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A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer

Phase 2
Completed
Conditions
Urologic Neoplasms
Renal Pelvis Neoplasms
Urinary Bladder Neoplasms
Urothelial Cancer
Urethral Neoplasms
Carcinoma, Transitional Cell
Ureteral Neoplasms
Interventions
Drug: Enfortumab vedotin
Registration Number
NCT03219333
Lead Sponsor
Astellas Pharma Inc
Brief Summary

This is a study that will test how an experimental drug (enfortumab vedotin) affects 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 clinical trial will enroll patients who were previously treated with a kind of anticancer drug called an immune checkpoint inhibitor (CPI). Some CPIs have been approved for the treatment of urothelial cancer.

This study will test if the cancer shrinks with treatment. This study will also look at the side effects of the drug. A side effect is a response to a drug that is not part of the treatment effect.

Patients who sign up for this trial must also fall into one of these categories:

* Patients have already received treatment with platinum-containing chemotherapy

* Patients have never received platinum-containing treatment and are not eligible for treatment with cisplatin.

Detailed Description

Japan Pharmaceuticals and Medical Devices Agency (PMDA) has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan.

This study will examine the safety and anticancer activity of enfortumab vedotin given intravenously to patients with locally advanced or metastatic urothelial cancer who previously received a CPI and either previously received platinum-containing chemotherapy (Cohort 1) or are platinum-naïve and cisplatin-ineligible (Cohort 2). Patients who received platinum in the adjuvant/neoadjuvant setting and did not progress within 12 months of completion will be considered platinum-naïve. Approximately 100 patients are expected to be enrolled in each cohort. The primary goal of the study is to determine the confirmed ORR of enfortumab vedotin.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
219
Inclusion Criteria
  • Histologically documented urothelial carcinoma (squamous differentiation or mixed cell types allowed).
  • Metastatic disease or locally advanced disease that is not resectable.
  • Must have received prior treatment with a CPI in the locally advanced or metastatic urothelial cancer setting. A CPI is defined as a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. Patients who received CPI therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during therapy or within 3 months of therapy completion are eligible.
  • Must either have prior treatment with platinum-containing chemotherapy (Cohort 1) or be platinum-naïve and ineligible for treatment with cisplatin at time of enrollment (Cohort 2).
  • Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy.
  • Tumor tissue samples must be available for submission to the sponsor prior to study treatment.
  • Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1).
  • An Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤1 for Cohort 1 or ≤2 for Cohort 2.
  • Anticipated life expectancy of ≥3 months as assessed by the investigator.
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Exclusion Criteria
  • Ongoing sensory or motor neuropathy Grade ≥2.
  • Active central nervous system (CNS) metastases.
  • Immunotherapy related myocarditis, colitis, uveitis, or pneumonitis.
  • Prior enrollment in an enfortumab vedotin study or prior treatment with other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
  • Uncontrolled tumor-related pain or impending spinal cord compression.
Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Enfortumab vedotinEnfortumab vedotinEnfortumab vedotin on days 1, 8 and 15 every 28 days
Primary Outcome Measures
NameTimeMethod
Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR)Cohort 1: median follow-up time: 10.15 months (range 0.49, 16.46); Cohort 2: median follow up time: 13.4 months (range 0.33 to 29.27)

ORR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). CR is defined as disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Secondary Outcome Measures
NameTimeMethod
DCR16 Per Investigator AssessmentUp to Week 16

Percentage of participants with CR, PR, or stable disease (SD) at Week 16 visit. CR is defined as disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. The appearance of one or more new lesions is also considered progression. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

PK Parameter for Free MMAE: AUC (Plasma)AUC0-7 was assessed (in cycles 1 and 2) based on concentration data from Day 1 to Day 8 (pre dose) and AUC0-14 was assessed based on data from D15 (pre dose) to D29 (pre-dose)

AUC was derived from the PK blood samples collected.

PK Parameter for Enfortumab Vedotin: Area Under Concentration-Time Curve (AUC) (Serum)AUC0-7 was assessed (in cycles 1 and 2) based on concentration data from Day 1 to Day 8 (pre dose) and AUC0-14 was assessed based on data from D15 (pre dose) to D29 (pre-dose)

AUC was derived from the PK blood samples collected.

Duration of Objective Response (DOR) Per BICRCohort 1: median follow-up time: 10.15 months (range 0.49, 16.46); Cohort 2: median follow up time: 13.4 months (range 0.33 to 29.27)

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD) or to death due to any cause, whichever comes first. CR is defined as disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. The appearance of one or more new lesions is also considered progression. DOR was analyzed using Kaplan-Meier methodology.

Progression-Free Survival (PFS) Per BICRCohort 1: median follow-up time: 10.15 months (range 0.49, 16.46); Cohort 2: median follow up time: 13.4 months (range 0.33 to 29.27)

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. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. The appearance of one or more new lesions is also considered progression.

ORR Per Investigator AssessmentCohort 1: median follow-up time: 10.15 months (range 0.49, 16.46); Cohort 2: median follow up time: 13.4 months (range 0.33 to 29.27)

ORR was defined as the percentage of participants with confirmed CR or PR according to RECIST 1.1. CR is defined as disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

DOR Per Investigator AssessmentCohort 1: median follow-up time: 10.15 months (range 0.49, 16.46); Cohort 2: median follow up time: 13.4 months (range 0.33 to 29.27)

CR is defined as disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. The appearance of one or more new lesions is also considered progression.

PFS Per Investigator AssessmentCohort 1: median follow-up time: 10.15 months (range 0.49, 16.46); Cohort 2: median follow up time: 13.4 months (range 0.33 to 29.27)

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. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. The appearance of one or more new lesions is also considered progression.

Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology)The median duration of treatment was 4.60 months for Cohort 1 [range: 0.5, 29.4 months] and 5.98 months for Cohort 2 [range: 0.3, 24.6 months]

A treatment-emergent laboratory abnormality is a value increases or decrease by 1 toxicity grade after the first study dose. Abnormalities were graded based on National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 - Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.

Number of Participants With Treatment-Emergent Laboratory Abnormalities (Serum Chemistry)The median duration of treatment was 4.60 months for Cohort 1 [full range: 0.5, 29.4 months] and 5.98 months for Cohort 2 [full range: 0.3, 24.6 months]

A treatment-emergent laboratory abnormality is a value increases or decrease by 1 toxicity grade after the first study dose. Abnormalities were graded based NCI CTCAE version 4.03 - Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.

Incidence of Antitherapeutic Antibody (ATA)The median duration of treatment was 4.60 months for Cohort 1 [full range: 0.5, 29.4 months] and 5.98 months for Cohort 2 [full range: 0.3, 24.6 months]

Participants who were tested positive for ATA at any time post-baseline were considered to be transiently positive or persistently positive if \>=2 consecutive samples were confirmed as positive.

Disease Control Rate at 16 Weeks (DCR16) Per BICRUp to Week 16

Percentage of participants with CR, PR, or stable disease (SD) at Week 16 visit. CR is defined as disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Overall Survival (OS): Primary AnalysisCohort 1 median follow-up time: 28.4 months [range 0.49, 32.62]; Cohort 2 median follow up time: 13.4 months [range 0.33 to 29.27]

OS is defined as the time from first dose of enfortumab vedotin to death from any cause.

Number of Participants With Adverse Events (AEs): Primary AnalysisThe median duration of treatment was 4.60 months for Cohort 1 [range: 0.5, 29.4 months] and 5.98 months for Cohort 2 [range: 0.3, 24.6 months]

AE=untoward medical occurrence associated with use of study intervention, whether or not considered related. Treatment emergent adverse event (TEAE)=newly occurring/worsening AE after first dose of study treatment, within 30 days after last dose. According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03: Grade(G)3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE. Participants who discontinued treatment due to treatment related TEAEs captured under TEAEs leading to treatment discontinuation. SAE=event at any dose led to death;life-threatening;required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Treatment relatedness was judged by investigator.

Pharmacokinetics (PK) Parameter for Enfortumab Vedotin: Maximum Concentration (Cmax) (Serum)Collected during cycle 1 and 2 of treatment (each cycle=28 days) at Day 1 pre-dose and end of infusion, Day 3, Day 8 pre-dose and end of infusion, Day 15 pre-dose and end of infusion, Day 17, and Day 22

Cmax was derived from the PK blood samples collected. Day 1 data informed by samples collected on Day 1, Day 3, and Day 8. Day 15 data informed by samples collected on Day 15, Day 17, and Day 22.

PK Parameter for Enfortumab Vedotin: Time to Maximum Concentration (Tmax) (Serum)Collected during cycle 1 and 2 of treatment (each cycle=28 days) at Day 1 pre-dose and end of infusion, Day 3, Day 8 pre-dose and end of infusion, Day 15 pre-dose and end of infusion, Day 17, and Day 22

Tmax was derived from the PK blood samples collected. Day 1 data informed by samples collected on Day 1, Day 3, and Day 8. Day 15 data informed by samples collected on Day 15, Day 17, and Day 22.

PK Parameter for Free Monomethyl Auristatin E (MMAE): Cmax (Plasma)Collected during cycle 1 and 2 of treatment (each cycle=28 days) at Day 1 pre-dose and end of infusion, Day 3, Day 8 pre-dose and end of infusion, Day 15 pre-dose and end of infusion, Day 17, and Day 22

Cmax was derived from the PK blood samples collected. Day 1 data informed by samples collected on Day 1, Day 3, and Day 8. Day 15 data informed by samples collected on Day 15, Day 17, and Day 22.

