Clinical trial NCT03288545: A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer
Official title: A Study of Enfortumab Vedotin (ASG-22CE) as Monotherapy or in Combination With Other Anticancer Therapies for the Treatment of Urothelial Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Carcinoma, Transitional Cell
Urinary Bladder Neoplasms
Urologic Neoplasms
Renal Pelvis Neoplasms
Urothelial Cancer
Ureteral Neoplasms
Urethral Neoplasms
Keywords: ASG-22ME
ASG-22CE
Antibody-drug conjugate
Antineoplastic agents
CPI
Enfortumab vedotin
MIBC
Locally advanced urothelial cancer
Cisplatin
Drug therapy
Carboplatin
Metastatic urothelial cancer
Nectin-4
Gemcitabine
Muscle invasive bladder cancer
Checkpoint Inhibitors
Pembrolizumab
PD-1 inhibitor
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
name: Seagen Inc.
First posted: 2017-09-20
Enrollment: 348
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: multi-cohort, open-label, multicenter study, global
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: Inclusion Criteria:

* Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K.

  * Histologically documented la/mUC, including squamous differentiation or mixed cell types.
  * An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2: Participants with ECOG performance status of 2 must meet the following additional criteria: hemoglobin ≥10 g/dL, GFR ≥50 mL/min, may not have NYHA Class III heart failure.
  * Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, G and K Combination Arm).
  * Dose-escalation cohorts: Ineligible for first-line cisplatin-based chemotherapy and no prior treatment for la/mUC, or have disease progression following at least 1 platinum-containing treatment.
  * Cohort A: Ineligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  * Cohort B: Must have disease progression during/following treatment with at least 1 platinum-containing regimen for la/mUC or disease recurrence.
  * Cohort D: Eligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  * Cohort E: Ineligible for cisplatin-based chemotherapy, eligible for carboplatin, and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  * Cohort F: Ineligible for platinum-based chemotherapy, or disease progression during/following at least 1 prior treatment for la/mUC. Eligible for gemcitabine.
  * Cohort G: Eligible for platinum-based chemotherapy (either cisplatin or carboplatin) and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  * Cohort K: Ineligible for cisplatin-based chemotherapy due to at least 1 of the following: Glomerular filtration rate (GFR) \<60 mL/min and ≥30 mL/min, ECOG performance status of 2, NCI CTCAE Version 4.03 Grade ≥2 hearing loss, New York Heart Association (NYHA) Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease. No adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
* Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.

  * Histologically confirmed MIBC with predominant \>50% urothelial histology: Cohorts H and J: Clinical stage cT2-T4aN0M0; Cohort L: Clinical stage cT2-T4aN0M0 or cT1-T4aN1M0: Participants with pT1 disease are eligible only if they have N1 disease on imaging. Mixed cell types are eligible if urothelial cancer is predominant (\>50%); Participants with plasmacytoid and/or neuroendocrine tumors are ineligible regardless of component percentage. Urothelial tumors not originating in the bladder (eg, upper tract tumors, urethral tumors) are ineligible.
  * Must be cisplatin-ineligible.
  * Cohort-specific eligibility: Cohort J, H, and L: No prior systemic treatment, chemoradiation, or radiation therapy for MIBC. May have received prior intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy for non-MIBC; Cohort J: Eligible for pembrolizumab.
  * ECOG performance status of 0, 1, or 2.
  * Anticipated life expectancy of ≥3 months.
  * Tumor samples with an associated pathology report from the diagnostic transurethral resection of a bladder tumor done 90 days prior to the first dose of study treatment must be available prior to enrollment and determined to be sufficient for pathology review and biomarker analysis.
  * Participants must be deemed eligible for RC+PLND.

Exclusion Criteria:

* la/mUC - Cohorts A, B, D, E, F, G, and K

  * Received any prior treatment with a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor, except Cohort F.
  * Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonists, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (except Cohort F).
  * Ongoing sensory or motor neuropathy Grade 2 or higher.
  * Active central nervous system (CNS) metastases.
  * Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).
  * Conditions requiring high doses of steroids or other immunosuppressive medications.
  * Prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
  * Uncontrolled diabetes mellitus.
* MIBC - Cohorts H, J, and L

  * Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive bladder cancer.
  * Received any prior treatment with a CPI.
  * Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists.
  * For participants in Cohort H, evidence of nodal disease on imaging. For participants in Cohort L, ≥N2 nodal disease on imaging.
  * Participant has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.
  * Ongoing sensory or motor neuropathy Grade 2 or higher.
  * Conditions requiring high doses of steroids or other immunosuppressive medications.
  * Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.
  * Participants with a history of another invasive malignancy within 3 years before first dose of study drug.

Primary outcomes:
measure: Type, incidence, severity, seriousness, and relatedness of adverse events (Dose escalation and Expansion Parts 1 to 3 cohorts only)
timeFrame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
measure: Type, incidence, and severity of laboratory abnormalities (Dose escalation and Expansion Parts 1 to 3 cohorts only)
timeFrame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
measure: Confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR) (Cohort K only)
timeFrame: Up to 3 years
measure: Pathological complete response (pCR) rate per central pathology review (MIBC cohorts only)
timeFrame: Up to approximately 5 months
Secondary outcomes:
measure: Incidence of dose-limiting toxicity (DLT)
timeFrame: 21 days
measure: Confirmed ORR by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)
timeFrame: Up to 3 years
measure: Confirmed ORR by BICR according to RECIST 1.1 (Dose escalation and Cohort A only)
timeFrame: Up to 3 years
measure: Confirmed ORR by investigator assessment per the modified RECIST 1.1 for immune-based therapeutics (iRECIST) (Dose escalation and Part 1-3 cohorts with pembrolizumab only)
timeFrame: Up to 3 years
measure: Disease control rate (DCR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)
timeFrame: Up to 5 years
measure: DCR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)
timeFrame: Up to 3 years
measure: DCR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts using pembrolizumab only)
timeFrame: Up to 3 years
measure: Duration of response (DOR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)
timeFrame: Up to 5 years
measure: DOR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)
timeFrame: Up to 5 years
measure: DOR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only)
timeFrame: Up to 5 years
measure: Progression free survival on study therapy (PFS) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)
timeFrame: Up to 5 years
measure: PFS by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)
timeFrame: Up to 5 years
measure: PFS by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only)
timeFrame: Up to 5 years
measure: Event-free (EFS) on study therapy by BICR (Cohort L only)
timeFrame: Up to 3 years
measure: Event-free (EFS) on study therapy by investigator assessment (MIBC cohorts only)
timeFrame: Up to 3 years
measure: Overall survival (OS) (all cohorts)
timeFrame: Up to 5 years
measure: Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: PK parameter for monomethyl auristatin E (MMAE): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: PK parameter for total antibody (Tab): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.
measure: PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: PK parameter for MMAE: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: PK parameter for Tab: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: PK parameter for enfortumab vedotin: Area under the concentration-time curve (AUC) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: PK parameter for MMAE: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: PK parameter for Tab: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)
timeFrame: Through 2 cycles of treatment, up to 42 days
measure: Pathologic downstaging (pDS) rate by central pathology review (MIBC cohorts only)
timeFrame: Up to approximately 5 months
measure: Disease-free survival (DFS) by investigator assessment (MIBC cohorts only)
timeFrame: Up to approximately 5 years
measure: DFS by BICR (Cohort L only)
timeFrame: Up to 3 years
measure: Type, incidence, severity, seriousness, and relatedness of AEs (Randomized Cohort K and MIBC cohorts only)
timeFrame: Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years
measure: Type, incidence, and severity of laboratory abnormalities (Randomized Cohort K and MIBC cohorts only)
timeFrame: Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years
measure: Percentage of planned radical cystectomy and pelvic lymph node dissections (RC+PLND) delayed due to treatment-related AEs (MIBC cohorts only)
timeFrame: Up to approximately 5 months
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Alaska Urological Institute
state: Alaska
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Tucson
country: United States
facility: Arizona Oncology Associates, PC - HOPE
state: Arizona
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Beverly Hills
country: United States
facility: Tower Hematology Oncology Medical Group
state: California
city: La Jolla
country: United States
facility: UC San Diego / Moores Cancer Center
state: California
city: Orange
country: United States
facility: University of California Irvine - Newport
state: California
city: Sacramento
country: United States
facility: University of California, Davis Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Santa Rosa
country: United States
facility: Saint Joseph Heritage Medical Group
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center / Blood & Marrow Transplant Program
state: California
city: Woodland Hills
country: United States
facility: Kaiser Permanente Southern California
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers - Aurora
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital / University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Norwich
country: United States
facility: Eastern CT Hematology and Oncology Associates
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Boca Raton
country: United States
facility: Boca Raton Regional Hospital / Lynn Cancer Institute
state: Florida
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital - Michael and Dianne Bienes Comprehensive Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Piedmont Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Winship Cancer Institute / Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital - Illinois
state: Illinois
city: DeKalb
country: United States
facility: Northwestern Medicine Cancer Center - Kishwaukee / Kishwaukee Cancer Center
state: Illinois
city: Geneva
country: United States
facility: Northwestern Medicine Cancer Center Delnor
state: Illinois
city: Maywood
country: United States
facility: Cardinal Bernardin Cancer Center / Loyola University Medical Center
state: Illinois
city: Warrenville
country: United States
facility: Northwestern Medicine Cancer Center - Warrenville / Central DuPage Hospital - Cancer Care
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: New Orleans
country: United States
facility: Tulane University Hospital and Clinic
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Silver Spring
country: United States
facility: Maryland Oncology Hematology, P.A.
state: Maryland
city: Fairhaven
country: United States
facility: Southcoast Centers for Cancer Care - Fairhaven Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Lansing
country: United States
facility: McLaren Greater Lansing Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine - Siteman Cancer Center
state: Missouri
city: Lincoln
country: United States
facility: Nebraska Hematology Oncology P.C.
state: Nebraska
city: Las Vegas
country: United States
facility: OptumCare Cancer Center
state: Nevada
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Cancer Center - Basking Ridge
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Cancer Center - Monmouth
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Cancer Center - Bergen
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Albany
country: United States
facility: New York Oncology Hematology, P.C.
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Commack
country: United States
facility: Memorial Sloan Kettering Cancer Center - Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Cancer Center - Westchester
state: New York
city: Lake Success
country: United States
facility: Northwell Cancer Center / Monter Cancer Center
state: New York
city: Mineola
country: United States
facility: NYU Winthrop Hospital
state: New York
city: New York
country: United States
facility: New York University (NYU) Cancer Institute
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Cancer Center - Nassau
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center / University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: Vidant Medical Center
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center Research, LLC
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University / University Hospitals Case Medical Center
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic Cancer Center
state: Ohio
city: Broomall
country: United States
facility: CMOH Broomall
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina/Hollings Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Saint Francis Hospital Cancer Center
state: South Carolina
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Chattanooga
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology / Sarah Cannon Research Institute
state: Tennessee
city: Fort Worth
country: United States
facility: Texas Oncology - Fort Worth Cancer Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Tyler
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates - Norfolk
state: Virginia
city: Spokane
country: United States
facility: Medical Oncology Associates
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin (Milwaukee)
state: Wisconsin
city: East Brampton
country: Canada
facility: Site CA11008
state: Ontario
city: Kingston
country: Canada
facility: Site CA11011
state: Ontario
city: Toronto
country: Canada
facility: Site CA11001
state: Ontario
city: Montreal
country: Canada
facility: Site CA11005
state: Quebec
city: Montreal
country: Canada
facility: Site CA11013
state: Quebec
city: Sherbrooke
country: Canada
facility: Site CA11002
state: Quebec
city: Bordeaux
country: France
facility: Site FR33008
city: Dijon
country: France
facility: Site FR33005
city: Lyon
country: France
facility: Site FR33003
city: Marseilles
country: France
facility: Site FR33004
city: Moselle
country: France
facility: Site FR33010
city: Nice Cedex
country: France
facility: Site FR33002
city: Pierre-Benite
country: France
facility: Site FR33006
city: Strasbourg
country: France
facility: Site FR33001
city: Terni
country: Italy
facility: Site IT39002
city: Rio Piedras
country: Puerto Rico
facility: Site PR78701
city: Barcelona
country: Spain
facility: Site ES34006
city: Madrid
country: Spain
facility: Site ES34008
city: Madrid
country: Spain
facility: Site ES34001
city: Madrid
country: Spain
facility: Site ES34012
city: Pamplona
country: Spain
facility: Site ES34007
city: Sabadell
country: Spain
facility: Site ES34005
city: Santander
country: Spain
facility: Site ES34004
Study officials:
affiliation: Seagen Inc.
name: Changting Meng, MD
role: STUDY_DIRECTOR
affiliation: Seagen Inc.
name: Jason Lukas, MD, PhD
role: STUDY_DIRECTOR
References: