Title
A Phase II Open-Label Study of Sacituzumab Govitecan in Unresectable Locally Advanced/Metastatic Urothelial Cancer

Description
The objective of this study is to evaluate the efficacy and safety of sacituzumab govitecan-hziy in participants with metastatic urothelial cancer (mUC).

Objective
Primary Outcome Measures:

Overall Response Rate (ORR) Based on Central Review by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Criteria. [ Time Frame: Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) ]


ORR will be defined as the rate of the best overall response as Complete Remission (CR) or Partial Response (PR) and based on central review by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) criteria.

Overall Response Rate (ORR) [ Time Frame: Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) ]


ORR will be defined as the rate of the best overall response as CR or PR and based on investigator review by RECIST 1.1 criteria for cohorts 3, 4, and 5. ORR will also be evaluated based on investigator review by Modified RECIST 1.1 for Immune-Based Therapeutics (iRECIST 1.1) for Cohort 3 only.


Duration of Response (DOR) [ Time Frame: Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) ]


DOR will be calculated from the date of the first evaluation showing documented response, PR, or CR, to the date of the first disease progression or death and based on central and investigator review by RECIST 1.1 criteria for all cohorts. DOR will also be evaluated based on investigator review by iRECIST 1.1 for Cohort 3 only.


Progression-Free Survival (PFS) [ Time Frame: Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) ]


PFS is defined as the time from the first dose until objective tumor progression,or death, whichever comes first and based on central and investigator review by RECIST 1.1 criteria for all cohorts. PFS will also be evaluated based on investigator review by iRECIST 1.1 for Cohort 3 only.


Overall Survival (OS) [ Time Frame: Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) ]


OS will be measured from the date of first dose to death from any cause.


Clinical Benefit Rate (CBR) [ Time Frame: Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) ]


CBR is defined as CR + PR + Stable Disease (SD) for at least 6 months and based on central and investigator review by RECIST 1.1 criteria for cohorts 3, 4, and 5. CBR will also be evaluated based on investigator review by iRECIST 1.1 for Cohort 3 only.


Cohorts 3, 4, and 5: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) [ Time Frame: First dose date up to last dose date plus 30 days (approximately 3 years) ]


Cohorts 3, 4, and 5: Percentage of Participants Experiencing any Clinically Significant Laboratory Abnormalities [ Time Frame: First dose date up to last dose date plus 30 days (approximately 3 years) ]

Treatment Cohort 1 and Cohort 2: sacituzumab govitecan 10 mg/kg intravenously (IV) on Days 1 and 8 of a 21-day cycle.
Cohort 3: Subjects will first receive sacituzumab govitecan 10 mg/kg IV on Days 1 and 8 of a 21-day cycle followed by pembrolizumab at the standard approved dose (200 mg) only on Day 1 of a 21-day cycle.
Cohort 4: Subjects will first receive cisplatin either at 70 mg/m2 on Day 1 of a 21-day cycle, or at a split dose of 35 mg/m2 on Days 1 and 8 of a 21-day cycle followed by sacituzumab govitecan at the specified dose on Days 1 and 8 of a 21-daycycle.
Cohort 5: Subjects will first receive cisplatin either at 70 mg/m2 on Day 1 of a 21-day cycle, or at a split dose of 35 mg/m2 on Days 1 and 8 of a 21-day cycle followed by sacituzumab govitecan at the recommended Phase 2 dose (RP2D) determined from Cohort 4 on Days 1 and 8 of a 21-day cycle, and then 800 mg of avelumab every 2 weeks beginning on Cycle 1, Day 1.

Key Eligibility Key Inclusion Criteria:

Participants with histologically confirmed urothelial cancer (UC).

Eastern Cooperative Oncology Group (ECOG) Performance status score of 0 or 1.

Cohort 1: Have had progression or recurrence of urothelial cancer following receipt of platinum-containing regimen (cisplatin or carboplatin):


Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease;

Or received neo/adjuvant platinum-containing therapy for localized muscle-invasive urothelial cancer, with recurrence/progression less than or equal to 12 months following completion of therapy.


Cohort 1: In addition to above criterion, have had progression or recurrence of urothelial cancer following receipt of an Anti-programmed Cell Death Protein 1 (anti-PD-1)/ Anti-programmed Death Ligand 1 (PD-L1) therapy.

Cohort 2: Were ineligible for platinum-based therapy for first line metastatic disease and have had progression or recurrence of urothelial cancer after a first-line therapy for metastatic disease with anti-PD-1/PD-L1 therapy. Individual may not have received any platinum for treatment of recurrent, metastatic or advanced disease.

Cohort 3: Progression or recurrence of UC following a platinum containing regimen in the metastatic setting, or progression or recurrence of UC within 12 months of completion of platinum-based therapy as neoadjuvant or adjuvant therapy.

Cohorts 4 and 5: Individual has not received any platinum-based chemotherapy in the metastatic or unresectable locally advanced setting. Creatinine clearance of at least 50 mL/min calculated by Cockcroft-Gault formula or another validated tool. For individuals receiving cisplatin at 70 mg/m^2 on Day 1 of every 21-day cycle, a creatinine clearance of least 60 mL/min calculated by Cockcroft -Gault formula or another validated tool is required. Individuals with creatinine clearance between 50 to 59 mL/min are to receive a split dose of cisplatin (35 mg/m^2 Day 1 and Day 8 of every 21-day cycle).

Adequate renal and hepatic function.

Adequate hematologic parameters without transfusional support.

Individuals must have a 3-month life expectancy.

Have measurable disease by Computed Tomography Imaging (CT) or Magnetic Resonance Imaging (MRI) as per RECIST 1.1 criteria.

Females who are pregnant or lactating.

Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

Requires concomitant medication interfering with ABCA1 transporter or UGT1A1

Has an active second malignancy.

Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

Has known active Hepatitis B or Hepatitis C

Has other concurrent medical or psychiatric conditions

Cohorts 3 to 5: Has active autoimmune disease requiring systemic treatment with steroids or other immunosuppressive agent or any condition that in the Investigator's judgment precludes treatment with pembrolizumab, has received a live vaccine within 30 days prior to the first dose of study drug(s), has history or evidence of interstitial lung disease (ILD) or non-infectious pneumonitis, has received anti-PD-1/PD-L1 therapy previously

Cohorts 4 and 5: Refractory to platinum (i.e., relapsed ≤ 12 months after completion of chemotherapy) in the neoadjuvant/adjuvant setting.

Applicable Disease Sites
Bladder

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital