The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

Clinical Trial Details

Geo Regions

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Genitourinary Cancer

Enfortumab vedotin

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
Phase 3
NCT04223856

Active enrolling

Globe
Locations

United States, 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

Study design

Participant Group/Arm

EXPERIMENTAL: Arm A

Enfortumab vedotin + pembrolizumab

Intervention/Treatment

DRUG: Enfortumab vedotin

Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle

DRUG: Pembrolizumab

IV infusion on Day 1 of every 3-week cycle

Participant Group/Arm

ACTIVE_COMPARATOR: Arm B

Gemcitabine + cisplatin or carboplatin

Intervention/Treatment

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

Participant Group/Arm

EXPERIMENTAL: Arm C (Not Recruiting)

Enfortumab vedotin + pembrolizumab + Cisplatin or carboplatin

Intervention/Treatment

DRUG: Enfortumab vedotin

Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle

DRUG: Pembrolizumab

IV infusion on Day 1 of every 3-week cycle

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

Key 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 thera
  • 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 permitt
  • 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

Key dates

Study start date
  • March 2020
Estimated primary completion date
  • September 2027

Key endpoints

Primary Outcome Measures
Outcome Measure

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)

Measure Description

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.

Time Frame

Up to approximately 5 years

Outcome Measure

Duration of Overall survival (OS) (Arms A and B only, global population)

Measure Description

OS is defined as the time from date of randomization to date of death due to any cause.

Time Frame

Up to approximately 5 years

Secondary Outcome Measures:
Outcome Measure

Objective response rate (ORR) per RECIST v1.1 by BICR (Arms A and B only)

Measure Description

Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1

Time Frame

Up to approximately 5 years

Outcome Measure

Time to pain progression (TTPP) (Arms A and B only)

Measure Description

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.

Time Frame

Up to approximately 5 years

Outcome Measure

Mean change from baseline in worst pain at Week 26 (Arms A and B only)

Measure Description

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.

Time Frame

Up to approximately 6 months

Outcome Measure

Duration of PFS per RECIST v1.1 by investigator assessment (Arms A and B only)

Measure Description

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

Time Frame

Up to approximately 5 years

Outcome Measure

ORR per RECIST v1.1 by investigator assessment (Arms A and B only)

Measure Description

Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1

Time Frame

Up to approximately 5 years

Outcome Measure

Duration of response (DOR) per RECIST v1.1 by BICR (Arms A and B only)

Measure Description

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

Time Frame

Up to approximately 5 years

Outcome Measure

DOR per RECIST v1.1 by investigator assessment (Arms A and B only)

Measure Description

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

Time Frame

Up to approximately 5 years

Outcome Measure

Disease control rate (DCR) per RECIST v1.1 by BICR (Arms A and B only)

Measure Description

Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1

Time Frame

Up to approximately 5 years

Outcome Measure

DCR per RECIST v1.1 by investigator assessment (Arms A and B only)

Measure Description

Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1

Time Frame

Up to approximately 5 years

Outcome Measure

Change from baseline in patient reported outcome assessment measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L)

Measure Description

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.

Time Frame

Up to approximately 5 years

Outcome Measure

Mean scores in patient reported outcome assessment measured by the EQ-5D-5L

Measure Description

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.

Time Frame

Up to approximately 5 years

Outcome Measure

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)

Measure Description

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.

Time Frame

Up to approximately 5 years

Outcome Measure

Mean scores in patient reported outcome assessment measured by EORTC QLQ-C30

Measure Description

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.

Time Frame

Up to approximately 5 years

Outcome Measure

Incidence of adverse events (AEs)

Measure Description

Descriptive statistics will be used to summarize results

Time Frame

Up to approximately 5 years

Outcome Measure

Incidence of laboratory abnormalities

Measure Description

Descriptive statistics will be used to summarize results

Time Frame

Up to approximately 5 years

Outcome Measure

Treatment discontinuation rate due to AEs

Measure Description

Descriptive statistics will be used to summarize results

Time Frame

Up to approximately 5 years

Number of participants

990

Collaborators and investigators

Sponsor: Astellas Pharma Global Development, Inc.

Collaborator: Merck Sharp & Dohme LLC, Seagen Inc.

This information is current as of May 30th 2024.