Clinical trial NCT03474107: A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Ureteral Cancer
Urothelial Cancer
Bladder Cancer
Keywords: antibody drug conjugate
enfortumab vedotin (EV)
ASG-22ME
ASG-22CE
urothelial cancer
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Seagen Inc.
First posted: 2018-03-22
Enrollment: 608
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Subject is legally an adult according to local regulation at the time of signing informed consent.
* Subject has histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible.
* Subject must have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease. Subjects who discontinued CPI treatment due to toxicity are eligible provided that the subjects have evidence of disease progression following discontinuation. The CPI need not be the most recent therapy. Subjects for whom the most recent therapy has been a non-CPI based regimen are eligible if the subjects have progressed/relapsed during or after the subjects most recent therapy. Locally advanced disease must not be amenable to resection with curative intent per the treating physician.
* Subject must have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting. If platinum was administered in the adjuvant/neoadjuvant setting subject must have progressed within 12 months of completion.
* Subject has radiologically documented metastatic or locally advanced disease at baseline.
* An archival tumor tissue sample should be available for submission to central laboratory prior to study treatment. If an archival tumor tissue sample is not available, a fresh tissue sample should be provided. If a fresh tissue sample cannot be provided due to safety concerns, enrollment into the study must be discussed with the medical monitor.
* Subject has ECOG PS of 0 or 1
* The subject has the following baseline laboratory data:

  * absolute neutrophil count (ANC) ≥ 1500/mm3
  * platelet count ≥ 100 × 10\^9/L
  * hemoglobin ≥ 9 g/dL
  * serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease
  * creatinine clearance (CrCl) ≥ 30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection (glomerular filtration rate \[GFR\] can also be used instead of CrCl)
  * alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 3 x ULN for subjects with liver metastases
* Female subject must either:

  * Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy).
  * Or, if of childbearing potential: Agree not to try to become pregnant during the study and for at least 6 months after the final study drug administration, and have a negative urine or serum pregnancy test within 7 days prior to Day 1 (Females with false positive results and documented verification of negative pregnancy status are eligible for participation), and if heterosexually active, agree to consistently use a condom plus 1 form of highly effective birth control per locally accepted standards starting at screening and throughout the study period and for at least 6 months after the final study drug administration.
* Female subject must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
* A sexually active male subject with female partner(s) who is of childbearing potential is eligible if:

  * Agrees to use a male condom starting at screening and continue throughout the study treatment and for at least 6 months after final study drug administration. If the male subject has not had a vasectomy or is not sterile as defined below the subjects female partner(s) is utilizing 1 form of highly effective birth control per locally accepted standards starting at screening and continue throughout study treatment and for at least 6 months after the male subject receives final study drug administration.
* Male subject must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
* Male subject with a pregnant or breastfeeding partner(s) must agree to abstinence or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final study drug administration.
* Subject agrees not to participate in another interventional study while on treatment in present study.

Inclusion Criteria for COE:

* Subject is eligible for the COE if they continue to meet all inclusion criteria from the main protocol in addition to the following when the patient is evaluated for eligibility to participate in the COE portion of the study:
* Institutional review board (IRB)/ independent ethics committee (IEC) approved written COE informed consent and privacy language as per national regulations (e.g., health insurance portability and accountability act \[HIPAA\] Authorization for US sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
* Subject was randomized to Arm B and is either currently on study treatment or has discontinued study treatment due to intolerance, AE or progression of disease and has not started a new systemic anticancer treatment.

Exclusion Criteria:

* Subject has preexisting sensory or motor neuropathy Grade ≥ 2.
* Subject has active central nervous system (CNS) metastases. Subjects with treated CNS metastases are permitted on study if all the following are true:

  * CNS metastases have been clinically stable for at least 6 weeks prior to screening
  * If requiring steroid treatment for CNS metastases, the subject is on a stable dose ≤ 20 mg/day of prednisone or equivalent for at least 2 weeks
  * Baseline scans show no evidence of new or enlarged brain metastasis
  * Subject does not have leptomeningeal disease
* Subject has ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery). Subject with ≤ Grade 2 immunotherapy-related hypothyroidism or panhypopituitarism may be enrolled when well-maintained/controlled on a stable dose of hormone replacement therapy (if indicated). Subjects with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Subjects with ongoing immunotherapy related colitis, uveitis, or pneumonitis or subjects with other immunotherapy related AEs requiring high doses of steroids (\> 20 mg/day of prednisone or equivalent) are excluded.
* Subject has prior treatment with EV or other monomethyl auristatin E (MMAE)-based Antibody drug conjugates (ADCs).
* Subject has received prior chemotherapy for urothelial cancer with all available study therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy).
* Subject has received more than 1 prior chemotherapy regimen for locally advanced or metastatic urothelial cancer, including chemotherapy for adjuvant or neo-adjuvant disease if recurrence occurred within 12 months of completing therapy. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen.
* Subject has 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 (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
* Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or fungal infection at the time of first dose of EV. Routine antimicrobial prophylaxis is permitted.
* Subject has known active Hepatitis B (e.g., hepatitis B surface antigen (HBsAg) reactive) or active hepatitis C (e.g., hepatitis C virus (HCV) Ribonucleic Acid (RNA) \[qualitative\] is detected).
* Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2).
* Subject has 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 study drug.
* Subject has radiotherapy or major surgery within 4 weeks prior to first dose of study drug.
* Subject has had chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug.
* Subject has known hypersensitivity to EV or to any excipient contained in the drug formulation of EV; OR subject has known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells.
* Subject has known hypersensitivity to the following: docetaxel or to any of the other excipients listed in product label, including polysorbate 80, paclitaxel or to any of the other excipients listed in product label, such as macrogolglycerol ricinoleate 35 (Ph.Eur.); and vinflunine or to any of the other excipients listed in product label such as other vinca alkaloids (vinblastine,vincristine, vindesine, vinorelbine).
* Subject has known active keratitis or corneal ulcerations.
* Subject has other underlying medical condition that would impair the ability of the subject to receive or tolerate the planned treatment and follow-up.
* History of uncontrolled diabetes mellitus within 3 months of the first dose of study drug. Uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥ 8% or HbA1c between 7 and \< 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.

