A Study of Enfortumab Vedotin (ASG-22CE) as Monotherapy or in Combination With Other Anticancer Therapies for the Treatment of Urothelial Cancer


Condition: Carcinoma, Transitional Cell, Urinary Bladder Neoplasms, Urologic Neoplasms, Renal Pelvis Neoplasms, Urothelial Cancer, Ureteral Neoplasms, Urethral Neoplasms

Intervention:

  • Drug: enfortumab vedotin
  • Drug: pembrolizumab
  • Drug: cisplatin
  • Drug: carboplatin
  • Drug: gemcitabine

Purpose: 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 and metastatic urothelial cancer, 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 urothelial cancer, 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.

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03288545

Sponsor: Astellas Pharma Global Development, Inc.

Primary Outcome Measures:

  • Measure: Type, incidence, severity, seriousness, and relatedness of adverse events (locally advanced/metastatic urothelial cancer [la/mUC] cohorts only)
  • Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
  • Safety Issue:
  • Measure: Type, incidence, and severity of laboratory abnormalities (la/mUC cohorts only)
  • Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
  • Safety Issue:
  • Measure: Pathological complete response (pCR) rate per local pathology review (muscle invasive urothelial cancer [MIUC] cohorts only)
  • Time Frame: Up to approximately 5 months
  • Safety Issue:

Secondary Outcome Measures:

  • Measure: Incidence of dose-limiting toxicity (DLT)
  • Time Frame: 21 days
  • Safety Issue:
  • Measure: Confirmed objective response rate (ORR) by investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) (la/mUC cohorts only)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: Confirmed ORR per the modified RECIST 1.1 for immune-based therapeutics (iRECIST) (la/mUC cohorts using pembrolizumab only)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: Disease control rate (DCR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: DCR by investigator assessment according to iRECIST 1.1 (la/mUC cohorts using pembrolizumab only)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: Duration of response (DOR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: DOR by investigator assessment according to iRECIST 1.1 (la/mUC cohorts using pembrolizumab only)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: Progression free survival (PFS) by investigator assessment according to RECIST 1.1 (all cohorts)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: PFS by investigator assessment according to iRECIST 1.1 (la/mUC cohorts using pembrolizumab only)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: Overall survival (OS) (all cohorts)
  • Time Frame: Up to 5 years
  • Safety Issue:
  • Measure: Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) (la/mUC cohorts only)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for monomethyl auristatin E (MMAE): Cmax (la/mUC cohorts only)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax) (la/mUC cohorts only)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for MMAE: Tmax (la/mUC cohorts only)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for enfortumab vedotin: Area under the concentration-time curve (AUC) (la/mUC cohorts only)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for MMAE: AUC (la/mUC cohorts only)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin (la/mUC cohorts only)
  • Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
  • Safety Issue:
  • Measure: pCR rate per central pathology review (MIUC cohorts only)
  • Time Frame: Up to approximately 5 months
  • Safety Issue:
  • Measure: Pathological response (PaR) rate per central pathology review (MIUC cohorts only)
  • Time Frame: Up to approximately 5 months
  • Safety Issue:
  • Measure: PaR rate per local pathology review (MIUC cohorts only)
  • Time Frame: Up to approximately 5 months
  • Safety Issue:
  • Measure: Disease-free survival (DFS) by investigator assessment according to RECIST 1.1 (MIUC cohorts only)
  • Time Frame: Up to approximately 5 months
  • Safety Issue:
  • Measure: Type, incidence, severity, seriousness, and relatedness of AEs (MIUC cohorts only)
  • Time Frame: Up to approximately 5 months
  • Safety Issue:
  • Measure: Type, incidence, and severity of laboratory abnormalities (MIUC cohorts only)
  • Time Frame: Up to approximately 5 months
  • Safety Issue:
  • Measure: Percentage of planned surgeries delayed due to treatment-related AEs (MIUC cohorts only)
  • Time Frame: Up to approximately 5 months
  • Safety Issue:

