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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04223856
Recruitment Status : Recruiting
First Posted : January 10, 2020
Last Update Posted : May 18, 2023
Sponsor:
Collaborators:
Merck Sharp & Dohme LLC
Seagen Inc.
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Description
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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.

Condition or disease Intervention/treatment Phase
Urothelial Cancer Drug: Enfortumab vedotin Drug: Pembrolizumab Drug: Cisplatin Drug: Carboplatin Drug: Gemcitabine Phase 3

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 990 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 30, 2020
Estimated Primary Completion Date : November 30, 2023
Estimated Study Completion Date : September 30, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A
Enfortumab vedotin + pembrolizumab
 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
Active Comparator: Arm B
Gemcitabine + cisplatin or carboplatin
 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
Experimental: Arm C (Not Recruiting)
Enfortumab vedotin + pembrolizumab + Cisplatin or carboplatin
 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


Outcome Measures
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Primary Outcome Measures :
  1. 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) [ 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.

  2. Duration of Overall survival (OS) (Arms A and B only) [ 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.


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. Incidence of adverse events (AEs) [ Time Frame: Up to approximately 5 years ]
    Descriptive statistics will be used to summarize results

  15. Incidence of laboratory abnormalities [ Time Frame: Up to approximately 5 years ]
    Descriptive statistics will be used to summarize results

  16. Treatment discontinuation rate due to AEs [ Time Frame: Up to approximately 5 years ]
    Descriptive statistics will be used to summarize results


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04223856


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

Locations
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Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Merck Sharp & Dohme LLC
Seagen Inc.
Investigators
Layout table for investigator information
Study Director: Sujata Narayanan, MD, MS Seagen Inc.
Study Director: John Lu, MD Seagen Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: 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 )
First Posted: January 10, 2020    Key Record Dates
Last Update Posted: May 18, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
Urothelial Cancer
Enfortumab vedotin
metastatic urothelial cancer
pembrolizumab
locally advanced urothelial cancer
Additional relevant MeSH terms:
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Carboplatin
Gemcitabine
Pembrolizumab
Antineoplastic Agents
Antimetabolites, Antineoplastic
 Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors