Clinical Trials /

A Study of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4

NCT02091999

Description:

The purpose of this study is to evaluate the safety and pharmacokinetics of enfortumab vedotin as well as assess the immunogenicity and antitumor activity in subjects with metastatic urothelial cancer and other malignant solid tumors that express Nectin-4.

Related Conditions:
  • Bladder Carcinoma
  • Fallopian Tube Carcinoma
  • Malignant Ovarian Epithelial Tumor
  • Malignant Solid Tumor
  • Primary Peritoneal Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4
  • Official Title: A Phase 1 Study of the Safety and Pharmacokinetics of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4

Clinical Trial IDs

  • ORG STUDY ID: ASG-22CE-13-2
  • NCT ID: NCT02091999

Conditions

  • Metastatic Urothelial Cancer and Other Malignant Solid Tumors

Interventions

DrugSynonymsArms
enfortumab vedotinASP7465, ASG-22CE, ASG-22MEPart A enfortumab vedotin Dose Escalation (Dose Levels 1-4)

Purpose

The purpose of this study is to evaluate the safety and pharmacokinetics of enfortumab vedotin as well as assess the immunogenicity and antitumor activity in subjects with metastatic urothelial cancer and other malignant solid tumors that express Nectin-4.

Detailed Description

      All subjects will receive a single 30 minute IV infusion of enfortumab vedotin once weekly
      for the first 3 weeks of every 4 weeks (i.e., on Days 1, 8, and 15). A cycle is 4 weeks.

      This is a 3 part study. Part A will evaluate enfortumab vedotin in subjects with
      histologically confirmed malignant solid tumors (excluding sarcomas) that are resistant or
      have recurred. Subjects will continue treatment until disease progression, intolerability of
      enfortumab vedotin, investigator decision or consent withdrawal. Part A will follow a
      modified Continual Reassessment Method (mCRM).

      Part B, will evaluate enfortumab vedotin in 3 different expansion cohorts: 1) Urothelial
      cancer subjects with renal insufficiency defined as a Creatinine Clearance ≥ 15 ml/min and <
      30 ml/min, 2) subjects with Metastatic Non Small Cell Lung Cancer (NSCLC) and 3) subjects
      with Metastatic Ovarian Cancer. With the exception of the renal insufficiency cohort,
      enrollment into Part B will occur at the recommended phase 2 dose (RP2D) established in Part
      A. Enrollment into the renal insufficiency cohort will begin at starting dose and escalated
      using a 3 + 3 dose escalation design. Subjects will continue treatment until disease
      progression, intolerability of enfortumab vedotin or consent withdrawal.

      Part C will evaluate enfortumab vedotin at the RP2D (determined from Part A) in subjects who
      have been previously treated with immune checkpoint inhibitors (CPI) in the metastatic
      setting. Subjects will continue treatment until disease progression, intolerability of
      enfortumab vedotin, investigator decision or consent withdrawal.

      All subjects will be followed post-treatment every 4 months via disease assessment or
      telephone contact to obtain information on disease progression and death.
    

Trial Arms

NameTypeDescriptionInterventions
Part A enfortumab vedotin Dose Escalation (Dose Levels 1-4)ExperimentalAll subjects will receive a single 30 minute intravenous (IV) infusion of enfortumab vedotin once weekly for the first 3 weeks of every 4 week cycle (i.e., on Days 1, 8 and 15).
  • enfortumab vedotin
Part B enfortumab vedotin Renal Insufficiency ExpansionExperimentalSubjects will receive a single 30 minute IV infusion of enfortumab vedotin at a dose level below and escalated up to the preliminary RP2D once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8 and 15) until disease progression, intolerability of the investigational product or consent withdrawal. A cycle is 4 weeks.
  • enfortumab vedotin
Part B enfortumab vedotin NSCLC ExpansionExperimentalSubjects will receive a single 30 minute IV infusion of enfortumab vedotin at the preliminary RP2D once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8 and 15) until disease progression, intolerability of the investigational product or consent withdrawal. A cycle is 4 weeks.
  • enfortumab vedotin
Part B enfortumab vedotin Ovarian Cancer ExpansionExperimentalSubjects will receive a single 30 minute IV infusion of enfortumab vedotin at the preliminary RP2D once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8 and 15) until disease progression, intolerability of the investigational product or consent withdrawal. A cycle is 4 weeks.
  • enfortumab vedotin
Part C enfortumab vedotin CPI Treated ExpansionExperimentalSubjects will receive a single 30 minute IV infusion of enfortumab vedotin at the preliminary RP2D once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8 and 15). A cycle is 4 weeks. Subjects will continue treatment until disease progression, intolerability of enfortumab vedotin, Investigator decision or consent withdrawal.
  • enfortumab vedotin

Eligibility Criteria

        Inclusion Criteria:

          -  Dose Escalation, Renal insufficiency and CPI-Treated Expansion cohorts: Histologically
             confirmed Transitional Cell Carcinoma of the Urothelium (TCCU) (i.e., cancer of the
             bladder, renal pelvis, ureter, or urethra). Subjects with Urothelial Carcinoma with
             squamous differentiation or mixed cell types are eligible.

