A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer
- Conditions
- Urologic NeoplasmsRenal Pelvis NeoplasmsUrinary Bladder NeoplasmsUrothelial CancerUrethral NeoplasmsCarcinoma, Transitional CellUreteral 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
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Enfortumab vedotin Enfortumab vedotin Enfortumab vedotin on days 1, 8 and 15 every 28 days
- Primary Outcome Measures
Name Time Method 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
Name Time Method DCR16 Per Investigator Assessment Up 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 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) 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 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) 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 Assessment 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 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 Assessment 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) 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 Assessment 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) 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 BICR Up 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 Analysis Cohort 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 Analysis 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] 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 Analysis Cohort 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 Analysis Cohort 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