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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)

NCT03474107

Description:

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.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 7465-CL-0301
  • SECONDARY ID: 2017-003344-21
  • NCT ID: NCT03474107

Conditions

  • Ureteral Cancer
  • Urothelial Cancer
  • Bladder Cancer

Interventions

DrugSynonymsArms
Enfortumab VedotinASG-22ME, ASG-22CEArm A: Enfortumab Vedotin 1.25 mg/kg
DocetaxelArm B: Chemotherapy
VinflunineArm B: Chemotherapy
PaclitaxelArm B: Chemotherapy

Purpose

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

      Participants considered an adult according to local regulation at the time of obtaining
      informed consent participated in the study. Sites in Japan Only: In case that EV is approved
      for marketing in Japan, the study will continue as "Phase 4 post-marketing study" in
      accordance with Good Post-marketing Study Practice after marketing authorization based on the
      indication approved. In this case, "Study" in the protocol is read as "Post-marketing study."
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Enfortumab Vedotin 1.25 mg/kgExperimentalParticipants 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.
  • Enfortumab Vedotin
Arm B: ChemotherapyActive ComparatorParticipants 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.
  • Docetaxel
  • Vinflunine
  • Paclitaxel

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 × 109/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 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, has not
             started a new systemic anticancer treatment and is still participating in the follow
             up phase of the 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 ≤ 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression Free Survival on Study Therapy (PFS1) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Time Frame:From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Safety Issue:
Description: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.
Measure:Overall Response Rate (ORR) as Per RECIST V1.1
Time Frame:From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Safety Issue:
Description: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.
Measure:Disease Control Rate (DCR) as Per RECIST V1.1
Time Frame:From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Safety Issue:
Description: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.
Measure:Duration of Response (DOR) as Per RECIST V1.1
Time Frame:From date of first objective response until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Safety Issue:
Description: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.
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)
Time Frame:Baseline and week 12
Safety Issue:
Description: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.
Measure:Change From Baseline to Week 12 in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)
Time Frame:Baseline and week 12
Safety Issue:
Description: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).
Measure:Number of Participants With Treatment Emergent Adverse Events
Time Frame: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)
Safety Issue:
Description: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.
Measure:Number of Participants With ECOG Performance Status
Time Frame: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)
Safety Issue:
Description:ECOG performance status was measured on an 6 point scale. 0-Fully active, able to carry on all pre-disease performance without restriction. 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. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Dead. Number of participants with ECOG PS was reported.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

  • antibody drug conjugate
  • enfortumab vedotin (EV)
  • ASG-22ME
  • ASG-22CE
  • urothelial cancer

Last Updated

August 24, 2021