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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 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.

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
  • NCT ID: NCT03474107

Conditions

  • Ureteral Cancer
  • Urothelial Cancer
  • Bladder Cancer

Interventions

DrugSynonymsArms
enfortumab vedotinASG-22ME, ASG-22CEArm A: enfortumab vedotin
docetaxelArm B: chemotherapy
vinflunineArm B: chemotherapy
paclitaxelArm B: chemotherapy

Purpose

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.

Detailed Description

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

Trial Arms

NameTypeDescriptionInterventions
Arm A: enfortumab vedotinExperimentalParticipants will receive enfortumab vedotin (EV) on days 1, 8 and 15 of each 28 day cycle.
  • enfortumab vedotin
Arm B: chemotherapyActive ComparatorParticipants 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.
  • 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.

        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.
      
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:Up to 36 months
Safety Issue:
Description:OS is defined as the time from randomization to the date of death.

Secondary Outcome Measures

Measure:Progression Free Survival on study therapy (PFS1) per Response Evaluation Criteria In Solid Tumors (RECIST) V1.1
Time Frame:Up to 24 months
Safety Issue:
Description: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.
Measure:Overall Response Rate (ORR) (Complete Response (CR) and Partial Response(PR)) per RECIST V1.1
Time Frame:Up to 24 months
Safety Issue:
Description:The ORR is defined as the proportion of participants with a complete or partial objective response based on the RECIST V1.1.
Measure:Disease Control Rate (DCR) (CR + PR + stable disease [SD]) per RECIST V1.1
Time Frame:Up to 24 months
Safety Issue:
Description: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.
Measure:Duration of Response (DOR) per RECIST V1.1
Time Frame:Up to 24 months
Safety Issue:
Description: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.
Measure:Safety assessed by Adverse Events (AEs)
Time Frame:Up to 25 months
Safety Issue:
Description: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.
Measure:Number of participants with laboratory value abnormalities and/or adverse events
Time Frame:Up to 24 months
Safety Issue:
Description:Number of participants with potentially clinically significant laboratory values.
Measure:Number of participants with vital signs abnormalities and/or adverse events
Time Frame:Up to 25 months
Safety Issue:
Description:Number of participants with potentially clinically significant vital sign values.
Measure:Safety assessed by 12- lead electrocardiogram (ECG)
Time Frame:Up to 24 months
Safety Issue:
Description: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.
Measure:Safety assessed by Eastern Cooperative Oncology Group Performance Status (ECOG PS)
Time Frame:Up to 25 months
Safety Issue:
Description: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.
Measure: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 25 months
Safety Issue:
Description: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).
Measure:Patient reported outcome assessed by quality of life: EuroQOL 5-dimensions (EQ-5D -5L) questionnaire
Time Frame:Up to 25 months
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

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

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