Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302)

• ClinicalTrials.gov Identifier: NCT04223856
• Recruitment Status: Recruiting
• First Posted: January 10, 2020
• Last Update Posted: December 6, 2023
• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Merck Sharp & Dohme LLC; Seagen Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Tracking Information

• First Submitted Date: January 6, 2020
• First Posted Date: January 10, 2020
• Last Update Posted Date: December 6, 2023
• Actual Study Start Date: March 30, 2020
• Actual Primary Completion Date: August 8, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 13, 2023)

• 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) [ Time Frame: Up to approximately 5 years ]
  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.
• Duration of Overall survival (OS) (Arms A and B only, global population) [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from date of randomization to date of death due to any cause.

Original Primary Outcome Measures (submitted: January 8, 2020)

• Duration of progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR) [ Time Frame: Up to approximately 5 years ]
  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.
• Duration of Overall survival (OS) [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from date of randomization to date of death due to any cause.

Current Secondary Outcome Measures (submitted: March 22, 2023)

• Objective response rate (ORR) per RECIST v1.1 by BICR (Arms A and B only) [ Time Frame: Up to approximately 5 years ]
  Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1
• Time to pain progression (TTPP) (Arms A and B only) [ Time Frame: Up to approximately 5 years ]
  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.
• Mean change from baseline in worst pain at Week 26 (Arms A and B only) [ Time Frame: Up to approximately 6 months ]
  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.
• Duration of PFS per RECIST v1.1 by investigator assessment (Arms A and B only) [ Time Frame: Up to approximately 5 years ]
  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
• ORR per RECIST v1.1 by investigator assessment (Arms A and B only) [ Time Frame: Up to approximately 5 years ]
  Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1
• Duration of response (DOR) per RECIST v1.1 by BICR (Arms A and B only) [ Time Frame: Up to approximately 5 years ]
  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
• DOR per RECIST v1.1 by investigator assessment (Arms A and B only) [ Time Frame: Up to approximately 5 years ]
  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
• Disease control rate (DCR) per RECIST v1.1 by BICR (Arms A and B only) [ Time Frame: Up to approximately 5 years ]
  Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1
• DCR per RECIST v1.1 by investigator assessment (Arms A and B only) [ Time Frame: Up to approximately 5 years ]
  Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1
• Change from baseline in patient reported outcome assessment measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) [ Time Frame: Up to approximately 5 years ]
  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.
• Mean scores in patient reported outcome assessment measured by the EQ-5D-5L [ Time Frame: Up to approximately 5 years ]
  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.
• 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) [ Time Frame: Up to approximately 5 years ]
  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.
• Mean scores in patient reported outcome assessment measured by EORTC QLQ-C30 [ Time Frame: Up to approximately 5 years ]
  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.
• Incidence of adverse events (AEs) [ Time Frame: Up to approximately 5 years ]
  Descriptive statistics will be used to summarize results
• Incidence of laboratory abnormalities [ Time Frame: Up to approximately 5 years ]
  Descriptive statistics will be used to summarize results
• Treatment discontinuation rate due to AEs [ Time Frame: Up to approximately 5 years ]
  Descriptive statistics will be used to summarize results

Original Secondary Outcome Measures (submitted: January 8, 2020)