Overall Survival (OS): Final AnalysisCohort 1: median follow-up: 61.0 months (range 59.63, 62.36); Cohort 2: median follow-up time: 45.8 months (range 44.91 to 48.95)

OS is defined as the time from first dose of enfortumab vedotin to death from any cause.

PK Parameter for Free MMAE: Tmax (Plasma)Collected during cycle 1 and 2 of treatment (each cycle=28 days) at Day 1 pre-dose and end of infusion, Day 3, Day 8 pre-dose and end of infusion, Day 15 pre-dose and end of infusion, Day 17, and Day 22

Tmax was derived from the PK blood samples collected. Day 1 data informed by samples collected on Day 1, Day 3, and Day 8. Day 15 data informed by samples collected on Day 15, Day 17, and Day 22.

PK Parameter for TAb: AUC (Serum)AUC0-7 was assessed (in cycles 1 and 2) based on concentration data from Day 1 to Day 8 (pre dose) and AUC0-14 was assessed based on data from D15 (pre dose) to D29 (pre-dose)

AUC was derived from the PK blood samples collected.

PK Parameter for Total Antibody (TAb): Cmax (Serum)Collected during cycle 1 and 2 of treatment (each cycle=28 days) at Day 1 pre-dose and end of infusion, Day 3, Day 8 pre-dose and end of infusion, Day 15 pre-dose and end of infusion, Day 17, and Day 22

Cmax was derived from the PK blood samples collected. Day 1 data informed by samples collected on Day 1, Day 3, and Day 8. Day 15 data informed by samples collected on Day 15, Day 17, and Day 22.

PK Parameter for TAb: Tmax (Serum)Collected during cycle 1 and 2 of treatment (each cycle=28 days) at Day 1 pre-dose and end of infusion, Day 3, Day 8 pre-dose and end of infusion, Day 15 pre-dose and end of infusion, Day 17, and Day 22

Tmax was derived from the PK blood samples collected. Time of maximum concentration corresponds to the end of infusion sample time. Day 1 data informed by samples collected on Day 1, Day 3, and Day 8. Day 15 data informed by samples collected on Day 15, Day 17, and Day 22.

Number of Participants With Adverse Events (AEs): Final AnalysisCohort 1: median treatment duration time: 4.60 months (range 0.5, 43.0); Cohort 2: median treatment duration time: 5.98 months (range 0.3 to 25.8)

AE=untoward medical occurrence associated with use of study intervention, whether or not considered related. Treatment emergent adverse event (TEAE)=newly occurring/worsening AE after first dose of study treatment, within 30 days after last dose. According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03: Grade(G)3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE. Participants who discontinued treatment due to treatment related TEAEs captured under TEAEs leading to treatment discontinuation. SAE=event at any dose led to death;life-threatening;required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Treatment relatedness was judged by investigator.

Trial Locations

Locations (81)

Johns Hopkins Medical Center

🇺🇸

Baltimore, Maryland, United States

James Cancer Hospital / Ohio State University

🇺🇸

Columbus, Ohio, United States

University of Pittsburgh Medical Center (UPMC)/Hillman Cancer Center

🇺🇸

Pittsburgh, Pennsylvania, United States

Massachusetts General Hospital

🇺🇸

Boston, Massachusetts, United States

Comprehensive Cancer Centers of Nevada

🇺🇸

Las Vegas, Nevada, United States

Kaiser Permanente Oakland

🇺🇸

Oakland, California, United States

Keck Medical Center / University of Southern California

🇺🇸

Los Angeles, California, United States

Keck Medical Center / Newport Beach

🇺🇸

Newport Beach, California, United States

Chao Family Comprehensive Cancer Center University of California Irvine

🇺🇸

Orange, California, United States

University of California Irvine - Newport

🇺🇸

Orange, California, United States

Kaiser Permanente Roseville

🇺🇸

Roseville, California, United States

Kaiser Permanente San Jose

🇺🇸

San Jose, California, United States

Kaiser Permanente Santa Clara

🇺🇸

Santa Clara, California, United States

Kaiser Permanente South San Francisco

🇺🇸

South San Francisco, California, United States

Kaiser Permanente Medical Center Northern California

🇺🇸

Vallejo, California, United States

Ocala Oncology Center

🇺🇸

Ocala, Florida, United States

Kaiser Permanente Walnut Creek

🇺🇸

Walnut Creek, California, United States

University of Chicago Medical Center

🇺🇸

Chicago, Illinois, United States

Maryland Oncology Hematology, P.A.

🇺🇸

Rockville, Maryland, United States

Washington University in St Louis

🇺🇸

Saint Louis, Missouri, United States

New York Oncology Hematology, P.C.