Exclusion Criteria for COE

* Subject will be excluded from participation in the COE if they meet any of the exclusion criteria listed in the main protocol or if any of the following apply when the patient is evaluated for eligibility to participate in the COE portion of the study:
* Subject has been diagnosed with a new malignancy while on Arm B in the EV-301 study. Subjects with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
* Subject has already started commercial EV or arrangements have been made for subject to start commercial EV which is reimbursed in their country. Additionally, if EV is commercially available with reimbursement in the potential subject's country, the subject can consider transitioning to the commercial product unless otherwise discussed with sponsor.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Secondary outcomes:
measure: Progression Free Survival on Study Therapy (PFS1) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
measure: Overall Response Rate (ORR) as Per RECIST V1.1
timeFrame: From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
measure: Disease Control Rate (DCR) as Per RECIST V1.1
timeFrame: From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
measure: Duration of Response (DOR) as Per RECIST V1.1
timeFrame: From date of first objective response until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
measure: 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)
timeFrame: Baseline and week 12
measure: Change From Baseline to Week 12 in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)
timeFrame: Baseline and week 12
measure: Number of Participants With Treatment Emergent Adverse Events
timeFrame: From first dose up to 30 days after last dose (Median (range) time on study drug was 4.99 (0.5, 19.4) months in enfortumab vedotin and 3.45 (0.2, 15.0) months in chemotherapy group)
measure: Number of Participants With ECOG Performance Status
timeFrame: End of treatment (EOT) (Median (range) time on study drug was 4.99 (0.5, 19.4) months in enfortumab vedotin and 3.45 (0.2, 15.0) months in chemotherapy group)
Other outcomes:
Locations:
city: Orange
country: United States
facility: UCI Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale-New Haven
state: Connecticut
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Lake Success
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: Sidney Kimmel Center for Prostate and Urologic Cancers
state: New York
city: White Plains
country: United States
facility: White Plains Hospital Center for Cancer Care - Oncology Site
state: New York
city: Toledo
country: United States
facility: Toledo Clinic Cancer Center
state: Ohio
city: Portland
country: United States
facility: Providence Portland Med Center
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Providence
country: United States
facility: Lifespan Rhode Island Hospital
state: Rhode Island
city: Greenville
country: United States
facility: Saint Francis Hospital
state: South Carolina
city: Tyler
country: United States
facility: HOPE Cancer Center of East Texas
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute at Virginia Mason
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Site AR54001
city: Adelaide
country: Australia
facility: Site AU61006
city: Miranda
country: Australia
facility: Site AU61001
city: St. Leonards
country: Australia
facility: Site AU61004
city: Sydney
country: Australia
facility: Site AU61002
city: Linz
country: Austria
facility: Site AT43005
city: Salzburg
country: Austria
facility: Site AT43001
city: Wien
country: Austria
facility: Site AT43004
city: Aalst
country: Belgium
facility: Site BE32011
city: Brussels
country: Belgium
facility: Site BE32007
city: Brussels
country: Belgium
facility: Site BE32013
city: Charleroi
country: Belgium
facility: Site BE32010
city: Gent
country: Belgium
facility: Site BE32001
city: Gent
country: Belgium
facility: Site BE32008
city: Hasselt
country: Belgium
facility: Site BE32005
city: Leuven
country: Belgium
facility: Site BE32003
city: Liège
country: Belgium
facility: Site BE32009
city: Calgary
country: Canada
facility: Site CA15015
city: Edmonton
country: Canada
facility: Site CA15012
city: London
country: Canada
facility: Site CA15014
city: Montreal
country: Canada
facility: Site CA15002
city: Montreal
country: Canada
facility: Site CA15007
city: Oshawa
country: Canada
facility: Site CA15011
city: Quebec
country: Canada
facility: Site CA15004
city: Saskatoon
country: Canada
facility: Site CA15008
city: Sherbrooke
country: Canada
facility: Site CA15001
city: Toronto
country: Canada
facility: Site CA15005
city: Vancouver
country: Canada
facility: Site CA15013
city: Aalborg
country: Denmark
facility: Site DK45003
city: Copenhagen
country: Denmark
facility: Site DK45004
city: Herlev
country: Denmark
facility: Site DK45001
city: Besancon
country: France
facility: Site FR33021
city: Bordeaux
country: France
facility: Site FR33009
city: Bordeaux
country: France
facility: Site FR33018
city: Brest
country: France
facility: Site FR33001
city: Caen
country: France
facility: Site FR33016
city: Lyon
country: France
facility: Site FR33015
city: Marseille
country: France
facility: Site FR33014
city: Nice
country: France
facility: Site FR33003
city: Paris
country: France
facility: Site FR33022
city: Pierre-Bénite
country: France
facility: Site FR33005
city: Saint-Mande
country: France
