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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

This study is currently recruiting participants.
Verified August 2017 by Astellas Pharma Inc ( Agensys, Inc. )
Sponsor:
ClinicalTrials.gov Identifier:
NCT02091999
First Posted: March 19, 2014
Last Update Posted: August 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Seattle Genetics, Inc.
Information provided by (Responsible Party):
Astellas Pharma Inc ( Agensys, Inc. )
  Purpose
The purpose of this study is to evaluate the safety and pharmacokinetics ASG-22CE as well as assess the immunogenicity and antitumor activity in subjects with metastatic urothelial cancer and other malignant solid tumors.

Condition Intervention Phase
Metastatic Urothelial Cancer and Other Malignant Solid Tumors Drug: ASG-22CE Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Further study details as provided by Astellas Pharma Inc ( Agensys, Inc. ):

Primary Outcome Measures:
  • Incidence of adverse events [ Time Frame: up to 36 months ]
  • Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Concentration at the end of infusion (CEOI) [ Time Frame: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months ]
  • Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Maximum observed concentration (Cmax) [ Time Frame: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months ]
  • Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Trough concentration (Ctrough) [ Time Frame: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months ]
  • Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Time to maximum concentration (Tmax) [ Time Frame: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months ]
  • Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Partial area under the serum concentration-time curve after first dose and as appropriate (AUC0-7) [ Time Frame: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months ]
  • Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Terminal or apparent terminal half-life (t1/2) [ Time Frame: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months ]
  • Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Systemic clearance (CL) [ Time Frame: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months ]
  • Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Volume of distribution at steady state (Vss) [ Time Frame: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months ]

Secondary Outcome Measures:
  • Incidence of Anti-Drug Antibody (ADA) [ Time Frame: up to 24 months ]
  • Tumor response [ Time Frame: up to 24 months ]
    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

  • Objective response rate [ Time Frame: up to 24 months ]
    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.

  • Disease control rate [ Time Frame: up to 24 months ]
    Defined as the percentage of subjects who experience a best response of CR, PR or stable disease (SD)

  • Progression Free Survival (PFS) [ Time Frame: 36 months ]
    Time from the date of first infusion to the earliest date of documented disease progression per radiological evidence or death from any cause

  • Overall Survival [ Time Frame: 36 months ]
    Time from the date of first infusion until the date of death from any cause.

  • Duration of Response [ Time Frame: 36 months ]
    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


Estimated Enrollment: 200
Actual Study Start Date: June 4, 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A ASG-22CE Dose Escalation (Dose Levels 1-4)
All subjects will receive a single 30 minute intravenous (IV) infusion of ASG-22CE once weekly for the first 3 weeks of every 4 week cycle (i.e., on Days 1, 8 and 15).
Drug: ASG-22CE
intravenous (IV) infusion
Experimental: Part B ASG-22CE Cisplatin Therapy-Ineligible Expansion
Subjects will receive a single 30 minute IV infusion of ASG-22CE at a dose one level below 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.
Drug: ASG-22CE
intravenous (IV) infusion
Experimental: Part B ASG-22CE Non Small Cell Lung Cancer Expansion
Subjects will receive a single 30 minute IV infusion of ASG-22CE 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.
Drug: ASG-22CE
intravenous (IV) infusion
Experimental: Part B ASG-22CE Ovarian Cancer Expansion
Subjects will receive a single 30 minute IV infusion of ASG-22CE 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.
Drug: ASG-22CE
intravenous (IV) infusion
Experimental: Part C ASG22CE Immune Checkpooint Inhibitor (CPI) Treated Expa
Subjects will receive a single 30 minute IV infusion of ASG-22CE 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 ASG22CE, Investigator decision or consent withdrawal.
Drug: ASG-22CE
intravenous (IV) infusion

Detailed Description:

All subjects will receive a single 30 minute IV infusion of ASG-22CE once weekly for 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 ASG-22CE 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 ASG-22CE, investigator decision or consent withdrawal. Part A will follow a modified Continual Reassessment Method (mCRM).