🇺🇸

Albany, New York, United States

Columbia University Medical Center

🇺🇸

New York, New York, United States

Mount Sinai Medical Center

🇺🇸

New York, New York, United States

Memorial Sloan Kettering Cancer Center

🇺🇸

New York, New York, United States

James P. Wilmot Cancer Center / University of Rochester Medical Center

🇺🇸

Rochester, New York, United States

New York University (NYU) Cancer Institute

🇺🇸

New York, New York, United States

Cleveland Clinic

🇺🇸

Cleveland, Ohio, United States

Northwest Cancer Specialists, P.C.

🇺🇸

Tigard, Oregon, United States

Texas Oncology - Austin Central

🇺🇸

Austin, Texas, United States

Texas Oncology - Baylor Sammons Cancer Center

🇺🇸

Dallas, Texas, United States

Houston Methodist Cancer Center

🇺🇸

Houston, Texas, United States

Virginia Cancer Specialists, PC

🇺🇸

Fairfax, Virginia, United States

Virginia Oncology Associates

🇺🇸

Norfolk, Virginia, United States

Seattle Cancer Care Alliance / University of Washington

🇺🇸

Seattle, Washington, United States

Site DE49001

🇩🇪

Tübingen, Germany

Site FR33001

🇫🇷

Villejuif-Cedex-France, France

Site DE49004

🇩🇪

Muenster, Germany

Site JP81011

🇯🇵

Fukuoka, Japan

Site JP81005

🇯🇵

Chiba, Japan

Site JP81012

🇯🇵

Fukuoka, Japan

Site JP81003

🇯🇵

Nigata, Japan

Site JP81010

🇯🇵

Tokushima, Japan

Site KR82005

🇰🇷

Daejeon, Korea, Republic of

Site KR82001

🇰🇷

Seoul, Korea, Republic of

Site KR82003

🇰🇷

Seongnam-si, Korea, Republic of

Site KR82004

🇰🇷

Seoul, Korea, Republic of

Site KR82002

🇰🇷

Seoul, Korea, Republic of

Site ES34005

🇪🇸

Barcelona, Spain

Site ES34002

🇪🇸

Barcelona, Spain

Site ES34003

🇪🇸

Santander, Spain

Site ES34004

🇪🇸

Sevilla, Spain

Duke University Medical Center

🇺🇸

Durham, North Carolina, United States

Kaiser Permanente San Francisco

🇺🇸

San Francisco, California, United States

Kaiser Permanente San Leandro

🇺🇸

San Leandro, California, United States

Vanderbilt University Medical Center

🇺🇸

Nashville, Tennessee, United States

Site JP81002

🇯🇵

Morioka, Iwate, Japan

Site JP81006

🇯🇵

Shinjuku-ku, Tokyo, Japan

Arizona Oncology Associates, PC - HOPE

🇺🇸

Tucson, Arizona, United States

Arizona Oncology Associates, PC - HAL

🇺🇸

Goodyear, Arizona, United States

Site JP81001

🇯🇵

Hirosaki, Aomori, Japan

Alaska Urological Institute

🇺🇸

Anchorage, Alaska, United States

Prisma Health

🇺🇸

Greenville, South Carolina, United States

Site JP81008

🇯🇵

Osakasayama, Osaka, Japan

University of Virginia

🇺🇸

Charlottesville, Virginia, United States

Site JP81004

🇯🇵

Tsukuba, Ibaraki, Japan

Site JP81009

🇯🇵

Ube, Yamaguchi, Japan

Site JP81007

🇯🇵

Osaka, Japan

Site NL31001

🇳🇱

Amsterdam, Netherlands

Mayo Clinic Arizona

🇺🇸

Phoenix, Arizona, United States

Karmanos Cancer Institute / Wayne State University

🇺🇸

Detroit, Michigan, United States

Site IT39001

🇮🇹

Milano, Italy

Site IT39003

🇮🇹

Terni, Italy

Augusta University

🇺🇸

Augusta, Georgia, United States

Rocky Mountain Cancer Centers - Aurora

🇺🇸

Aurora, Colorado, United States

H. Lee Moffitt Cancer Center & Research Institute

🇺🇸

Tampa, Florida, United States

University of California Davis

🇺🇸

Sacramento, California, United States

Kaiser Permanente Sacramento

🇺🇸

Sacramento, California, United States

Yale Cancer Center

🇺🇸

New Haven, Connecticut, United States

Norton Cancer Institute, St. Matthews Campus

🇺🇸

Louisville, Kentucky, United States

Dana Farber Cancer Institute

🇺🇸

Boston, Massachusetts, United States

Thomas Jefferson University

🇺🇸

Philadelphia, Pennsylvania, United States

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