Pembrolizumab-Sacituzumab Govitecan Combination to Treat High-risk, Localized Bladder Cancer

Study Overview
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Brief Summary
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This is a perioperative Phase 2, open-label, non-randomized, single-cohort study in patients with urothelial carcinoma of the bladder who cannot receive or refuse to receive cisplatin-based chemotherapy.

Detailed Description
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A transurethral resection of the bladder tumor (TURBT) for biopsy, histological characterization, and local staging will be executed first, according to the guidelines. Eligible patients will receive neoadjuvant treatment: 10 mg/kg sacituzumab govitecan IV, on days 1, 8, of each 21 day cycle. Pembrolizumab will be administered in combination with sacituzumab on day 1, every 21 days, at the standard dose of 200 mg intravenously. A total of 4 cycles is planned before surgery. Surgery will be planned at the time of study inclusion to be done ideally within 4 weeks of the last dose of study drug, and not later than 12 weeks from the last dose of study drug. After surgery patients will receive additional 13 cycles of pembrolizumab at the standard dose, every 3 weeks, accounting for a total of 17 cycles of perioperative pembrolizumab (neoadjuvant + adjuvant). Imaging assessments post-cystectomy will be managed according to the current EAU guidelines. At the end of the adjuvant period, patients will enter the follow-up period which will last until 12 months from the last dose of pembrolizumab.

Official Title
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An Open Label, Single-arm, Phase 2 Study of Perioperative Pembrolizumab Plus Sacituzumab Govitecan for Patients With Muscle-invasive Bladder Cancer Who Cannot Receive or Refuse Cisplatin-based Chemotherapy

Conditions
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Muscle-invasive Urothelial Carcinoma of the Bladder

Intervention / Treatment
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* Drug: Pembrolizumab 25 mg/1 ML Intravenous Solution [KEYTRUDA]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: written informed consent >18 years of age Histopathologically confirmed urothelial carcinoma. Fit and planned for RC ECOG performance status score of 0 or 1 Adequate hematologic counts , hepatic and renal function. Negative pregnancy test and Effective contraception during the study, unless evidence of infertility exists Clinical stage T2-T4aN0M0 MIBC, assessed by CT + PET/CT + mpMRI. Ineligibility to receive cisplatin-based neoadjuvant chemotherapy based on Galsky's criteria OR refusal to receive neoadjuvant cisplatin-based chemotherapy Exclusion Criteria: prior systemic anti-cancer therapy including investigational agents and immunotherapy, prior radiotherapy on the bladder tumor, partial cystectomy. Refusal to undergo RC.live vaccine, antibiotics within 30 days prior to the first dose of study drug. Participation in a study of an investigational agent or device, additional known malignancy , severe hypersensitivity to study drugs and/or any of their excipients, active autoimmune disease that required systemic treatment. history of (non-infectious) pneumonitis that required steroids or current pneumonitis. active chronic inflammatory bowel disease, any condition that is not in the best interest of the subject to participate, in the opinion of the treating investigator. active cardiac disease, defined as: A) Myocardial infarction or unstable angina pectoris within 6 months of C1D1 B) History of serious ventricular arrhythmia, high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications; history of QT interval prolongation C) NYHA Class III or greater congestive heart failure or left ventricular ejection fraction of < 40% known history of HIV-1/2 infection, known history of Hepatitis B active Hepatitis C virus infection. other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations. High dose systemic corticosteroids are not allowed within 2 weeks of C1D1. Have received or are currently receiving (within the previous 2 weeks) antibiotics.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single Arm<br>Single Arm treatment | Drug: Pembrolizumab 25 mg/1 ML Intravenous Solution [KEYTRUDA]<br>* Neoadjuvant treatment: 10 mg/kg sacituzumab-govitecan IV, on days 1, 8, of each 21 day cycle; Pembrolizumab will be administered in combination with sacituzumab-govitecan on day 1, every 21 days, at the standard dose of 200 mg intravenously. A total of 4 cycles is planned before surgery. After surgery patients will receive additional 13 cycles of pembrolizumab at the standard dose, every 3 weeks, accounting for a total of 17 cycles of perioperative pembrolizumab (neoadjuvant + adjuvant).<br>* Other names: sacituzumab-govitecan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of complete pathological responses, defined as the absence of viable tumor cells on the histological examination of the cystectomy | Number of complete pathological responses, defined as the absence of viable tumor cells on the histological examination of the cystectomy | Upon completion of the study up to 40 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the proportion of patients who will be pathologically downstaged to ypT minor or equal to 1N0M0. | To evaluate the proportion of patients who will be pathologically downstaged to ypT minor or equal to 1N0M0. | Upon completion of the study up to 40 months | 
| To evaluate radiological response on those patients with measurable disease. Response (CR and PR) will be assessed after the full neoadjuvant course of 4 cycles. | To evaluate radiological response on those patients with measurable disease. Response CR and PR) will be assessed after the full neoadjuvant course of 4 cycles. | up to 16 months | 
| To evaluate the surgical and medical safety of neoadjuvant combination therapy, as well as of the adjuvant pembrolizumab therapy. | To evaluate the surgical and medical safety of neoadjuvant combination therapy, as well as of the adjuvant pembrolizumab therapy. | Up to 6 months | 
| To assess survival outcomes (event-free survival and overall survival), in the total population and in the subgroups according to the pathological response. | To assess survival outcomes (event-free survival and overall survival), in the total population and in the subgroups according to the pathological response. | Up to 40 months |