Estimated Enrollment: 257

Study Start Date: October 11, 2017

Phase: Phase 1

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Locally advanced or metastatic urothelial (la/mUC)
  • Cohorts A, B, D, E, F, and G
  • 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.
  • 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.
  • Muscle Invasive Urothelial Cancer (MIUC)
  • Cohorts H and J
  • Histologically confirmed muscle invasive urothelial cancer of the bladder at clinical stage cT2-T4a.
  • Medically fit (i.e. eligible for surgery) and scheduled for radical cystectomy.
  • ECOG performance status of 0, 1, or 2.
  • Cohort H and J: Ineligible for cisplatin-based chemotherapy and no prior systemic treatment, chemoradiation, or radiation therapy for MIUC. May have received prior intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy for non-muscle invasive urothelial cancer.
  • Cohort J: Eligible for pembrolizumab.

Exclusion Criteria:

  • la/mUC
  • Cohorts A, B, D, E, F, and G
  • 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.
  • MIUC
  • Cohorts H and J
  • Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive urothelial 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.
  • Evidence of measurable nodal or metastatic disease.
  • Ongoing sensory or motor neuropathy Grade 2 or higher.
  • Conditions requiring high doses of steroids or other immunosuppressive medications.
  • Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.
  • History of another malignancy within 3 years before first dose of study drug.

Contact:

  • Seattle Genetics Trial Information Support
  • 866-333-7436

Locations:

  • Alaska Urological Institute
  • Anchorage Alaska 99503 United States
  • Banner MD Anderson Cancer Center
  • Gilbert Arizona 85234 United States
  • Highlands Oncology Group
  • Fayetteville Arkansas 72703 United States
  • UC San Diego / Moores Cancer Center
  • La Jolla California 92093 United States
  • University of California Irvine - Newport
  • Orange California 92868 United States
  • University of California at San Francisco
  • San Francisco California 94134 United States
  • Stanford Cancer Center / Blood & Marrow Transplant Program
  • Stanford California 94305 United States
  • University of Colorado Hospital / University of Colorado
  • Aurora Colorado 80045-0510 United States
  • Yale Cancer Center
  • New Haven Connecticut 06520 United States
  • University of Miami
  • Miami Florida 33136 United States
  • Winship Cancer Institute / Emory University School of Medicine
  • Atlanta Georgia 30322 United States
  • Decatur Memorial Hospital - Illinois
  • Decatur Illinois 62526 United States
  • Cardinal Bernardin Cancer Center / Loyola University Medical Center
  • Maywood Illinois 60153 United States
  • University of Kansas Cancer Center
  • Westwood Kansas 66205 United States
  • Tulane University Hospital and Clinic
  • New Orleans Louisiana 70112 United States
  • University of Michigan Comprehensive Cancer Center
  • Ann Arbor Michigan 48109 United States
  • University of Minnesota
  • Minneapolis Minnesota 55455 United States
  • Hackensack University Medical Center
  • Hackensack New Jersey 07601 United States
  • Roswell Park Cancer Institute
  • Buffalo New York 14263 United States
  • New York University (NYU) Cancer Institute
  • New York New York 10016 United States
  • Weill Cornell Medical College
  • New York New York 10065 United States
  • Memorial Sloan Kettering Cancer Center
  • New York New York 10087-9049 United States
  • UNC Lineberger Comprehensive Cancer Center / University of North Carolina
  • Chapel Hill North Carolina 27599 United States
  • Levine Cancer Institute
  • Charlotte North Carolina 28204 United States
  • Case Western Reserve University / University Hospitals Case Medical Center
  • Cleveland Ohio 44106 United States
  • Medical University of South Carolina/Hollings Cancer Center
  • Charleston South Carolina 29425 United States
  • Medical College of Wisconsin (Milwaukee)
  • Milwaukee Wisconsin 53226 United States

View trial on ClinicalTrials.gov