          -  Ovarian Expansion Cohort: Subjects with recurrent disease or histologically or
             cytologically confirmed Stage III/IV diagnosis of epithelial ovarian cancer, fallopian
             tube cancer, or primary peritoneal carcinoma who have previously progressed while
             receiving or within 6 months of completing a platinum-containing regimen.

          -  NSCLC Expansion Cohort: Histologic or cytologic diagnosis of NSCLC (squamous or
             non-squamous or NSCLC-not specified)

          -  Dose Escalation, Renal insufficiency, NSCLC and CPI-Treated Expansion Cohorts: For
             subjects with urothelial cancer and NSCLC: Subjects must submit a tumor tissue for
             Nectin-4 expression. Enrollment for these subjects is not dependent on the
             immunohistochemistry using the H-Score (IHC H-Score).

          -  Ovarian Expansion Cohort: Subjects must have tumor tissue positive (IHC H-score ≥150)
             for Nectin-4 expression

          -  For Dose Escalation, NSCLC and Ovarian Expansion Cohorts: Subject must have failed at
             least one prior chemotherapy regimen for metastatic disease (urothelial and bladder
             cancer subjects are not required to have failed prior chemotherapy regimen if
             considered unfit for cisplatin-based chemotherapy)

          -  For the CPI-Treated Expansion Cohort: Subject must have received prior treatment with
             a CPI in the metastatic setting.

          -  Subjects must have measurable disease according to RECIST (version 1.1)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Life expectancy of ≥ 3 months

          -  Negative pregnancy test (women of childbearing potential)

          -  Hematologic function, as follows (no red blood cell or platelet transfusions are
             allowed within 14 days of the first dose of enfortumab vedotin):

               -  Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L

               -  Platelet count ≥ 100 x 10^9/L

               -  Hemoglobin ≥ 9 g/dL

          -  Renal function, as follows: Dose Escalation, NSCLC, Ovarian, and CPI Treated Expansion
             Cohorts: creatinine clearance of ≥ 30 mL/min by the Cockcroft-Gault equation or as
             measured by 24 hour urine collection. For the Renal Insufficiency Expansion Cohort:
             creatinine clearance estimate ≥15 ml/min and <30 ml/min by Cockcroft-Gault equation or
             as measured by 24 hour urine collection.

          -  Total bilirubin ≤ 1.5 x ULN (upper limit of normal)

          -  Serum albumin ≥2.5 g/dL

          -  Aspartate aminotransferase (AST) ≤ 1.5 x ULN

          -  Alanine aminotransferase (ALT) ≤ 1.5 x ULN

          -  International normal ratio (INR) < 1.3 or ≤ institutional ULN (or ≤ 3.0 if on
             therapeutic anticoagulation)

          -  Sexually active fertile subjects, and their partners, must agree to use medically
             accepted double-barrier methods of contraception (e.g., barrier methods, including
             male condom, female condom, or diaphragm with spermicidal gel) during the study and at
             least 6 months after termination of study therapy

          -  Competent to comprehend, sign, and date an independent ethics committee/institutional
             review board/research ethics board (IEC/IRB/REB) approved informed consent form

        Exclusion Criteria:

          -  Preexisting sensory neuropathy Grade ≥ 2

          -  Preexisting motor neuropathy Grade ≥ 2

          -  Uncontrolled central nervous system metastases

          -  Use of any investigational drug within 14 days prior to the first dose of study drug

          -  Any anticancer therapy within 14 days prior to the first dose of study drug,
             including: small molecules, immunotherapy, chemotherapy, monoclonal antibody therapy,
             radiotherapy or any other agents to treat cancer (anti-hormonal therapy given as
             adjuvant therapy for early-stage estrogen receptor (ER) positive breast cancer is not
             considered cancer therapy for the purpose of this protocol)

          -  Subjects with immunotherapy related adverse events requiring high doses of steroids (≥
             40 mg/day of prednisone) are not eligible.