• Duration of PFS per RECIST v1.1 by investigator assessment [ Time Frame: Up to approximately 5 years ]
  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
• Overall response rate (ORR) per RECIST v1.1 by BICR [ Time Frame: Up to approximately 5 years ]
  Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1
• ORR per RECIST v1.1 by investigator assessment [ Time Frame: Up to approximately 5 years ]
  Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1
• Duration of response (DOR) per RECIST v1.1 by BICR [ Time Frame: Up to approximately 5 years ]
  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
• DOR per RECIST v1.1 by investigator assessment [ Time Frame: Up to approximately 5 years ]
  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
• Disease control rate (DCR) per RECIST v1.1 by BICR [ Time Frame: Up to approximately 5 years ]
  Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1
• DCR per RECIST v1.1 by investigator assessment [ Time Frame: Up to approximately 5 years ]
  Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1
• Change from baseline in patient reported outcome assessment measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) questionnaire [ Time Frame: Up to approximately 5 years ]
  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.
• 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) [ Time Frame: Up to approximately 5 years ]
  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.
• Change from baseline in patient reported outcome assessment measured by Brief Pain Inventory - Short Form (BPI-SF) [ Time Frame: Up to approximately 5 years ]
  The Short Form is a single assessment of overall pain where 0 equals no pain and 10 equals extreme pain. Low pain scores are considered a better outcome than a high pain score.
• Incidence of adverse events (AEs) [ Time Frame: Up to approximately 5 years ]
  Descriptive statistics will be used to summarize results
• Incidence of laboratory abnormalities [ Time Frame: Up to approximately 5 years ]
  Descriptive statistics will be used to summarize results
• Treatment discontinuation rate due to AEs [ Time Frame: Up to approximately 5 years ]
  Descriptive statistics will be used to summarize results

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Urothelial Cancer

Intervention

• Drug: Enfortumab vedotin
  Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle
  Other Names:

  • ASG-22CE
  • ASG-22ME
  • PADCEV
• Drug: Pembrolizumab
  IV infusion on Day 1 of every 3-week cycle
  Other Name: Keytruda
• Drug: Cisplatin
  administered as IV infusion on Day 1 of each 3-week cycle
• Drug: Carboplatin
  Dosed according to local guidelines and will be administered as IV infusion on Day 1 of each 3-week cycle
• Drug: Gemcitabine
  IV infusion on Days 1 and 8 of every 3 week cycle

Study Arms

• Experimental: Arm A
  Enfortumab vedotin + pembrolizumab
  Interventions:

  • Drug: Enfortumab vedotin
  • Drug: Pembrolizumab
• Active Comparator: Arm B
  Gemcitabine + cisplatin or carboplatin
  Interventions:

  • Drug: Cisplatin
  • Drug: Carboplatin
  • Drug: Gemcitabine
• Experimental: Arm C (Not Recruiting)
  Enfortumab vedotin + pembrolizumab + Cisplatin or carboplatin
  Interventions:

  • Drug: Enfortumab vedotin
  • Drug: Pembrolizumab
  • Drug: Cisplatin
  • Drug: Carboplatin

• Publications *: Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, Merchan JR, McKay RR, Petrylak DP, Sasse C, Moreno BH, Yu Y, Carret AS, Rosenberg JE. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31. doi: 10.1200/JCO.22.01643. Epub 2022 Aug 30.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 20, 2022): 990
• Original Estimated Enrollment (submitted: January 8, 2020): 1095
• Estimated Study Completion Date: September 30, 2027
• Actual Primary Completion Date: August 8, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Seagen Inc. Trial Information Support; 866-333-7436; clinicaltrials@seagen.com

• Listed Location Countries: Argentina, Australia, Belgium, Canada, China, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Singapore, Spain, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04223856
• Other Study ID Numbers: SGN22E-003; 2019-004542-15 ( EudraCT Number ); MK-3475-A39 ( Other Identifier: Merck ); KEYNOTE KN-A39 ( Other Identifier: Merck ); jRCT2031200284 ( Registry Identifier: Japan Registry of Clinical Trials (jRCT) ); CTR20220974 ( Other Identifier: ChinaDrugTrials.org.cn )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Astellas Pharma Global Development, Inc.
• Original Study Sponsor: Same as current

Collaborators

• Merck Sharp & Dohme LLC
• Seagen Inc.

Investigators

• Study Director: Zejing Wang, MD, PhD; Seagen Inc.
• Study Director: John Lu, MD; Seagen Inc.

• PRS Account: Astellas Pharma Inc
• Verification Date: December 2023