occurs later).

Exclusion Criteria:

1. Previously received therapies targeting PD-1, PD-L1, PD-L2, CTLA4, Her2 or other antibodies or drugs that specifically target T cell co-stimulation or checkpoint channels.

2. Received other approved systemic anticancer therapy or systemic immunomodulators (including but not limited to interferon, interleukin 2 and tumor necrosis factor) within 28 days before enrollment.

3. Previously received radiotherapy for bladder cancer.

4. Received drug treatment for tumors in the past, except for the following:

   1. For patients who have received systemic chemotherapy in the past, a treatment-free interval of at least 12 months from the last treatment to the start of neoadjuvant drug therapy;
   2. Local intravesical chemotherapy or immunotherapy ended at least 1 week before the initiation of study neoadjuvant drug therapy.

5. Major surgery or major trauma within 28 days before enrollment (implantation of vascular access device and TURBT are not considered major surgery).

6. Serious infection requiring systemic antibacterial, antifungal or antiviral treatment within 14 days before enrollment (HBV infection is performed according to the instructions of exclusion criterion 12).

7. Have been vaccinated with live vaccines within 28 days before enrollment (seasonal influenza vaccines are usually inactivated vaccines, so they are allowed to be used. Intranasal vaccines are live vaccines, so they are not allowed to be used).

8. Received any Chinese herbal medicine or proprietary Chinese medicine for cancer control within 14 days before enrollment.

9. Active autoimmune disease that requires systemic treatment, and the investigator evaluates that it has an impact on the study treatment.

10. Long-term use of large amounts of hormones or other immunosuppressive agents is required, and the investigator evaluates that it has an impact on the study treatment.

11. History of potassium, sodium, calcium abnormalities or hypoalbuminemia, interstitial lung disease, non-infectious pneumonia, or other uncontrolled systemic diseases, including diabetes, hypertension, cardiovascular disease, that the investigator believes may affect treatment (such as active heart disease within 6 months before enrollment, including: severe/unstable angina pectoris, myocardial infarction, symptomatic congestive heart failure and ventricular arrhythmia requiring drug treatment, etc.), etc.

12. Untreated chronic hepatitis B subjects or hepatitis B virus (HBV) carriers with HBV DNA ≥ 500 IU/mL (2500 copies/mL) are not allowed to enter the study. Note: Inactive hepatitis B surface antigen carriers or patients with stable active HBV infection (HBV DNA <500 IU/mL [2500 copies/mL]) after continuous antiviral therapy can be enrolled. HBV DNA testing is performed only in patients who are positive for antibodies to hepatitis B surface antigen.

13. Patients with active hepatitis C are not eligible. Patients who tested negative for HCV antibodies during the screening period, or those who tested negative for HCV RNA after positive HCV antibody tests could be enrolled. Only patients who test positive for HCV antibodies require HCV RNA testing.

14. A history of immunodeficiency (including positive human immunodeficiency virus HIV test, other acquired and congenital immunodeficiency diseases) or a history of allogeneic stem cell transplantation or organ transplantation.

15. Known hypersensitivity to other monoclonal antibodies.

16. Known allergy to any study drug or excipient.

17. Concurrently participate in another therapeutic clinical study.