Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Urinary Bladder Neoplasms

Ureteral Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urologic Diseases

Male Urogenital Diseases

Ureteral Diseases

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Docetaxel

Albumin-Bound Paclitaxel

Antibodies

Immunoglobulins

Tubulin Modulators

Antimitotic Agents

Participants received 1.25 milligrams per kilogram (mg/kg) of body weight enfortumab vedotin by intravenous infusion over approximately 30 minutes on days 1, 8 and 15 of every 28-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Participants received either 75 milligrams per square meter (mg/m\^2) docetaxel by IV infusion over approximately 1 hour or 320 mg/m\^2 vinflunine by IV infusion over approximately 20 minutes or 175 mg/m\^2 paclitaxel by IV infusion over approximately 1 hour on day 1 of every 21-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Eligible participants from chemotherapy arm who met the criteria for COE will receive 1.25 mg/kg of body weight enfortumab vedotin by intravenous infusion over approximately 30 minutes on days 1, 8 and 15 of every 28-day cycle until discontinuation criteria is met.

Enfortumab Vedotin

Vinflunine

Medical Director

The purpose of this study was to compare the overall survival (OS) of participants with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin (EV) to the OS of participants treated with chemotherapy.

This study compared progression-free survival on study therapy (PFS1); the overall response rate (ORR) and the disease control rate (DCR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 of participants treated with EV to participants treated with chemotherapy.

In addition, this study evaluated the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy and assessed the safety and tolerability of EV, as well as, the quality of life (QOL) and Patient Reported Outcomes (PRO) parameters.

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

Participants considered an adult according to local regulation at the time of obtaining informed consent participated in the study.

A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)

An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

OS was defined as the time from the date of randomization until the documented date of death from any cause. OS was analyzed using Kaplan-Meier estimates. Participants who were still alive at the time of data cutoff date were to be censored at the last known alive date or at the data cutoff date, whichever was earlier.

PFS: time from date of randomization until date of documented radiological disease progression (PD) per investigator based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: \>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression. A participant who neither progressed nor died was censored at date of last radiological assessment (RA)/ date of randomization if no post-baseline RA was available. Participants who received any further anticancer therapy (ACT) for disease before radiological progression was censored at date of last RA before ACT started and participants who had PD/death after \>=2 missed RAs were censored at last RA prior to 2 or more missed RAs. Kaplan-Meier estimates was used. Median time of follow-up for PFS was based on data cut-off \& is same as median follow-up time for OS.

ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) based on the RECIST v1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. ORR was analysed using exact method based on binomial distribution (Clopper-Pearson). Median time of follow up for ORR was based on data cut-off and is same as median follow-up time for OS.

DCR was defined as the percentage of participants with a CR, PR or a stable disease (SD) based on RECIST v1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug. Progressive disease is defined in PFS1 endpoint. DCR was analysed using exact method based on binomial distribution (Clopper-Pearson). Median time of follow up for DCR was based on data cut-off and is same as median follow-up time for OS.

DOR: time from the date of the first CR/PR (whichever is first recorded) that was subsequently confirmed as assessed by investigator to the date of documented PD or death due to any cause whichever occurred first. If a participant has neither progressed nor died, the participant was censored at the date of last RA or at the date of first CR/PR if no subsequent post-baseline RA was available. Participants who received any further ACT for the disease before radiological progression were censored at the date of the last RA before the ACT started. In addition, participants who had PD/death after \>= 2 missed RAs were censored at the last RA prior to the 2 or more missed RAs. Kaplan-Meier estimates was used. Median time of follow up for DOR was based on data cut-off and is same as median follow-up time for OS. CR/PR and PD were defined in ORR and PFS1 endpoints, respectively.

EORTC QLQ-C30 is a generic questionnaire consisting of 30 items. The instrument yields functional scales (physical, role, emotional, cognitive, social), symptom scales/items (fatigue, Nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea), global health status, and financial impact score. Most items are scored 1 ("not at all") to 4 ("very much") except for the items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The recall period for each question is "during the past week". All raw domain scores are linearly transformed to a 0-100 scale with higher scores on symptoms indicate a worse health state. Higher scores on the global health status and functioning scales indicate better health status/function.

EQ-5D-5L is a health status instrument for self-reported assessment of 5 domains of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each domain is rated by selecting 1 of 5 standardized categorizations ranging from no problem to extreme problem. The final question is a visual analogue scale (VAS) to rank health status from 0 (best health imaginable) to 100 (worst health imaginable).

An AE is any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A TEAE is defined as an AE observed or worsened after starting administration of the study drug.

ECOG performance status was measured on an 6 point scale. 0-Fully active, able to carry on all pre-disease performance without restriction.

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.
2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5. Dead. Number of participants with ECOG PS was reported.

Seagen Inc.

Astellas Pharma Global Development, Inc.

Participants received 1.25 mg/kg of body weight enfortumab vedotin by IV infusion over approximately 30 minutes on days 1, 8 and 15 of every 28-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Participants received either 75 mg/m\^2 docetaxel by IV infusion over approximately 1 hour or 320 mg/m\^2 vinflunine by IV infusion over approximately 20 minutes or 175 mg/m\^2 paclitaxel by IV infusion over approximately 3 hours on day 1 of every 21-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Chemotherapy

Participants received 1.25 mg/kg of body weight enfortumab vedotin by IV infusion over approximately 30 minutes on days 1, 8 and 15 of every 28day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Enfortumab Vedotin 1.25 mg/kg

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

ECOG PS=0

ECOG PS=1

ECOG PS was measured on 6 point scale 0-Fully active, able to carry on all pre-disease performance without restriction

1. Restricted in physically strenuous activity but ambulatory \& able to carry out work of a light or sedentary nature
2. Ambulatory \& capable of all self-care but unable to carry out any work activities.Up \& about more than 50% of waking hours
3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5. Dead Participants were categorized based on ECOG PS 0 or 1

ECOG PS

Liver Metastasis=No

Liver Metastasis=Yes

Participants were categorized based on liver metastasis (yes or no).

Liver Metastasis

Western Europe

United States

Rest of the World

Participants were categorized based on region western europe, US and rest of the world.

Region

The full analysis set (FAS) consisted of all participants who were randomized.

Clinical Trial Disclosure

Overall Survival (OS)

Progression Free Survival on Study Therapy (PFS1) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

Response Evaluable Set (RES): The RES was defined as all participants in the FAS who had measurable disease (per RECIST v1.1) per investigator at baseline.

Overall Response Rate (ORR) as Per RECIST V1.1

Disease Control Rate (DCR) as Per RECIST V1.1

Duration of Response (DOR) as Per RECIST V1.1

Change From Baseline to Week 12 in European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Global Health Status (QL2 Score)

Change From Baseline to Week 12 in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)

The safety analysis set (SAF) consisted of all participants who received any amount of study drug, and was used for safety analyses.

Number of Participants With Treatment Emergent Adverse Events

ECOG PS = 0

ECOG PS = 1

ECOG PS >1

Number of Participants With ECOG Performance Status

Participants received 1.25 milligrams per kilogram (mg/kg) of body weight enfortumab vedotin by intravenous (IV) infusion over approximately 30 minutes on days 1, 8 and 15 of every 28-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Enfortumab Vedotin 1.25mg/kg

Participants received either 75 milligram per square meter (mg/m\^2) docetaxel by IV infusion over approximately 1 hour or 320 mg/m\^2 vinflunine by IV infusion over approximately 20 minutes or 175 mg/m\^2 paclitaxel by IV infusion over approximately 3 hours on day 1 of every 21-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Overall Study

Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

Participants will receive an intravenously (IV) administered dose once weekly for the first 3 weeks of every 4-week cycle (i.e., on days 1, 8, and 15)

enfortumab vedotin (EV)

The primary purpose of this expanded access program is to evaluate safety and tolerability of enfortumab vedotin (EV) in participants in the United States with locally advanced or metastatic urothelial carcinoma (UC) who have exhausted standard of care therapies and are not eligible to participate in an ongoing EV clinical study. This program will also evaluate the efficacy of EV.

This treatment protocol is being conducted while a phase 3 enfortumab vedotin (EV) study is ongoing for participants with previously treated locally advanced or metastatic urothelial carcinoma (UC).

This is an expanded access program to provide EV to participants with locally advanced or metastatic UC who have previously been treated with a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum containing regimen and for whom, in the judgment of the investigator, there is no available standard of care therapy. The participants must not be eligible for an ongoing EV clinical study. Participants who have previously participated in any EV studies or studies that included EV as one of the treatment options are not eligible, even if the participants was not given or assigned EV. To request enrollment, the investigator or designee will submit the candidate participant's relevant medical history and other records in order to support the participant's protocol eligibility.

Safety of EV will be assessed through evaluation of adverse events (AEs), serious adverse events (SAEs), Eastern Cooperative Oncology Group (ECOG) performance status, laboratory measurements, vital signs and physical examinations.

Participants will be provided with study medication until FDA approval and commercial availability of enfortumab vedotin (EV) or termination by the sponsor.

An Expanded Access Treatment Protocol of Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Urothelial Carcinoma

A Multicenter, Open-label, Expanded Access Treatment Protocol of Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Urothelial Carcinoma (EV-901)

Pelvic Neoplasms

Urethral Neoplasms

Urinary Bladder Diseases

Urethral Diseases

Gemcitabine

Pembrolizumab

Carboplatin

Cisplatin

Antimetabolites

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Dose Escalation: Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Enfortumab vedotin on days 1 and 8 plus cisplatin on day 1 every 21 days

Enfortumab vedotin on days 1 and 8 plus carboplatin on day 1 every 21 days

Enfortumab vedotin and gemcitabine on days 1 and 8 every 21 days

Enfortumab vedotin on days 1 and 8 plus cisplatin or carboplatin on day 1 plus pembrolizumab on day 1 every 21 days

