Locally Advanced or Metastatic Unresectable Urothelial Cancer
Conditions
Brief summary
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).
Interventions
DRUGSacituzumab Govitecan-hziy
Administered intravenously
DRUGPaclitaxel
Administered intravenously
DRUGDocetaxel
Administered intravenously
DRUGVinflunine
Administered intravenously
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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. * 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. * 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. * 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: * Creatinine Clearance \< 60 mL/min * Grade ≥ 2 Audiometric Hearing Loss * Grade ≥ 2 Peripheral Neuropathy * New York Heart Association (NYHA) Class III heart failure * ECOG PS ≥ 2 * Anti PD-1/PD-L1 therapy administered as part of maintenance therapy may be counted towards eligibility for the study * 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 * 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 central nervous system 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 standard of care (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 adverse events 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 42 months | OS was defined as time from the date of randomization to the date of death, regardless of cause. Kaplan-Meier (KM) estimates were used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) by Investigator Assessment | Up to 42 months | PFS was defined as the time from the date of randomization to the date of the first objectively documented disease progression (PD), per response evaluation criteria in solid tumors (RECIST) v1.1 criteria as determined by investigator assessment, or death regardless of cause, whichever occurs first. PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). KM estimates were used for analysis. |
| Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) | Up to 42 months | PFS is defined as the time from the date of randomization to the date of the first objectively documented disease progression (PD), per RECIST v1.1 criteria as determined by BICR, or death regardless of cause, whichever occurs first. PD was defined in outcome measure (OM) #2. KM estimates were used for analysis. |
| Objective Response Rate (ORR) by Investigator Assessment | Up to 42 months | ORR was defined as the percentage of participants who achieved a complete response (CR) or partial response (PR) as best overall response (BOR) as assessed by investigator assessment. CR was defined as disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Percentages were rounded off. |
| Objective Response Rate (ORR) by BICR | Up to 42 months | ORR was defined as the percentage of participants who achieved a CR or PR as BOR as assessed by BICR. CR and PR are defined in OM#4. Percentages were rounded off. |
| Clinical Benefit Rate (CBR) by Investigator Assessment | Up to 42 months | CBR was defined as the percentage of participants who achieved a BOR of confirmed CR, PR, or stable disease (SD) for ≥ 6 months, per RECIST v1.1, as assessed by investigator assessment. SD is defined as Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the treatment started; PD was defined in OM#2; BOR, CR and PR are defined in OM#4. Percentages were rounded off. |
| Clinical Benefit Rate (CBR) by BICR | Up to 42 months | CBR was defined as the percentage of participants who achieved a BOR of confirmed CR, PR, or SD for ≥ 6 months, per RECIST v1.1, as assessed by BICR. PD was defined in OM#2; BOR, CR and PR are defined in OM#4; SD was defined in OM#6. Percentages were rounded off. |
| Duration of Objective Tumor Response (DOR) by Investigator Assessment | Up to 42 months | DOR was defined as the time from the date when the criteria is first met for a CR or PR to the first date that PD is documented per RECIST 1.1 as determined by investigator assessment, or date of death, whichever occurs first. KM estimates were used in analysis. PD was defined in OM#2, CR and PR are defined in OM#4. |
| Duration of Objective Tumor Response (DOR) by BICR | Up to 42 months | DOR was defined as the time from the date when the criteria is first met for a CR or PR to the first date that PD is documented per RECIST 1.1 as determined by BICR, or date of death, whichever occurs first. KM estimates were used in analysis. PD was defined in OM#2, CR and PR are defined in OM#4. |
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | From first dose up to 33.6 months | An adverse event (AE) was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. The SAE was defined as any untoward medical occurrence that at any dose which was fatal (results in death) or life-threatening or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant disability/incapacity or is a congenital anomaly/birth defect or an important medical event. TEAEs were defined as an AE that onset in the period from the first dose of study treatment to 30 days after the last dose of study treatment. Percentages were rounded off. |
| Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities | From first dose up to 33.6 months | A laboratory abnormality was defined as an increase of at least 1 toxicity grade from baseline at any time of postbaseline up to and including the date of last study drug dose plus 30 days. Severity grades were defined by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death. Percentages were rounded off. |
| European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core 30 (EORTC-QLQ-C30) Domain Score | Baseline (Day 0) | The EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer participants, it is composed of 30 questions (items) resulting in 5 functional scales, 1 global health status scale, 3 symptom scales, and 6 single items. Domain scores were reported for following scales: Physical Functioning, Global Health Status, Pain, and Fatigue Score. Scoring of the QLQ-C30 was 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). For Symptom scales, a lower score means better quality of life. For Global Health Status and Functional Scales, a higher score signifies better quality of life. |
| Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core 30 (EORTC-QLQ-C30) Domain Score | Cycle 5 Day 1; Cycle length = 21 days | The EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer participants, it is composed of 30 questions (items) resulting in 5 functional scales, 1 global health status scale, 3 symptom scales, and 6 single items. Domain scores were reported for following scales: Physical Functioning, Global Health Status, Pain, and Fatigue Score. Scoring of the QLQ-C30 was 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). For Symptom scales, a lower score means better quality of life. For Global Health Status and Functional Scales, a higher score signifies better quality of life. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, China, Croatia, Czechia, France, Georgia, Germany, Greece, Hong Kong, Ireland, Israel, Italy, Portugal, Puerto Rico, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORGilead Study Director
Gilead Sciences
Participant flow
Recruitment details
Participants were enrolled at study sites in Asia, Australia, Europe, and North America.
Pre-assignment details
886 participants were screened.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 225 Participants |
| Age, Categorical Between 18 and 65 years | 131 Participants |
| Age, Continuous | 67 years STANDARD_DEVIATION 9.6 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 14 Participants |
| Race/Ethnicity, Customized Ethnicity Not Collected | 68 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 279 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 174 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race Not Collected | 151 Participants |
| Race/Ethnicity, Customized Race Other or More Than One Race | 2 Participants |
| Race/Ethnicity, Customized Race White | 194 Participants |
| Region of Enrollment Australia | 11 Participants |
| Region of Enrollment Austria | 5 Participants |
| Region of Enrollment Belgium | 22 Participants |
| Region of Enrollment Bulgaria | 2 Participants |
| Region of Enrollment Canada | 19 Participants |
| Region of Enrollment China | 83 Participants |
| Region of Enrollment Croatia | 1 Participants |
| Region of Enrollment France | 69 Participants |
| Region of Enrollment Georgia | 3 Participants |
| Region of Enrollment Germany | 26 Participants |
| Region of Enrollment Greece | 14 Participants |
| Region of Enrollment Hong Kong | 1 Participants |
| Region of Enrollment Ireland | 1 Participants |
| Region of Enrollment Israel | 3 Participants |
| Region of Enrollment Italy | 47 Participants |
| Region of Enrollment Portugal | 4 Participants |
| Region of Enrollment Singapore | 1 Participants |
| Region of Enrollment South Korea | 27 Participants |
| Region of Enrollment Spain | 88 Participants |
| Region of Enrollment Sweden | 3 Participants |
| Region of Enrollment Switzerland | 0 Participants |
| Region of Enrollment Taiwan | 10 Participants |
| Region of Enrollment Turkey | 0 Participants |
| Region of Enrollment United Kingdom | 28 Participants |
| Region of Enrollment United States | 6 Participants |
| Sex: Female, Male Female | 77 Participants |
| Sex: Female, Male Male | 563 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 305 / 355 | 310 / 356 |
| other Total, other adverse events | 341 / 349 | 303 / 337 |
| serious Total, serious adverse events | 185 / 349 | 110 / 337 |
Outcome results
None listed