Clinical Trials /

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

NCT03288545

Description:

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.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: SGN22E-002
  • NCT ID: NCT03288545

Conditions

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

Interventions

DrugSynonymsArms
enfortumab vedotinASG-22CE, ASG-22MEOptional Cohort B: Enfortumab Vedotin + Pembrolizumab
pembrolizumabKeytrudaOptional Cohort B: Enfortumab Vedotin + Pembrolizumab
cisplatinCohort G: Enfortumab Vedotin + Platinum + Pembrolizumab
carboplatinCohort G: Enfortumab Vedotin + Platinum + Pembrolizumab
gemcitabineOptional Cohort F: Enfortumab Vedotin + 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.

Detailed Description

      This study will examine the safety and anticancer activity of enfortumab vedotin given
      intravenously as monotherapy and in combination with other anticancer therapies to 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: dose escalation
      (enfortumab vedotin + pembrolizumab) and dose expansion (cohorts of enfortumab vedotin +
      pembrolizumab and/or chemotherapy) for locally advanced and metastatic urothelial cancer, and
      enfortumab alone and combination with pembrolizumab in patients with earlier stage of the
      disease (muscle invasive urothelial cancer).
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation: Enfortumab Vedotin + PembrolizumabExperimentalEnfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
  • enfortumab vedotin
  • pembrolizumab
Cohort A: Enfortumab Vedotin + PembrolizumabExperimentalEnfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
  • enfortumab vedotin
  • pembrolizumab
Optional Cohort B: Enfortumab Vedotin + PembrolizumabExperimentalEnfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
  • enfortumab vedotin
  • pembrolizumab
Cohort D: Enfortumab Vedotin + CisplatinExperimentalEnfortumab vedotin on days 1 and 8 plus cisplatin on day 1 every 21 days
  • enfortumab vedotin
  • cisplatin
Cohort E: Enfortumab Vedotin + CarboplatinExperimentalEnfortumab vedotin on days 1 and 8 plus carboplatin on day 1 every 21 days
  • enfortumab vedotin
  • carboplatin
Optional Cohort F: Enfortumab Vedotin + GemcitabineExperimentalEnfortumab vedotin and gemcitabine on days 1 and 8 every 21 days
  • enfortumab vedotin
  • gemcitabine
Cohort G: Enfortumab Vedotin + Platinum + PembrolizumabExperimentalEnfortumab vedotin on days 1 and 8 plus cisplatin or carboplatin on day 1 plus pembrolizumab on day 1 every 21 days
  • enfortumab vedotin
  • pembrolizumab
  • cisplatin
  • carboplatin
Cohort H: Enfortumab vedotinExperimentalEnfortumab vedotin on days 1 and 8 every 21 days
  • enfortumab vedotin
Cohort J: Enfortumab vedotin + PembrolizumabExperimentalEnfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days
  • enfortumab vedotin
  • pembrolizumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

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:
Description:Descriptive statistics will be used to summarize results.

Secondary Outcome Measures

Measure:Incidence of dose-limiting toxicity (DLT)
Time Frame:21 days
Safety Issue:
Description:Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G).
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:
Description:The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1.
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:
Description:The proportion of patients with confirmed CR or PR according to iRECIST 1.1.
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:
Description:Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1.
Measure:DCR by investigator assessment according to iRECIST 1.1 (la/mUC cohorts using pembrolizumab only)
Time Frame:Up to 5 years
Safety Issue:
Description:Proportion of patients with CR, PR, or SD according to iRECIST 1.1.
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:
Description: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.
Measure:DOR by investigator assessment according to iRECIST 1.1 (la/mUC cohorts using pembrolizumab only)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Progression free survival (PFS) by investigator assessment according to RECIST 1.1 (all cohorts)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:PFS by investigator assessment according to iRECIST 1.1 (la/mUC cohorts using pembrolizumab only)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Overall survival (OS) (all cohorts)
Time Frame:Up to 5 years
Safety Issue:
Description:The time from start of study treatment to date of death due to any cause.
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:
Description:Cmax will be derived from the PK blood samples collected.
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:
Description:Cmax will be derived from the PK blood samples collected.
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:
Description:Tmax will be derived from the PK blood samples collected.
Measure:PK parameter for MMAE: Tmax (la/mUC cohorts only)
Time Frame:Through 2 cycles of treatment, up to 42 days
Safety Issue:
Description:Tmax will be derived from the PK blood samples collected.
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:
Description:AUC will be derived from the PK blood samples collected.
Measure:PK parameter for MMAE: AUC (la/mUC cohorts only)
Time Frame:Through 2 cycles of treatment, up to 42 days
Safety Issue:
Description:AUC will be derived from the PK blood samples collected.
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:
Description:Blood samples for ATA analysis will be collected.
Measure:pCR rate per central pathology review (MIUC cohorts only)
Time Frame:Up to approximately 5 months
Safety Issue:
Description:Defined as the proportion of patients with pCR at the time of RC.
Measure:Pathological response (PaR) rate per central pathology review (MIUC cohorts only)
Time Frame:Up to approximately 5 months
Safety Issue:
Description:The PaR rate is defined as the proportion of patients with pathologic downstaging to ≤ pT1pN0 at the time of RC.
Measure:PaR rate per local pathology review (MIUC cohorts only)
Time Frame:Up to approximately 5 months
Safety Issue:
Description:The PaR rate is defined as the proportion of patients with pathologic downstaging to ≤ pT1pN0 at the time of RC.
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:
Description:DFS is defined as the time from RC to the time of first occurrence of a DFS event, including local recurrence of urothelial cancer (UC), urinary tract recurrence of UC, distant metastasis of UC, or death from any cause.
Measure:Type, incidence, severity, seriousness, and relatedness of AEs (MIUC cohorts only)
Time Frame:Up to approximately 5 months
Safety Issue:
Description:Descriptive statistics will be used to summarize results.
Measure:Type, incidence, and severity of laboratory abnormalities (MIUC cohorts only)
Time Frame:Up to approximately 5 months
Safety Issue:
Description:Descriptive statistics will be used to summarize results.
Measure:Percentage of planned surgeries delayed due to treatment-related AEs (MIUC cohorts only)
Time Frame:Up to approximately 5 months
Safety Issue:
Description:Delayed is defined as greater than 12 weeks after the last dose of treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

  • MIUC
  • ASG-22ME
  • ASG-22CE
  • Antibody-drug conjugate
  • Antineoplastic agents
  • CPI
  • Enfortumab vedotin
  • MIBC
  • Locally advanced urothelial cancer
  • Cisplatin
  • Drug therapy
  • Carboplatin
  • Metastatic urothelial cancer
  • Nectin-4
  • Gemcitabine
  • Muscle invasive urothelial cancer
  • Muscle invasive bladder cancer
  • Checkpoint Inhibitors
  • Pembrolizumab

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