Part B, will evaluate ASG-22CE in 3 different expansion cohorts: 1) Urothelial cancer subjects who have not received any prior lines of therapy and who are unfit for Cisplatin-based chemotherapy (Cisineligible) defined as a Creatinine Clearance ≥ 15 ml/min and < 60 ml/min, 2) subjects with Metastatic Non Small Cell Lung Cancer (NSCLC) and 3) subjects with Metastatic Ovarian Cancer. Enrollment into Part B will occur after the maximum tolerated dose (MTD) has been assessed in Part A, and the preliminary recommended phase 2 dose (RP2D) has been established. Subjects will continue treatment until disease progression, intolerability of ASG-22CE or consent withdrawal.

Part C will evaluate ASG-22CE at the preliminary 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 ASG-22CE, investigator decision or consent withdrawal.

All subjects will be followed post-treatment every 2 months via disease assessment or telephone contact to obtain information on disease progression and death.

For Part A (Dose Escalation) and Part B (Cis-ineligible), a data review team (DRT) will review cumulative unaudited data on an interim basis to explore additional doses and/or schedules, or the expansion of existing cohorts. Doses intermediate to those predefined in the protocol may be explored with DRT endorsement.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Dose Escalation, Cis-ineligible and CPI-Treated Expansion cohorts: Subjects must have 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: Subjects must have histologic or cytologic diagnosis of NSCLC (squamous or non-squamous or NSCLC-not specified)
  • For Dose Escalation, Cis-ineligible and CPI-Treated Expansion Cohorts, subjects must submit a tumor tissue for Nectin-4 expression; however, the results are not required for enrollment.
  • For the NSCLC and Ovarian Expansion Cohorts: 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 Cis-ineligible Expansion Cohort: Subject must not have received any prior lines of chemotherapy (prior treatment with immunotherapy is allowed).
  • 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)
  • For Dose Escalation, NSCLC, Ovarian, and CPI Treated Expansion Cohorts: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • For the Cis-ineligible expansion Cohort: Subject must have an ECOG performance status of ≤ 2
  • 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 ASG-22CE):

    • 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: serum creatinine ≤ 2.0 mg/dL, or measured 24 hour creatinine clearance of ≥ 45 mL/min. For Cis-ineligible Expansion Cohort: creatinine clearance estimate ≥15 ml/min and <60 ml/min by Cockcroft-Gault equation adjusted for body weight
  • 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 weeks 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
  • History of 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
  • Active angina or Class III or IV Congestive Heart Failure (CHF) (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, congestive heart failure, uncontrolled hypertension, or arrhythmias not controlled by outpatient medication
  • Known Human Immunodeficiency Virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS)
  • Positive Hepatitis B surface antigen test
  • Positive Hepatitis C antibody test
  • 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 ASG-22CE
  • Major surgery within 28 days prior to first dose of study drug
  • History of a primary invasive malignancy not listed in the inclusion criteria, which has not been in remission for at least 3 years. The following are exempt from the 3 year limit:

    • non-melanoma skin cancer;
    • adenocarcinoma of the prostate that has been surgically treated with a post-treatment Prostate Specific Antigen (PSA) that is undetectable;
    • cervical carcinoma in situ on biopsy or squamous intraepithelial lesion on Pap smear; and
    • definitively treated, stage I/II ER positive breast cancer; and
    • epithelial ovarian tumors of low malignant potential
  • History of uncontrolled diabetes mellitus or diabetic neuropathy within 3 months of the first dose of study drug
  • Active infection requiring treatment ≤7 days before dose of study drug
  • 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02091999


Contacts
Contact: Agensys Clinical Research and Development 424-280-5000 Astellas.registration@astellas.com

  Show 28 Study Locations
Sponsors and Collaborators
Agensys, Inc.
Seattle Genetics, Inc.
Investigators
Study Director: Medical Director Agensys, Inc.
  More Information

Responsible Party: Agensys, Inc.
ClinicalTrials.gov Identifier: NCT02091999     History of Changes
Other Study ID Numbers: ASG-22CE-13-2
First Submitted: March 18, 2014
First Posted: March 19, 2014
Last Update Posted: August 30, 2017
Last Verified: August 2017

Keywords provided by Astellas Pharma Inc ( Agensys, Inc. ):
Metastatic Urothelial Cancer
Safety
AGS-22C3E
Nectin 4 protein, humans
Clinical Trial, Phase 1
ASG-22CE
ASG-22ME
Pharmacokinetics of ASG-22CE

Additional relevant MeSH terms:
Neoplasms