A Study to Evaluate Enfortumab Vedotin (ASG-22CE) in Chinese Participants With Locally Advanced or Metastatic Urothelial Cancer Who Previously Received Platinum-containing Chemotherapy and Programmed Cell Death Protein-1 ( PD 1) / (Programmed Death Ligand-1 (PD-L1) Inhibitor Therapy
Condition: Metastatic Urothelial Cancer
Intervention: Enfortumab vedotin
Intervention description: Intravenous Infusion
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Enfortumab Vedotin; PADCEV; ASG-22CE; Pharmacokinetics; Urothelial cancer

Summary:

      The purpose of this study was to determine the antitumor activity of enfortumab vedotin (EV)
      confirmed by the objective response rate (ORR).

      This study also evaluated the effect of antibody-drug conjugate (ADC), total antibody (TAb)
      and monomethyl auristatin E (MMAE) in Chinese participants with locally advanced or
      metastatic urothelial cancer.

      In addition, the study also evaluated the duration of response (DOR), disease control rate
      (DCR), progression-free survival (PFS), overall survival (OS), and immunogenicity determined
      by the incidence of antitherapeutic antibodies (ATA).

      Safety and tolerability of EV in participants with locally advanced or metastatic urothelial
      cancer was also evaluated.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
             1.

          -  Participant must have histologically or cytologically documented
             urothelial/transitional cell carcinoma of the bladder, renal pelvis, ureter or
             urethra. Other histologies including adenocarcinoma, squamous differentiation or mixed
             are eligible.

          -  Participant has locally advanced or metastatic disease that is not amenable to
             curative intent treatment. Participants must have measurable disease at baseline
             according to Response Evaluation Criteria in Solid Tumors (RECIST) ( Version 1.1).
             Lesions in a prior radiation field must have progressed subsequent to radiotherapy to
             be considered measurable.

          -  Participant must have received prior treatment with PD-1/PD-L1 inhibitor therapy in
             the locally advanced or metastatic urothelial cancer setting. Participants who
             received PD-1/PD-L1 therapy in the neoadjuvant/adjuvant setting and had recurrent or
             progressive disease either during therapy or within 3 months of therapy completion are
             eligible.

          -  Participant who received prior treatment with platinum-containing chemotherapy defined
             as those who received platinum in the neoadjuvant/adjuvant setting and had recurrent
             or progressive disease within 12 months of completion or received treatment with
             platinum in the locally advanced (defined as unresectable with curative intent) or
             metastatic setting.

               -  Platinum based chemotherapy may include combination use with a PD-1 or PD-L1
                  inhibitor.

          -  Participant has the following baseline laboratory data. If a participant has received
             a recent blood transfusion or growth factor, the hematology tests must be obtained ≥7
             days after any growth factor and ≥ 28 days after any blood transfusion.

               -  absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L

               -  platelet count ≥ 100 × 10^9/L

               -  hemoglobin ≥ 9 g/dL

               -  serum total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for
                  participants with Gilbert's disease

               -  creatinine clearance (CrCl) ≥ 30 mL/min as estimated per institutional standards
                  or as measured by 24-hour urine collection (glomerular filtration rate [GFR] can
                  also be used instead of CrCl).

               -  alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN

          -  Female participant is not pregnant and at least one of the following conditions apply:

               -  Not a woman of childbearing potential (WOCBP)

               -  WOCBP who agrees to follow the contraceptive guidance from the time of informed
                  consent through at least 6 months after the last dose of study treatment
                  administration.

          -  Female participant must agree not to breastfeed starting at screening and throughout
             the study period and for at least 6 months after the last dose of study treatment
             administration.

          -  Female participant must not donate ova starting at first dose of study treatment and
             throughout the study period and for 6 months after the last dose of study treatment
             administration.

          -  Male participant with female partner(s) of childbearing potential (including
             breastfeeding partner) must agree to use contraception throughout the treatment period
             and for 6 months after the last dose of study treatment administration.

          -  Male participant must not donate sperm during the treatment period and for 6 months
             after the last dose of study treatment administration.

          -  Male participant with pregnant partner(s) must agree to remain abstinent or use a
             condom for the duration of the pregnancy throughout the study period and for 6 months
             after the last dose of study treatment administration.

          -  Participant agrees not to participate in another interventional study while receiving
             study treatment in the present study.

