Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer

Study Overview
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Brief Summary
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This study is being done to see how well two drugs (enfortumab vedotin and pembrolizumab) work together to treat patients with urothelial cancer. The study will compare these drugs to other drugs that are usually used to treat this cancer (standard of care). The patients in this study will have cancer that has spread from their urinary system to other parts of their body.

Detailed Description
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Japan PMDA has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan. This study is being conducted to evaluate the combination of enfortumab vedotin + pembrolizumab versus standard of care gemcitabine + platinum-containing chemotherapy, in subjects with previously untreated locally advanced or metastatic urothelial cancer. Enfortumab vedotin may be administered for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs. Pembrolizumab may be administered for a maximum of 35 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first. Cisplatin or carboplatin plus gemcitabine may be administered for a maximum of 6 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first.

Official Title
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An Open-label, Randomized, Controlled Phase 3 Study of Enfortumab Vedotin in Combination With Pembrolizumab Versus Chemotherapy Alone in Previously Untreated Locally Advanced or Metastatic Urothelial Cancer

Conditions
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Urothelial Cancer

Intervention / Treatment
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* Drug: Enfortumab vedotin
* Drug: Pembrolizumab
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented, unresectable locally advanced or metastatic urothelial carcinoma Measurable disease by investigator assessment according to RECIST v1.1 Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: Participants that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted Participants that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2 Adequate hematologic and organ function Exclusion Criteria: Previously received enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADCs) Received prior treatment with a programmed cell death ligand-1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage urothelial cancer (UC), defined as a PD-1 inhibitor or PD-L1 inhibitor Received prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor Received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment Uncontrolled diabetes Estimated life expectancy of less than 12 weeks Active central nervous system (CNS) metastases Ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted. Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection. History of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months prior to randomization Receipt of radiotherapy within 2 weeks prior to randomization Received major surgery (defined as requiring general anesthesia and >24 hour inpatient hospitalization) within 4 weeks prior to randomization Known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin Active keratitis or corneal ulcerations History of autoimmune disease that has required systemic treatment in the past 2 years History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan Prior allogeneic stem cell or solid organ transplant Received a live attenuated vaccine within 30 days prior to randomization

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: Arm A<br>Enfortumab vedotin + pembrolizumab | Drug: Enfortumab vedotin<br>* Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle<br>* Other names: PADCEV;Drug: Pembrolizumab<br>* IV infusion on Day 1 of every 3-week cycle<br>* Other names: Keytruda;|
| Active Comparator: Arm B<br>Gemcitabine + cisplatin or carboplatin | Drug: Cisplatin<br>* administered as IV infusion on Day 1 of each 3-week cycle<br>Drug: Carboplatin<br>* Dosed according to local guidelines and will be administered as IV infusion on Day 1 of each 3-week cycle<br>Drug: Gemcitabine<br>* IV infusion on Days 1 and 8 of every 3 week cycle<br>|
| Experimental: Arm C (Not Recruiting)<br>Enfortumab vedotin + pembrolizumab + Cisplatin or carboplatin | Drug: Enfortumab vedotin<br>* Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle<br>* Other names: PADCEV;Drug: Pembrolizumab<br>* IV infusion on Day 1 of every 3-week cycle<br>* Other names: Keytruda;Drug: Cisplatin<br>* administered as IV infusion on Day 1 of each 3-week cycle<br>Drug: Carboplatin<br>* Dosed according to local guidelines and will be administered as IV infusion on Day 1 of each 3-week cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR) (Arms A and B only, global population) | Defined as the time from randomization to first documentation of disease progression per RECIST v1.1 by BICR, or to death due to any cause, whichever comes first. | Up to approximately 5 years | 
| Duration of Overall survival (OS) (Arms A and B only, global population) | OS is defined as the time from date of randomization to date of death due to any cause. | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) per RECIST v1.1 by BICR (Arms A and B only) | Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1 | Up to approximately 5 years | 
| Time to pain progression (TTPP) (Arms A and B only) | Defined as the time from randomization to the first date a subject experiences a pain progression. Pain progression is defined as either an increase of 2 or more points from baseline on question 3 of the Brief Pain Inventory - Short Form (BPI-SF) or initiation of new opioid pain medication. | Up to approximately 5 years | 
| Mean change from baseline in worst pain at Week 26 (Arms A and B only) | Using the BPI-SF question 3, mean change from baseline in worst pain will be calculated for each postbaseline assessment timepoint for Arm A and Arm B. | Up to approximately 6 months | 
| Duration of PFS per RECIST v1.1 by investigator assessment (Arms A and B only) | Defined as the time from randomization to first documentation of disease progression per RECIST v1.1, or to death due to any cause, whichever comes first | Up to approximately 5 years | 
| ORR per RECIST v1.1 by investigator assessment (Arms A and B only) | Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1 | Up to approximately 5 years | 
| Duration of response (DOR) per RECIST v1.1 by BICR (Arms A and B only) | Defined as the time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause, whichever comes first | Up to approximately 5 years | 
| DOR per RECIST v1.1 by investigator assessment (Arms A and B only) | Defined as the time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause, whichever comes first | Up to approximately 5 years | 
| Disease control rate (DCR) per RECIST v1.1 by BICR (Arms A and B only) | Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1 | Up to approximately 5 years | 
| DCR per RECIST v1.1 by investigator assessment (Arms A and B only) | Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1 | Up to approximately 5 years | 
| Change from baseline in patient reported outcome assessment measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) | The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a generic, preference-based measure of health outcomes. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems). A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions. This questionnaire also records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale. | Up to approximately 5 years | 
| Mean scores in patient reported outcome assessment measured by the EQ-5D-5L | The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a generic, preference-based measure of health outcomes. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems). A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions. This questionnaire also records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale. | Up to approximately 5 years | 
| Change from baseline in patient reported outcome assessment measured by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) | EORTC-QLQ-C30 is a cancer-specific 30-item questionnaire. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Up to approximately 5 years | 
| Mean scores in patient reported outcome assessment measured by EORTC QLQ-C30 | EORTC-QLQ-C30 is a cancer-specific 30-item questionnaire. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Up to approximately 5 years | 
| Incidence of adverse events (AEs) | Descriptive statistics will be used to summarize results | Up to approximately 5 years | 
| Incidence of laboratory abnormalities | Descriptive statistics will be used to summarize results | Up to approximately 5 years | 
| Treatment discontinuation rate due to AEs | Descriptive statistics will be used to summarize results | Up to approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial Cancer, Enfortumab vedotin, metastatic urothelial cancer, pembrolizumab, locally advanced urothelial cancer