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


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) 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.

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
  • 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
  • Time Frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
  • 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)
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: Confirmed ORR per the modified RECIST 1.1 for immune-based therapeutics (iRECIST)
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: Disease control rate (DCR) by investigator assessment according to RECIST 1.1
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: DCR by investigator assessment according to iRECIST 1.1
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: Duration of response (DOR) by investigator assessment according to RECIST 1.1
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: DOR by investigator assessment according to iRECIST 1.1
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: Progression free survival (PFS) by investigator assessment according to RECIST 1.1
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: PFS by investigator assessment according to iRECIST 1.1
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: Overall survival (OS)
  • Time Frame: Up to 7 years
  • Safety Issue:
  • Measure: Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for monomethyl auristatin E (MMAE): Cmax
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for MMAE: Tmax
  • 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)
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: PK parameter for MMAE: AUC
  • Time Frame: Through 2 cycles of treatment, up to 42 days
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:

Estimated Enrollment: 159

Study Start Date: October 11, 2017

Phase: Phase 1

Eligibility:

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

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

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

View trial on ClinicalTrials.gov


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