Enfortumab vedotin on days 1 and 8 every 21 days

Enfortumab vedotin on days 1 and 8 and every 21 days

Intravenous (IV) infusion on days 1 and 8 every 21 days

pembrolizumab

cisplatin

carboplatin

IV infusion on days 1 and 8 every 21 days

gemcitabine

Changting Meng, MD

Jason Lukas, MD, PhD

This study will test an experimental drug (enfortumab vedotin) alone and with different combinations of anticancer therapies. Pembrolizumab is an immune checkpoint inhibitor (CPI) that is used to treat patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra. Some parts of the study will look at locally advanced or metastatic urothelial cancer (la/mUC), which means the cancer has spread to nearby tissues or to other areas of the body. Other parts of the study will look at muscle-invasive bladder cancer (MIBC), which is cancer at an earlier stage that has spread into the muscle wall of the bladder. This study will look at the side effects of enfortumab vedotin alone and with other anticancer therapies. A side effect is a response to a drug that is not part of the treatment effect. This study will also test if the cancer shrinks with the different treatment combinations.

This study will examine the safety and anticancer activity of enfortumab vedotin (EV) given intravenously as monotherapy and in combination with other anticancer therapies as first line (1L) and second line (2L) treatment for patients with urothelial cancer. The primary goal of the study is to determine the safety, tolerability, and efficacy of enfortumab vedotin alone and in combination with pembrolizumab and/or chemotherapy. The study will be conducted in multiple parts:

Locally advanced or metastatic urothelial cancer:

* Dose escalation
* Expansion

  * Part 1: Cohorts A and Optional B
  * Part 2: Cohorts D, E, and Optional F
  * Part 3: Cohort G.
* Randomized Cohort K

  * EV Monotherapy Arm
  * EV Combination Arm

Muscle invasive bladder cancer:

* Cohort H
* Optional Cohort J
* Cohort L

multi-cohort, open-label, multicenter study, global

A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer

A Study of Enfortumab Vedotin (ASG-22CE) as Monotherapy or in Combination With Other Anticancer Therapies for the Treatment of Urothelial Cancer

Descriptive statistics will be used to summarize results.

The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1

The proportion of patients with absence of viable tumor tissue at the time of radical cystectomy.

Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G).

The proportion of patients with confirmed CR or PR according to RECIST 1.1.

The proportion of patients with confirmed CR or PR according to RECIST 1.1

The proportion of patients with confirmed CR or PR according to iRECIST.

Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1.

Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1

Proportion of patients with CR, PR, or SD according to iRECIST.

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD per RECIST 1.1) or to death due to any cause, whichever comes first.

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per RECIST 1.1 or to death due to any cause, whichever comes first

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per iRECIST or to death due to any cause, whichever comes first.

The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first.

The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first

The time from start of study treatment to first documentation of objective tumor progression (PD per iRECIST) on or following study therapy, or to death due to any cause, whichever comes first.

The time from the start of study treatment to the first occurrence of any of the following events: (1) Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC+PLND. (2) Failure to undergo RC+PLND for participants with residual muscle-invasive disease and/or any radiographic disease present. (3) Gross residual disease left behind at time of RC+PLND. (4) Local or distant recurrence post-RC as assessed by CT or MRI and/or biopsy. (5) Death from any cause.

The time from start of study treatment to date of death due to any cause.

Cmax will be derived from the PK blood samples collected.

Blood samples for ATA analysis will be collected.

Tmax will be derived from the PK blood samples collected.

AUC will be derived from the PK blood samples collected.

The pDS rate is defined as patients with tumors \<pT2 and N0 in examined tissue from radical cystectomy (RC) and pelvic lymph node dissection (PLND).

DFS is defined as the time from RC to the time of first occurrence of a DFS event, including local recurrence of urothelial cancer (UC), urinary tract recurrence of UC, distant metastasis of UC, or death from any cause.

DFS is defined as the time from RC to the time of first occurrence of a DFS event

Delayed is defined as greater than 12 weeks after the last dose of treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)	NCT03474107	Ureteral Cancer Urothelial Canc... Bladder Cancer	Enfortumab Vedo... Docetaxel Vinflunine Paclitaxel	18 Years -	Astellas Pharma Inc
An Expanded Access Treatment Protocol of Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Urothelial Carcinoma	NCT04136808	Locally Advance...	enfortumab vedo...	18 Years -	Astellas Pharma Inc
An Expanded Access Treatment Protocol of Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Urothelial Carcinoma	NCT04136808	Locally Advance...	enfortumab vedo...	18 Years -	Astellas Pharma Inc
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer	NCT03288545	Carcinoma, Tran... Urinary Bladder... Urologic Neopla... Renal Pelvis Ne... Urothelial Canc... Ureteral Neopla... Urethral Neopla...	enfortumab vedo... pembrolizumab cisplatin carboplatin gemcitabine	18 Years -	Astellas Pharma Inc

Spots Global Cancer Trial Database for enfortumab vedotin (ev)