A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer

  • STATUS
    Recruiting
  • End date
    Dec 31, 2026
  • participants needed
    457
  • sponsor
    Astellas Pharma Global Development, Inc.
Updated on 24 September 2021
radical cystectomy
cancer
combinations
hearing loss
glomerular filtration rate
experimental drug
metastasis
carboplatin
gemcitabine
pembrolizumab
bladder cancer
immune checkpoint inhibitor
metastatic cancer
invasive bladder cancer
bacillus calmette-guerin
transurethral resection
bladder tumor
intravesical bcg
platinum-based chemotherapy
bcg vaccine
intravesical chemotherapy
metastatic urothelial carcinoma
chemoradiation
enfortumab vedotin

Summary

This study will test an experimental drug (enfortumab vedotin) alone and with different combinations of anticancer therapies. 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. Some parts of the study will look at locally advanced or metastatic urothelial cancer (la/mUC), which means the cancer has spread to nearby tissues or to other areas of the body. Other parts of the study will look at muscle-invasive bladder cancer (MIBC), which is cancer at an earlier stage that has spread into the muscle wall of the bladder. This study will look at the side effects of enfortumab vedotin alone and with other anticancer therapies. 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.

Description

This study will examine the safety and anticancer activity of enfortumab vedotin (EV) given intravenously as monotherapy and in combination with other anticancer therapies as first line (1L) and second line (2L) treatment for patients with urothelial cancer. The primary goal of the study is to determine the safety, tolerability, and efficacy of enfortumab vedotin alone and in combination with pembrolizumab and/or chemotherapy. The study will be conducted in multiple parts:

Locally advanced or metastatic urothelial cancer:

  • Dose escalation
  • Expansion
  • Part 1: Cohorts A and Optional B
  • Part 2: Cohorts D, E, and Optional F
  • Part 3: Cohort G.
  • Randomized Cohort K
  • EV Monotherapy Arm
  • EV Combination Arm

Muscle invasive bladder cancer:

  • Cohort H
  • Optional Cohort J
  • Cohort L

Details
Condition Urethral Cancer, urinary tract neoplasm, Malignant neoplasm of ureter, bladder cancer, bladder disorder, Genitourinary Neoplasms, Transitional cell carcinoma, Urothelial Cancer, Renal Pelvis Neoplasms, Bladder Disorders, Genitourinary Cancer, Bladder Carcinoma, Urologic Cancer, Urothelial Carcinoma, bladder tumor
Treatment cisplatin, carboplatin, Gemcitabine, Pembrolizumab, Atezolizumab, Enfortumab vedotin, enfortumab vedotin (EV)
Clinical Study IdentifierNCT03288545
SponsorAstellas Pharma Global Development, Inc.
Last Modified on24 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K
Histologically documented la/mUC, including squamous differentiation or mixed cell types
An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2: Participants with ECOG performance status of 2 must meet the following additional criteria: hemoglobin 10 g/dL, GFR 50 mL/min, may not have NYHA Class III heart failure
Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, G and K Combination Arm)
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
Cohort K: Ineligible for cisplatin-based chemotherapy due to at least 1 of the following: Glomerular filtration rate (GFR) <60 mL/min and 30 mL/min, ECOG performance status of 2, NCI CTCAE Version 4.03 Grade 2 hearing loss, New York Heart Association (NYHA) Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease. No adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization
Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L
Histologically confirmed MIBC with predominant >50% urothelial histology: Cohorts H and J: Clinical stage cT2-T4aN0M0; Cohort L: Clinical stage cT2-T4aN0M0 or cT1-T4aN1M0: Participants with pT1 disease are eligible only if they have N1 disease on imaging. Mixed cell types are eligible if urothelial cancer is predominant (>50%); Participants with plasmacytoid and/or neuroendocrine tumors are ineligible regardless of component percentage. Urothelial tumors not originating in the bladder (eg, upper tract tumors, urethral tumors) are ineligible
Must be cisplatin-ineligible
Cohort-specific eligibility: Cohort J, H, and L: No prior systemic treatment, chemoradiation, or radiation therapy for MIBC. May have received prior intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy for non-MIBC; Cohort J: Eligible for pembrolizumab
ECOG performance status of 0, 1, or 2
Anticipated life expectancy of 3 months
Tumor samples with an associated pathology report from the diagnostic transurethral resection of a bladder tumor done 90 days prior to the first dose of study treatment must be available prior to enrollment and determined to be sufficient for pathology review and biomarker analysis
Participants must be deemed eligible for RC+PLND

Exclusion Criteria

la/mUC - Cohorts A, B, D, E, F, G, and K
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
MIBC - Cohorts H, J, and L
Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive bladder cancer
Received any prior treatment with a CPI
Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists
For participants in Cohort H, evidence of nodal disease on imaging. For participants in Cohort L, N2 nodal disease on imaging
Ongoing sensory or motor neuropathy Grade 2 or higher
Participant has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC
Conditions requiring high doses of steroids or other immunosuppressive medications
Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer
Participants with a history of another invasive malignancy within 3 years before first dose of study drug
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