          -  Any P-glycoprotein (P-gp) inducers/inhibitors or strong cytochrome P4503A (CYP3A)
             inhibitors within 14 days prior to the first dose of study drug

          -  Thromboembolic events and/or bleeding disorders ≤ 14 days (e.g., deep vein thrombosis
             (DVT) or pulmonary embolism (PE)) prior to the first dose of study drug

          -  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 enfortumab vedotin.

          -  Known Human Immunodeficiency Virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS)

          -  Subjects with a positive Hepatitis B surface antigen and/or antihepatitis B core
             antibody. Subjects with a negative polymerase chain reaction (PCR) assay are permitted
             with appropriate antiviral prophylaxis.

          -  Active Hepatitis C infection. Subjects who have been treated for Hepatitis C infection
             can be included if they have documented sustained virologic response of ≥ 12 weeks.

          -  Decompensated liver disease as evidenced by clinically significant ascites refractory
             to diuretic therapy, hepatic encephalopathy, or coagulopathy

          -  Known sensitivity to any of the ingredients of the investigational product enfortumab
             vedotin (ASG-22CE)

          -  Major surgery within 28 days prior to first dose of study drug

          -  History of another malignancy within 3 years before the first dose of study drug, or
             any evidence of residual disease from a previously diagnosed malignancy. Subjects with
             nonmelanoma skin cancer, localized prostate cancer treated with curative intent with
             no evidence of progression, low-risk or very low risk localized prostate cancer under
             active surveillance/watchful waiting without intent to treat, or carcinoma in situ of
             any time (if complete resection was performed) are allowed.

          -  History of uncontrolled diabetes mellitus or diabetic neuropathy within 3 months of
             the first dose of study drug. Uncontrolled diabetes is defined as hemoglobin A1C
             (HbA1c) ≥ 8% or HbA1c > 7 to < 8% with associated diabetes symptoms (polyuria or
             polydipsia) that are not otherwise explained.

          -  Currently receiving systemic antimicrobial treatment for active infection (viral,
             bacterial, or fungal) at the time of first dose of enfortumab vedotin. Routine
             antimicrobial prophylaxis is permitted.

          -  Condition or situation which may put the subject at significant risk, may confound the
             study results, or may interfere significantly with subject's participation in the
             study

          -  Any medical, psychiatric, addictive or other kind of disorder which compromises the
             ability of the subject to give written informed consent and/or to comply with
             procedures

          -  Has ocular conditions such as:

               -  Active infection or corneal ulcer (e.g. keratitis)

               -  Monocularity

               -  History of corneal transplantation

               -  Contact lens dependent (if using contact lens, must be able to switch to glasses
                  during the entire study duration)

               -  Uncontrolled glaucoma (topical medications allowed)

               -  Uncontrolled or evolving retinopathy, wet macular degeneration, uveitis,
                  papilledema, or optic disc disorder
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:up to 36 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of Anti-Drug Antibody (ADA)
Time Frame:up to 24 months
Safety Issue:
Description:
Measure:Tumor response
Time Frame:up to 24 months
Safety Issue:
Description:Incidence of tumor response defined as either a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) that is confirmed ≥ 28 days later
Measure:Objective response rate
Time Frame:up to 24 months
Safety Issue:
Description:Defined as the percentage of subjects who experience a best response of either CR or PR in that cohort. CR and PR must be confirmed ≥ 28 days later.
Measure:Disease control rate
Time Frame:up to 24 months
Safety Issue:
Description:Defined as the percentage of subjects who experience a best response of CR, PR or stable disease (SD)
Measure:Progression Free Survival (PFS)
Time Frame:36 months
Safety Issue:
Description:Time from the date of first infusion to the earliest date of documented disease progression per radiological evidence or death from any cause
Measure:Overall Survival
Time Frame:36 months
Safety Issue:
Description:Time from the date of first infusion until the date of death from any cause.
Measure:Duration of Response
Time Frame:36 months
Safety Issue:
Description:Time from the date of the first response complete response (CRC) or partial response (PR) to the earliest date of disease progression or death from any cause. DOR is only defined for subjects who have best overall response of CR or PR

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

  • enfortumab vedotin
  • Metastatic Urothelial Cancer
  • Safety
  • AGS-22C3E
  • EV-101
  • Nectin 4 protein, humans
  • Clinical Trial, Phase 1
  • ASG-22CE
  • ASG-22ME
  • Pharmacokinetics of ASG-22CE

Last Updated

February 25, 2021