facility: Site FR33004
city: Strasbourg
country: France
facility: Site FR33002
city: Toulouse
country: France
facility: Site FR33019
city: Villejuif
country: France
facility: Site FR33006
city: Essen
country: Germany
facility: Site DE49011
city: Heidelberg
country: Germany
facility: Site DE49008
city: Münster
country: Germany
facility: Site DE49010
city: Tübingen
country: Germany
facility: Site DE49003
city: Würzburg
country: Germany
facility: Site DE49009
city: Arezzo
country: Italy
facility: Site IT39008
city: Cremona
country: Italy
facility: Site IT39019
city: Milan
country: Italy
facility: Site IT39010
city: Modena
country: Italy
facility: Site IT39025
city: Pisa
country: Italy
facility: Site IT39013
city: Reggio Emilia
country: Italy
facility: Site IT39014
city: Terni
country: Italy
facility: Site IT39004
city: Hirosaki
country: Japan
facility: Site JP81010
state: Aomori
city: Kashiwa
country: Japan
facility: Site JP81014
state: Chiba
city: Sapporo
country: Japan
facility: Site JP81007
state: Hokkaido
city: Sapporo
country: Japan
facility: Site JP81026
state: Hokkaido
city: Tsukuba
country: Japan
facility: Site JP81020
state: Ibaraki
city: Morioka
country: Japan
facility: Site JP81018
state: Iwate
city: Kita-gun
country: Japan
facility: Site JP81009
state: Kagawa
city: Yokohama
country: Japan
facility: Site JP81002
state: Kanagawa
city: Sendai
country: Japan
facility: Site JP81005
state: Miyagi
city: Osakasayama
country: Japan
facility: Site JP81016
state: Osaka
city: Takatsuki
country: Japan
facility: Site JP81024
state: Osaka
city: Bunkyo-ku
country: Japan
facility: Site JP81008
state: Tokyo
city: Koto-ku
country: Japan
facility: Site JP81012
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Site JP81013
state: Tokyo
city: Ube
country: Japan
facility: Site JP81011
state: Yamaguchi
city: Chiba
country: Japan
facility: Site JP81015
city: Fukuoka
country: Japan
facility: Site JP81019
city: Fukuoka
country: Japan
facility: Site JP81023
city: Hiroshima
country: Japan
facility: Site JP81004
city: Kyoto
country: Japan
facility: Site JP81001
city: Niigata
country: Japan
facility: Site JP81017
city: Okayama
country: Japan
facility: Site JP81003
city: Osaka
country: Japan
facility: Site JP81022
city: Tokushima
country: Japan
facility: Site JP81021
city: Toyama
country: Japan
facility: Site JP81006
city: Daejeon
country: Korea, Republic of
facility: Site KR82006
city: Goyang-Si
country: Korea, Republic of
facility: Site KR82007
city: Hwasun-gun
country: Korea, Republic of
facility: Site KR82012
city: Incheon
country: Korea, Republic of
facility: Site KR82002
city: Seongnam-si
country: Korea, Republic of
facility: Site KR82001
city: Seoul
country: Korea, Republic of
facility: Site KR82003
city: Seoul
country: Korea, Republic of
facility: Site KR82004
city: Seoul
country: Korea, Republic of
facility: Site KR82008
city: Seoul
country: Korea, Republic of
facility: Site KR82009
city: Seoul
country: Korea, Republic of
facility: Site KR82010
city: Shin
country: Korea, Republic of
facility: Site KR82005
city: Amsterdam
country: Netherlands
facility: Site NL31002
city: Amsterdam
country: Netherlands
facility: Site NL31003
city: Nijmegen
country: Netherlands
facility: Site NL31009
city: Tilburg
country: Netherlands
facility: Site NL31001
city: Lisboa
country: Portugal
facility: Site PT35105
city: Lisbon
country: Portugal
facility: Site PT35102
city: Porto
country: Portugal
facility: Site PT35106
city: Ivanovo
country: Russian Federation
facility: Site RU70002
city: Obninsk
country: Russian Federation
facility: Site RU70009
city: Omsk
country: Russian Federation
facility: Site RU70005
city: Vologda
country: Russian Federation
facility: Site RU70015
city: Badajoz
country: Spain
facility: Site ES34010
city: Badalona
country: Spain
facility: Site ES34002
city: Barcelona
country: Spain
facility: Site ES34001
city: Barcelona
country: Spain
facility: Site ES34012
city: Barcelona
country: Spain
facility: Site ES34023
city: Córdoba
country: Spain
facility: Site ES34014
city: Madrid
country: Spain
facility: Site ES34003
city: Madrid
country: Spain
facility: Site ES34013
city: Madrid
country: Spain
facility: Site ES34015
city: Madrid
country: Spain
facility: Site ES34017
city: Manresa
country: Spain
facility: Site ES34011
city: Pamplona
country: Spain
facility: Site ES34019
city: Seville
country: Spain
facility: Site ES34005
city: Valencia
country: Spain
facility: Site ES34007
city: Valencia
country: Spain
facility: Site ES34008
city: Bern
country: Switzerland
facility: Site CH41002
city: Chur
country: Switzerland
facility: Site CH41001
city: Kaohsiung
country: Taiwan
facility: Site TW88602
city: Kaohsiung
country: Taiwan
facility: Site TW88605
city: Taichung
country: Taiwan
facility: Site TW88606
city: Tainan
country: Taiwan
facility: Site TW88601
city: Taipei
country: Taiwan
facility: Site TW88604
city: Taoyuan
country: Taiwan
facility: Site TW88607
city: London
country: United Kingdom
facility: Site GB44005
city: London
country: United Kingdom
facility: Site GB44006
city: Sheffield
country: United Kingdom
facility: Site GB44002
city: Southampton
country: United Kingdom
facility: Site GB44011
city: Sutton
country: United Kingdom
facility: Site GB44013
city: Wirral
country: United Kingdom
facility: Site GB44004
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. doi: 10.1056/NEJMoa2035807. Epub 2021 Feb 12.