          -  Participant must have had progression or recurrence of urothelial cancer during or
             following receipt of most recent therapy.

          -  Participant must have an anticipated life expectancy of ≥ 3 months.

        Exclusion Criteria:

          -  Participant has preexisting sensory or motor neuropathy Grade ≥ 2.

          -  Participant has active central nervous system (CNS) metastases. Participants with
             treated CNS metastases are permitted on study if all the following are true:

               -  CNS metastases have been clinically stable for ≥ 6 weeks prior to screening.

               -  If requiring steroid treatment for CNS metastases, the participant is on a stable
                  dose ≤ 20 mg/day of prednisone or equivalent for ≥ 2 weeks.

               -  Baseline imaging scans show no evidence of new or enlarged brain metastasis.

               -  Participant does not have leptomeningeal disease.

          -  Participant has ongoing clinically significant toxicity (Grade 2 or higher with the
             exception of alopecia) associated with prior treatment (including systemic therapy,
             radiotherapy or surgery).

          -  Participant with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or
             panhypopituitarism is excluded. Participant with ongoing immunotherapy-related
             colitis, uveitis, myocarditis or pneumonitis, or participants with other
             immunotherapy-related AEs requiring high doses of steroids (> 20 mg/day of prednisone
             or equivalent), is excluded. Participant with ≤ Grade 2 immunotherapy-related
             hypothyroidism or panhypopituitarism may be enrolled when well-maintained/controlled
             on a stable dose of hormone replacement therapy (if indicated).

          -  Participant has a history of uncontrolled diabetes mellitus within 3 months before the
             first dose of study treatment. Uncontrolled diabetes is defined as hemoglobin A1c
             (HbA1c) ≥ 8 percent or HbA1c between 7 percent and < 8 percent with associated
             diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.

          -  Participant has prior treatment with enfortumab vedotin or other monomethyl auristatin
             E (MMAE)-based antibody-drug conjugate (ADCs).

          -  Participant has a second malignancy diagnosed within 3 years before first dose of
             study drug, or any evidence of residual disease from a previously diagnosed
             malignancy. Participants with non-melanoma skin cancer, localized prostate cancer
             treated with curative intent with no evidence of progression, low-risk or very
             low-risk (per standard guidelines) localized prostate cancer under active
             surveillance/watchful waiting without intent to treat, or carcinoma in situ of any
             type (if complete resection was performed) are allowed.

          -  Participant is currently receiving systemic antimicrobial treatment for viral,
             bacterial or fungal infection at the time of first dose of study treatment. Routine
             antimicrobial prophylaxis is permitted.

          -  Participants with a positive hepatitis B surface antigen and/or anti-hepatitis B core
             antibody and a negative polymerase chain reaction (PCR) assay at baseline should
             receive appropriate antiviral prophylaxis or regular surveillance monitoring as per
             local or institutional guidelines.

          -  Active hepatitis C infection or known human immunodeficiency virus (HIV) infection.
             Participant who have been treated for hepatitis C infection are permitted if they have
             documented sustained virologic response of ≥ 12 weeks.

          -  Participant has documented history of a cerebral vascular event (stroke or transient
             ischemic attack), unstable angina, myocardial infarction or cardiac symptoms
             (including congestive heart failure) consistent with New York Heart Association Class
             III-IV within 6 months prior to the first dose of study drug.

          -  Participant had major surgery within 2 weeks or radiotherapy, chemotherapy, biologics,
             investigational agents, and/or antitumor treatment with immunotherapy that is not
             completed 2 weeks prior to first dose of study drug. Toxicities from these therapies
             must have resolved or adequately stabilized before starting study treatment.

          -  Participant has known hypersensitivity to enfortumab vedotin or to any excipient
             contained in the drug formulation of enfortumab vedotin (including histidine,
             trehalose dihydrate and polysorbate 20) or participant has known hypersensitivity to
             biopharmaceuticals produced in CHO cells.

          -  Participant has known active keratitis or corneal ulcerations. Participant with
             superficial punctate keratitis is allowed if the disorder is being adequately treated.

          -  Participant has any condition which makes the participant unsuitable for study
             participation.

          -  Uncontrolled tumor-related bone pain or impending spinal cord compression. Participant
             requiring pain medication must be on a stable regimen for at least 2 weeks at the time
             of first dose.