Study of Sacituzumab Govitecan-hziy (IMMU-132) Versus Treatment of Physician's Choice in Participants With Metastatic or Locally Advanced Unresectable Urothelial Cancer

Study Overview
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Brief Summary
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The primary objective of this study is to assess overall survival (OS) with sacituzumab govitecan-hziy in comparison with treatment of physician's choice (TPC) in participants with metastatic or locally advanced unresectable urothelial cancer (UC).

Official Title
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A Randomized Open-Label Phase III Study of Sacituzumab Govitecan Versus Treatment of Physician's Choice in Subjects With Metastatic or Locally Advanced Unresectable Urothelial Cancer

Conditions
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Locally Advanced or Metastatic Unresectable Urothelial Cancer

Intervention / Treatment
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* Biological: Sacituzumab Govitecan-hziy
* Drug: Paclitaxel
* Drug: Docetaxel
* Drug: Vinflunine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Individuals with histologically documented metastatic or locally advanced unresectable UC defined as Tumor (T) 4b, any node (N) or Any T, N 2-3 Tumors of upper and lower urinary tract are permitted. Mixed histologic types are allowed if urothelial is the predominant histology. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1. Individuals with progression or recurrence following receipt of platinum-containing regimen and anti programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) therapy for metastatic or locally advanced unresectable disease will be enrolled. a. Individuals with recurrence or progression ≤12 months following completion of cisplatin-containing chemotherapy given in the neo-adjuvant/adjuvant setting may utilize that line of therapy to be eligible for the study. The 12-month period is counted from completion of surgical intervention or platinum therapy, respectively. These individuals must receive anti PD-1/PD-L1 therapy in the metastatic or locally advanced unresectable setting to be eligible. b. Individuals who received either carboplatin or anti PD-1/PD-L1 therapy in the neo- adjuvant/adjuvant setting will not be able to count that line of therapy towards eligibility for the study. c. Cisplatin ineligible individuals who meet one of the below criteria and who were treated with carboplatin in the metastatic or locally advanced unresectable settings may count that line of therapy towards eligibility. They must then have received anti PD-1/PD-L1 therapy in metastatic or locally advanced unresectable setting to be eligible for the study. Cisplatin ineligibility is defined as meeting one of the following criteria: 1. Creatinine Clearance < 60 mL/min 2. Grade ≥ 2 Audiometric Hearing Loss 3. Grade ≥ 2 Peripheral Neuropathy 4. New York Heart Association (NYHA) Class III heart failure 5. ECOG PS ≥ 2 d. Anti PD-1/PD-L1 therapy administered as part of maintenance therapy may be counted towards eligibility for the study e. Individuals who have progressed after receiving enfortumab vedotin in prior lines of therapy, and individuals who are either ineligible or unable to tolerate enfortumab vedotin therapy, are eligible to enroll in the study f. Individuals who received only concurrent chemoradiation for bladder preservation without further systemic therapy are not eligible to enroll in the study. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen and no progression was noted prior to the change in platinum. Individuals with previously treated brain metastases may participate in the study provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and stabilization of all neurologic symptoms, have no evidence of new or enlarging brain metastases, and are not using steroids >20 mg of prednisone (or equivalent) daily for brain metastases for at least 7 days prior to first dose of the study drug. Adequate hematologic counts without transfusion or growth factor support within 2 weeks of study drug initiation (hemoglobin ≥ 9 g/dL, absolute neutrophil count (ANC) ≥1,500/mm^3, and platelets ≥100,000/µL). Adequate hepatic function (bilirubin ≤1.5x institutional upper limit of normal (IULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x IULN or ≤ 5 x IULN if known liver metastases and serum albumin >3 g/dL). Docetaxel will only be option in TPC arm for Individuals with a total bilirubin ≤1 x IULN, and an AST and/or ALT ≤1.5x IULN if alkaline phosphatase is also >2.5 x IULN. Creatinine clearance ≥30 mL/min as assessed by the Cockcroft-Gault equation or other validated instruments (e.g. Modification of Diet in Renal Disease (MDRD) equation). Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Females of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study drug. Individuals of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >2 years. Males must agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy. Key Exclusion Criteria: Females who are pregnant or lactating. Have had a prior anti-cancer monoclonal antibody (mAb)/ antibody-drug conjugate (ADC) within 4 weeks prior to Cycle 1 Day 1 (C1D1) or have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to C1D1. Individuals participating in observational studies are eligible. Have received prior chemotherapy for UC with any available SOC therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is approved and is commercially available). Have not recovered (i.e., ≤ Grade 1) from AEs due to previously administered chemotherapeutic agent. Note: Individuals with ≤ Grade 2 neuropathy or any grade of alopecia are an exception to this criterion and will qualify for the study. Note: If Individuals received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study therapy. Have previously received topoisomerase 1 inhibitors. Have an active second malignancy. • Note: Individuals with a history of malignancy that have been completely treated and with no evidence of active cancer for 3 years prior to enrollment, or individuals with surgically cured tumors with low risk of recurrence are allowed to enroll in the study after discussion with the medical monitor. Have active cardiac disease, defined as: Myocardial infarction or unstable angina pectoris within 6 months of C1D1. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation. NYHA Class III or greater congestive heart failure or left ventricular ejection fraction of <40%. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or gastrointestinal (GI) perforation within 6 months of enrollment. Have an active serious infection requiring anti-infective therapy (Contact medical monitor for clarification). Have known history of Human Immunodeficiency Virus (HIV)-1/2 with undetectable viral load and on medications that may interfere with SN-38 metabolism. Have active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). In individuals with a history of HBV or HCV, individuals with a detectable viral load will be excluded. Have 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. Have inability to tolerate or are allergic to any potential TPC agent or sacituzumab govitecan-hziy or unable or unwilling to receive the doses specified in the protocol. Have inability to complete all specified study procedures for any reason. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sacituzumab Govitecan-hziy<br>Participants will receive 10 mg/kg of sacituzumab govitecan-hziy intravenously on Day 1 and Day 8 of 21-day cycles. | Biological: Sacituzumab Govitecan-hziy<br>* Administered intravenously<br>* Other names: GS-0132;|
| Active Comparator: Treatment of Physician's Choice<br>Participants will have the choice of receiving paclitaxel, docetaxel, or vinflunine at standard of care (SOC) doses of 175, 75, and 320 mg/m^2 respectively, every 3 weeks on Day 1 of 21-day cycles. | Drug: Paclitaxel<br>* Administered intravenously<br>* Other names: Taxol®;Drug: Docetaxel<br>* Administered intravenously<br>* Other names: Taxotere®;Drug: Vinflunine<br>* Administered intravenously<br>* Other names: Javlor ®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as time from the date of randomization to the date of death, regardless of cause. | Up to 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) by Investigator Assessment | PFS is defined as the time from the date of randomization to the date of the first objectively documented disease progression, per response evaluation criteria in solid tumors version 1.1 (RECIST v1.1) criteria, as determined by investigator assessment, or death regardless of cause, whichever occurs first. | Up to 3.5 years | 
| Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) | PFS is defined as the time from the date of randomization to the date of the first objectively documented disease progression, per RECIST v1.1 criteria as determined by BICR, or death regardless of cause, whichever occurs first. | Up to 3.5 years | 
| Objective Response Rate (ORR) by Investigator Assessment | ORR is defined as the proportion of participants who achieved a complete response or partial response as best overall response (BOR). BOR is determined per RECIST 1.1 as determined by investigator assessment. | Up to 3.5 years | 
| Objective Response Rate (ORR) by BICR | ORR is defined as the proportion of participants who achieved a complete response or partial response as best overall response (BOR). BOR is determined per RECIST 1.1 as determined by BICR. | Up to 3.5 years | 
| Clinical Benefit Rate (CBR) by Investigator Assessment | CBR is defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease for greater than or equal to 6 months to therapeutic intervention in a clinical study. CBR will be determined per RECIST v1.1 by investigator assessment. | Up to 3.5 years | 
| Clinical Benefit Rate (CBR) by BICR | CBR is defined as the percentage of participants with advanced or metastatic cancer who have achieved complete response, partial response and stable disease for greater than or equal to 6 months to therapeutic intervention in a clinical study. CBR will be determined per RECIST v1.1 by BICR. | Up to 3.5 years | 
| Duration of Objective Tumor Response (DOR) by Investigator Assessment | DOR is defined as the time from the date when the criteria is first met for a complete response or partial response to the first date that disease progression is documented per RECIST 1.1 as determined by investigator assessment, or date of death, whichever occurs first. | Up to 3.5 years | 
| Duration of Objective Tumor Response (DOR) by BICR | DOR is defined as the time from the date when the criteria is first met for a complete response or partial response to the first date that disease progression is documented per RECIST 1.1 as determined by BICR, or date of death, whichever occurs first. | Up to 3.5 years | 
| Percentage of Participants Experiencing any Treatment Emergent Adverse Events |  | Up to 3.5 years | 
| Percentage of Participants Experiencing any Serious Treatment Emergent Adverse Events |  | Up to 3.5 years | 
| Percentage of Participants Experiencing any Clinically Significant Laboratory Abnormalities |  | Up to 3.5 years | 
| European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) Score | The EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer patients, it is composed of 30 questions (items) resulting in 5 functional scales, 1 global health status scale, 3 symptom scales, and 6 single items. Scoring of the QLQ-C30 is performed according to QLQ-C30 Scoring manual. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the participant), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the participant). | Up to 3.5 years | 
| European Quality of Life 5-Dimensions 5 Levels Instrument (EuroQOL EQ-5D-5L) Score | The EQ-5D-5L is a standard measure of health-related quality of life. The tool consists of the EQ-5D-5L descriptive part and the EQ visual analogue scale (VAS). The descriptive part comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each of these 5 dimensions has 5 levels (no problem, slight problems, moderate problems, severe problems, and extreme problems). Results for each of the 5 dimensions are combined into a 5-digit number to describe the participant's health state. The EQ-VAS records the participant's health on a 0-100 mm VAS scale, with 0 indicating the worst health you can imagine and 100 indicating the best health you can imagine. Higher scores of EQ VAS indicate better health. | Up to 3.5 years |