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A Study of Enfortumab Vedotin Plus Pembrolizumab and/or Chemotherapy for Patients With Urothelial Bladder Cancer (EV-103)

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ClinicalTrials.gov Identifier: NCT03288545
Recruitment Status : Recruiting
First Posted : September 20, 2017
Last Update Posted : July 23, 2019
Sponsor:
Collaborator:
Seattle Genetics, Inc.
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:
This study will test an experimental drug (enfortumab vedotin) with different combinations of pembrolizumab and/or chemotherapy. Pembrolizumab is an immune checkpoint inhibitor (CPI) that is used to treat patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra that has spread to nearby tissues or to other areas of the body. This study will have different parts to look at the side effects of (1) enfortumab vedotin with pembrolizumab, (2) enfortumab vedotin with chemotherapy, and (3) enfortumab vedotin with pembrolizumab and chemotherapy. A side effect is a response to a drug that is not part of the treatment effect. This study will also test if the cancer shrinks with the different treatment combinations.

Condition or disease Intervention/treatment Phase
Carcinoma, Transitional Cell Urinary Bladder Neoplasms Urologic Neoplasms Renal Pelvis Neoplasms Urothelial Cancer Ureteral Neoplasms Urethral Neoplasms Drug: enfortumab vedotin Drug: pembrolizumab Drug: cisplatin Drug: carboplatin Drug: gemcitabine Phase 1

Detailed Description:
This study will examine the safety and anticancer activity of enfortumab vedotin given intravenously in combination with pembrolizumab and/or chemotherapy to patients with locally advanced or metastatic urothelial cancer. The primary goal of the study is to determine the safety and tolerability of enfortumab vedotin in combination with pembrolizumab and/or chemotherapy. The study will be conducted in multiple parts: dose escalation (enfortumab vedotin + pembrolizumab) and dose expansion (cohorts of enfortumab vedotin + pembrolizumab and/or chemotherapy).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 159 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: multi-cohort, open-label, multicenter study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Dose-escalation and Dose-expansion Study of Enfortumab Vedotin (ASG-22CE) in Combination With Pembrolizumab and/or Chemotherapy for Treatment of Patients With Locally Advanced or Metastatic Urothelial Cancer
Actual Study Start Date : October 11, 2017
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : September 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Escalation: Enfortumab Vedotin + Pembrolizumab
Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
Drug: enfortumab vedotin
Intravenous (IV) infusion on days 1 and 8 every 21 days
Other Names:
  • ASG-22CE
  • ASG-22ME

Drug: pembrolizumab
IV infusion on day 1 every 21 days
Other Name: Keytruda

Experimental: Cohort A: Enfortumab Vedotin + Pembrolizumab
Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
Drug: enfortumab vedotin
Intravenous (IV) infusion on days 1 and 8 every 21 days
Other Names:
  • ASG-22CE
  • ASG-22ME

Drug: pembrolizumab
IV infusion on day 1 every 21 days
Other Name: Keytruda

Experimental: Optional Cohort B: Enfortumab Vedotin + Pembrolizumab
Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
Drug: enfortumab vedotin
Intravenous (IV) infusion on days 1 and 8 every 21 days
Other Names:
  • ASG-22CE
  • ASG-22ME

Drug: pembrolizumab
IV infusion on day 1 every 21 days
Other Name: Keytruda

Experimental: Cohort D: Enfortumab Vedotin + Cisplatin
Enfortumab vedotin on days 1 and 8 plus cisplatin on day 1 every 21 days
Drug: enfortumab vedotin
Intravenous (IV) infusion on days 1 and 8 every 21 days
Other Names:
  • ASG-22CE
  • ASG-22ME

Drug: cisplatin
IV infusion on day 1 every 21 days

Experimental: Cohort E: Enfortumab Vedotin + Carboplatin
Enfortumab vedotin on days 1 and 8 plus carboplatin on day 1 every 21 days
Drug: enfortumab vedotin
Intravenous (IV) infusion on days 1 and 8 every 21 days
Other Names:
  • ASG-22CE
  • ASG-22ME

Drug: carboplatin
IV infusion on day 1 every 21 days

Experimental: Optional Cohort F: Enfortumab Vedotin + Gemcitabine
Enfortumab vedotin and gemcitabine on days 1 and 8 every 21 days
Drug: enfortumab vedotin
Intravenous (IV) infusion on days 1 and 8 every 21 days
Other Names:
  • ASG-22CE
  • ASG-22ME

Drug: gemcitabine
IV infusion on days 1 and 8 every 21 days

Experimental: Cohort G: Enfortumab Vedotin +Chemotherapy + Pembrolizumab
Enfortumab vedotin on days 1 and 8 plus cisplatin or carboplatin on day 1 plus pembrolizumab on day 1 every 21 days
Drug: enfortumab vedotin
Intravenous (IV) infusion on days 1 and 8 every 21 days
Other Names:
  • ASG-22CE
  • ASG-22ME

Drug: pembrolizumab
IV infusion on day 1 every 21 days
Other Name: Keytruda

Drug: cisplatin
IV infusion on day 1 every 21 days

Drug: carboplatin
IV infusion on day 1 every 21 days




Primary Outcome Measures :
  1. Type, incidence, severity, seriousness, and relatedness of adverse events [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated. ]
    Descriptive statistics will be used to summarize results

  2. Type, incidence, and severity of laboratory abnormalities [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated. ]
    Descriptive statistics will be used to summarize results


Secondary Outcome Measures :
  1. Incidence of dose-limiting toxicity (DLT) [ Time Frame: 21 days ]
    Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G)

  2. Confirmed objective response rate (ORR) by investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) [ Time Frame: Up to 7 years ]
    The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1 (all cohorts)

  3. Confirmed ORR per the modified RECIST 1.1 for immune-based therapeutics (iRECIST) [ Time Frame: Up to 7 years ]
    The proportion of patients with confirmed CR or PR according to iRECIST 1.1 (cohorts using pembrolizumab)

  4. Disease control rate (DCR) by investigator assessment according to RECIST 1.1 [ Time Frame: Up to 7 years ]
    Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1 (all cohorts)

  5. DCR by investigator assessment according to iRECIST 1.1 [ Time Frame: Up to 7 years ]
    Proportion of patients with CR, PR, or SD according to iRECIST 1.1 (cohorts using pembrolizumab)

  6. Duration of response (DOR) by investigator assessment according to RECIST 1.1 [ Time Frame: Up to 7 years ]
    The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD per RECIST 1.1) or to death due to any cause, whichever comes first (all cohorts)

  7. DOR by investigator assessment according to iRECIST 1.1 [ Time Frame: Up to 7 years ]
    The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD per iRECIST 1.1) or to death due to any cause, whichever comes first (cohorts using pembrolizumab)

  8. Progression free survival (PFS) by investigator assessment according to RECIST 1.1 [ Time Frame: Up to 7 years ]
    The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1), or to death due to any cause, whichever comes first

  9. PFS by investigator assessment according to iRECIST 1.1 [ Time Frame: Up to 7 years ]
    The time from start of study treatment to first documentation of objective tumor progression (PD per iRECIST 1.1), or to death due to any cause, whichever comes first

  10. Overall survival (OS) [ Time Frame: Up to 7 years ]
    The time from start of study treatment to date of death due to any cause

  11. Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
    Cmax will be derived from the PK blood samples collected

  12. PK parameter for monomethyl auristatin E (MMAE): Cmax [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
    Cmax will be derived from the PK blood samples collected

  13. PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
    Tmax will be derived from the PK blood samples collected

  14. PK parameter for MMAE: Tmax [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
    Tmax will be derived from the PK blood samples collected

  15. PK parameter for enfortumab vedotin: Area under the concentration-time curve (AUC) [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
    AUC will be derived from the PK blood samples collected

  16. PK parameter for MMAE: AUC [ Time Frame: Through 2 cycles of treatment, up to 42 days ]
    AUC will be derived from the PK blood samples collected

  17. Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin [ Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated. ]
    Blood samples for ATA analysis will be collected



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 locally advanced or metastatic urothelial carcinoma (la/mUC), including squamous differentiation or mixed cell types.
  • An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.
  • Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, and G)
  • Dose-escalation cohorts: Ineligible for first-line cisplatin-based chemotherapy and no prior treatment for la/mUC, or have disease progression following at least 1 platinum-containing treatment.
  • Cohort A: Ineligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  • Cohort B: Must have disease progression during/following treatment with at least 1 platinum-containing regimen for la/mUC or disease recurrence.
  • Cohort D: Eligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  • Cohort E: Ineligible for cisplatin-based chemotherapy, eligible for carboplatin, and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  • Cohort F: Ineligible for platinum-based chemotherapy, or disease progression during/following at least 1 prior treatment for la/mUC. Eligible for gemcitabine.
  • Cohort G: Eligible for platinum-based chemotherapy (either cisplatin or carboplatin) and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.

Exclusion Criteria:

  • Received any prior treatment with a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor, except Cohort F.
  • Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonists, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (except Cohort F).
  • Ongoing sensory or motor neuropathy Grade 2 or higher.
  • Active central nervous system (CNS) metastases.
  • Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).
  • Conditions requiring high doses of steroids or other immunosuppressive medications
  • Prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
  • Uncontrolled diabetes mellitus

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): NCT03288545


Contacts
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Contact: Seattle Genetics Trial Information Support 866-333-7436 clinicaltrials@seagen.com

  Show 26 Study Locations
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Seattle Genetics, Inc.
Investigators
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Study Director: Anne-Sophie Carret, MD Seattle Genetics, Inc.

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Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT03288545     History of Changes
Other Study ID Numbers: SGN22E-002
First Posted: September 20, 2017    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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. ):
ASG-22ME
ASG-22CE
Antibody-drug conjugate
Antineoplastic agents
CPI
Enfortumab vedotin
Locally advanced urothelial cancer
Cisplatin
Drug therapy
Carboplatin
Metastatic urothelial cancer
Nectin-4
Gemcitabine
Checkpoint Inhibitors
Pembrolizumab
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Carcinoma, Transitional Cell
Ureteral Neoplasms
Urethral Neoplasms
Pelvic Neoplasms
Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Ureteral Diseases
Urethral Diseases
Gemcitabine
Cisplatin
Carboplatin
Pembrolizumab
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs