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

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ClinicalTrials.gov Identifier: NCT03474107
Recruitment Status : Recruiting
First Posted : March 22, 2018
Last Update Posted : June 21, 2018
Sponsor:
Collaborator:
Seattle Genetics, Inc.
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:

The purpose of this study is 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 will also compare 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 will evaluate the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy and assess the safety and tolerability of EV, as well as, the quality of life (QOL) and Patient Reported Outcomes (PRO) parameters.


Condition or disease Intervention/treatment Phase
Ureteral Cancer Urothelial Cancer Bladder Cancer Drug: enfortumab vedotin Drug: docetaxel Drug: vinflunine Drug: paclitaxel Phase 3

Detailed Description:
Participants considered an adult according to local regulation at the time of obtaining informed consent may participate in the study.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : April 16, 2018
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: enfortumab vedotin
Participants will receive enfortumab vedotin (EV) on days 1, 8 and 15 of each 28 day cycle.
Drug: enfortumab vedotin
Intravenously (IV)
Other Names:
  • ASG-22ME
  • ASG-22CE

Active Comparator: Arm B: chemotherapy
Participants will receive either docetaxel, vinflunine or paclitaxel as determined prior to participant's randomization. Participants will receive the assigned drug on day 1 of every 21 day cycle.
Drug: docetaxel
Intravenously (IV)

Drug: vinflunine
Intravenously (IV)

Drug: paclitaxel
IV infusion




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to 36 months ]
    OS is defined as the time from randomization to the date of death.


Secondary Outcome Measures :
  1. Progression Free Survival on study therapy (PFS1) per Response Evaluation Criteria In Solid Tumors (RECIST) V1.1 [ Time Frame: Up to 24 months ]
    PFS1 is defined as the time from the date of randomization until the date of radiological disease progression (per RECIST V1.1), or until death due to any cause.

  2. Overall Response Rate (ORR) (Complete Response (CR) and Partial Response(PR)) per RECIST V1.1 [ Time Frame: Up to 24 months ]
    The ORR is defined as the proportion of participants with a complete or partial objective response based on the RECIST V1.1.

  3. Disease Control Rate (DCR) (CR + PR + stable disease [SD]) per RECIST V1.1 [ Time Frame: Up to 24 months ]
    The DCR is defined as the proportion of participants with a complete or partial objective response or a stable disease based on RECIST V1.1.

  4. Duration of Response (DOR) per RECIST V1.1 [ Time Frame: Up to 24 months ]
    DOR is defined as the time from the date of the first response CR/PR per RECIST V1.1 (whichever is first recorded) to the date of radiological progression or date of death for participants who achieved CR or PR.

  5. Safety assessed by Adverse Events (AEs) [ Time Frame: Up to 24 months ]

    Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).

    Treatment Emergent Adverse Event (TEAE) is defined as an adverse event observed or worsened after starting administration of the study drug. The number and percentage of participants with treatment-emergent AEs, Serious Adverse Events (SAEs), AEs leading to withdrawal of treatment, and AEs related to study drug will be summarized by system organ class, preferred term and treatment group. The number and percentage of AEs by severity will also be summarized. All AEs will be listed. A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the investigator.


  6. Number of participants with laboratory value abnormalities and/or adverse events [ Time Frame: Up to 24 months ]
    Number of participants with potentially clinically significant laboratory values.

  7. Number of participants with vital signs abnormalities and/or adverse events [ Time Frame: Up to 24 months ]
    Number of participants with potentially clinically significant vital sign values.

  8. Safety assessed by 12- lead electrocardiogram (ECG) [ Time Frame: Up to 24 months ]

    A standard 12-lead ECG will be performed and assessed using local standard procedures. Clinically significant abnormal findings at screening should be recorded as medical history.

    Any abnormal ECGs, including those that worsen from baseline, that is considered to be clinically significant and not related to underlying disease, is to be reported as an (S)AE.


  9. Safety assessed by Eastern Cooperative Oncology Group Performance Status (ECOG PS) [ Time Frame: Up to 24 months ]
    Summary statistics (number and percent of participants) for each category of the ECOG PS at each assessment will be provided. The change from baseline to final visit or early termination will also be summarized. Negative change scores indicate an improvement. Positive scores indicate a decline in performance.

  10. Patient reported outcome assessed by quality of life: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) [ Time Frame: Up to 24 months ]
    The QLQ-C30 was developed to measure aspects of Quality of Life (QoL) pertinent to participants with a broad range of cancers who are participating in clinical trials. The current version of the core instrument (QLQ-C30, Version 3) is a 30-item questionnaire consisting of the following: functional domains (physical, role, cognitive, emotional, social); 3 symptom scales (fatigue, pain, nausea & vomiting); single items for symptoms (shortness of breath, loss of appetite, sleep disturbance, constipation, diarrhea) and financial impact of the disease; and 2 global items (health, overall QoL). Questions 1-28 range from 1 (not at all) to 4 (very much); questions 29-30 range from 1 (very poor) to 7 (excellent).

  11. Patient reported outcome assessed by quality of life: EuroQOL 5-dimensions (EQ-5D -5L) questionnaire [ Time Frame: Up to 24 months ]
    The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a generic, preference-based measure of health outcomes. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems). A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions. This questionnaire also records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale. Responses to the 5 items will also be converted to a weighted health state index (utility score) based on values derived from general population samples.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 × 109/L
    • hemoglobin ≥ 9 g/dL
    • serum 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 1 form of highly effective birth control 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 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 starting at screening and continue throughout study treatment and for 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.

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 hypothyroidism or panhypopituitarism related to treatment with PD-1 and PD-L1 inhibitors may be enrolled. Subject on hormone replacement therapy may be enrolled if on a stable dose. 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.
  • Subject has known severe hypersensitivity to docetaxel, paclitaxel, polysorbate 80, and vinflunine or other vinca alkaloids (vinblastine,vincristine, vindesine, vinorelbine).
  • Subject requires ongoing therapy with a medication that is a strong inhibitor or inducer of the cytochrome P450 3A4 (CYP3A4) enzymes.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03474107


Contacts
Contact: Astellas Pharma Global Development 800-888-7704 astellas.registration@astellas.com

Locations
United States, Alaska
Alaska Clinical Research Center Recruiting
Anchorage, Alaska, United States, 99508
United States, Kentucky
Norton Cancer Institute Recruiting
Louisville, Kentucky, United States, 40207
United States, Nebraska
Nebraska Cancer Specialists Recruiting
Omaha, Nebraska, United States, 68130
United States, Oregon
Providence Portland Med Center Recruiting
Portland, Oregon, United States, 97213
United States, South Carolina
Saint Francis Hospital Recruiting
Greenville, South Carolina, United States, 29607
United States, Texas
HOPE Cancer Center of East Texas Recruiting
Tyler, Texas, United States, 75701
United States, Washington
Providence St. Mary Regional Center Recruiting
Lacey, Washington, United States, 98503
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Seattle Genetics, Inc.
Investigators
Study Director: Senior Medical Director Astellas Pharma Global Development, Inc.

Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT03474107     History of Changes
Other Study ID Numbers: 7465-CL-0301
First Posted: March 22, 2018    Key Record Dates
Last Update Posted: June 21, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
antibody drug conjugate
enfortumab vedotin (EV)
ASG-22ME
ASG-22CE
urothelial cancer

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Ureteral Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Ureteral Diseases
Paclitaxel
Docetaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action