Phase 3 Study of Enfortumab Vedotin and Pembrolizumab Versus Chemotherapy in Untreated Locally Advanced or Metastatic Urothelial Cancer
- Trial ID
- 2023-503421-19-00
- Protocol
- C5701003
- Sponsor
- Seagen Inc.
Trial statistics
Objectives
The primary objective of this study is to compare **progression-free survival (PFS)** between the experimental arm, which includes enfortumab vedotin in combination with pembrolizumab (Arm A), and the control arm, which consists of gemcitabine combined with either cisplatin or carboplatin (Arm B). This comparison is conducted through a blinded independent central review (BICR). Additionally, the study aims to compare overall survival (OS) between these two treatment arms. These objectives are clinically relevant as they assess the efficacy of the experimental treatment in extending the time patients with previously untreated locally advanced or metastatic **urothelial cancer** live without disease progression and overall survival, which are critical endpoints in oncology trials.
The secondary objectives of the study include:
- Comparing the objective response rate (ORR) between the experimental and control arms by BICR.
- Comparing the time to pain progression (TTPP) and average change in pain from the subject perspective between the two arms.
- Evaluating PFS and ORR between the arms by investigator assessment.
- Assessing the duration of response (DOR) and disease control rate (DCR) between the arms.
- Evaluating the impact of study treatment on quality of life (QOL), functioning, and symptoms from the subject perspective.
- Assessing the safety profile of each treatment regimen.
Participants
The clinical trial involves a total of **719 participants** diagnosed with **urothelial cancer**, which includes cancer of the bladder, renal pelvis, ureter, or urethra. The study population comprises both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, such as having histologically documented, unresectable locally advanced or metastatic urothelial carcinoma, and an **ECOG Performance Status** score of 0, 1, or 2. The trial includes individuals with squamous or sarcomatoid differentiation or mixed cell types. Subjects must have measurable disease according to RECIST v1.1 and adequate hematologic and organ function. Lifestyle considerations, such as diet and physical activity, are not specified. The trial population includes vulnerable groups, and both genders are represented. Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma, with certain exceptions for those who received neoadjuvant or adjuvant chemotherapy with recurrence more than 12 months after completion. The selection process ensures that subjects are eligible to receive cisplatin- or carboplatin-containing chemotherapy, based on the investigator's judgment.
Plans and Procedures
The clinical trial is designed as an open-label, randomized, controlled phase 3 study to evaluate the efficacy and safety of **enfortumab vedotin** in combination with **pembrolizumab** compared to chemotherapy alone in patients with previously untreated locally advanced or metastatic **urothelial cancer**. The trial aims to compare progression-free survival (PFS) and overall survival (OS) between the experimental arm (enfortumab vedotin + pembrolizumab) and the control arm (gemcitabine + cisplatin or carboplatin). The study is expected to conclude by November 2025, with recruitment having commenced in February 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically documented urothelial carcinoma, measurable disease per RECIST v1.1, and adequate hematologic and organ function. Following randomization, participants will receive treatment according to their assigned arm. The trial includes regular follow-up visits to monitor treatment response and safety, with assessments conducted by blinded independent central review (BICR) and investigator assessment. The end-of-study visit will occur after the final treatment cycle or upon early termination.
The expected duration of participant involvement is up to 18 months for those receiving chemotherapy and up to 105 weeks for those in the experimental arm. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will assess primary endpoints such as PFS and OS, along with secondary endpoints including overall response rate (ORR), time to progression (TTP), and quality of life measures. The study is conducted under rigorous ethical standards, with informed consent obtained from all participants prior to enrollment.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The **experimental treatment** consists of **enfortumab vedotin** and **pembrolizumab**. Enfortumab vedotin is provided as a 30 mg powder for concentrate for solution for infusion, with a maximum daily dose of 1.25 mg/kg and a total dose of 125 mg. It is administered intravenously and is of protein origin. Pembrolizumab is available as a 25 mg/mL concentrate for solution for infusion, with a maximum daily and total dose of 200 mg. It is also administered intravenously and is of protein origin. The treatment period for pembrolizumab is up to 105 weeks.
The **comparator treatment** includes **gemcitabine** and either **cisplatin** or **carboplatin**. Gemcitabine is supplied as a 38 mg/mL powder for the preparation of an infusion solution, with a maximum daily and total dose of 1000 mg/m². It is administered intravenously and is of chemical origin. Cisplatin is available as a 1 mg/mL concentrate for solution for infusion, with a maximum daily and total dose of 70 mg/m². It is administered intravenously and is of chemical origin. Carboplatin is provided as a 10 mg/mL concentrate for solution for infusion, with a maximum daily and total dose of 400 mg/m². It is administered intravenously and is of chemical origin. The treatment period for gemcitabine, cisplatin, and carboplatin is up to 18 weeks.
All treatments are administered intravenously, and participant compliance is monitored throughout the study. The trial aims to compare progression-free survival and overall survival between the experimental and control arms in patients with locally advanced or metastatic urothelial cancer.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** per RECIST v1.1 by Blinded Independent Central Review (BICR) and **Overall Survival (OS)**. Secondary endpoints encompass a range of measures such as **Objective Response Rate (ORR)** per RECIST v1.1 by BICR, **Time to Progression of Pain (TTPP)**, and mean change from baseline in worst pain at Week 26. Additional secondary endpoints include PFS and ORR per RECIST v1.1 by investigator assessment, **Duration of Response (DOR)** per RECIST v1.1 by both BICR and investigator assessment, and **Disease Control Rate (DCR)** per RECIST v1.1 by both BICR and investigator assessment.
Quality of life will be evaluated using mean scores and changes from baseline of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30) and EuroQOL 5-dimensions (EQ-5D-5L), including visual analogue scale (VAS) and utility scores. Safety and tolerability will be monitored through the type, incidence, relatedness, severity, and seriousness of adverse events (AEs), as well as the type, incidence, and severity of laboratory abnormalities. The treatment discontinuation rate due to AEs will also be recorded. These efficacy parameters will be measured and analyzed at specified timepoints throughout the trial to ensure comprehensive assessment of the treatment's impact on patients with locally advanced or metastatic urothelial cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects must have histologically documented, unresectable locally advanced or metastatic urothelial carcinoma (ie, cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible.
- 2.Subjects must have measurable disease by investigator assessment according to RECIST v1.1.:
- 2a. Subjects with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy.
- Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
- 3a. Subjects that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted;
- 3b. Subjects that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted;
- Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator’s judgment.
- 4a. Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria:
- 4a)i. GFR <60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD] or 24-hour urine): Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgment;
- 4a)ii. ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects);
- 4a)iii. NCI CTCAE Grade ≥2 audiometric hearing loss;
- 4a)iv. NYHA Class III heart failure.
- Subjects must be age 18 years or older.
- Archival tumor tissue comprising muscle-invasive urothelial carcinoma, or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization. If adequate archival tumor sample is not available, or evaluable, a new biopsy sample may be performed.
- Subjects must have an ECOG Performance Status score of 0, 1, or 2:
- 7a. Subjects with ECOG performance status of 2 must additionally meet the following criteria:
- 7a)i. Hemoglobin ≥10 g/dL;
- 7a)ii. GFR ≥50 mL/min;
- 7a)iii. May not have NYHA Class III heart failure.
- Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 3 (see protocol).
- Female subjects of childbearing potential must meet the following conditions:
- 9a. Agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug.
- 9b. Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) within 1 day prior to administration of study drug. Female subjects with false positive results and documented verification of negative pregnancy status are eligible for participation.
- 9c. If heterosexually active, must consistently use highly effective methods of birth control, with a failure rate of less than 1% starting at screening, throughout the study period, and for at least 6 months after the final dose of study drug.
- 9d. Female subjects 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 dose of study drug.
- Male subjects who can father children, must meet the following conditions:
- 10a. Must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug (see protocol);
- 10b. Must consistently use highly effective methods of birth control, with a failure rate of less than 1% starting at screening and continue throughout study period and for at least 6 months after the final dose of study drug;
- 10c. Male subjects with a pregnant or breastfeeding partner(s) must consistently use one of 2 contraception options for preventing secondary exposure to seminal fluid for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final dose of study drug.
- Subjects must provide written informed consent.
Exclusion Criteria
- Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs.
- Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
- Subjects who have known active hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] detected) infection, testing for hepatitis B and hepatitis C is required if mandated by country health authority. Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
- Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority.
- Subjects with conditions requiring high doses of steroids (>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency.
- Subjects with a history of another invasive 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 or carcinoma in situ of any type (if complete resection was performed) are allowed (for details eligible exceptions see protocol).
- Subjects with a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class IV within 6 months prior to randomization.
- Subjects who have received radiotherapy within 2 weeks prior to randomization. Subject must have recovered adequately from the toxicity from the intervention prior to starting study treatment.
- Subjects who have received major surgery within 4 weeks prior to randomization. Subject must have recovered adequately from complications from the intervention prior to starting study treatment.
- Subjects with known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin; any pembrolizumab excipient contained in the drug formulations of pembrolizumab; the platinum agent selected by the investigator for study treatment; the gemcitabine.
- Subjects with active keratitis or corneal ulcerations. Subjects with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator
- Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor (see protocol).
- History of autoimmune disease that has required systemic treatment in the past 2 years (see protocol):
- Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor (see protocol).
- Subjects who have received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment (see protocol).
- Subjects with uncontrolled diabetes (see protocol).
- Subjects with an estimated life expectancy <12 weeks.
- Subjects with ongoing sensory or motor neuropathy Grade 2 or higher.
- Subjects with active CNS metastases. Subjects with treated CNS metastases are permitted on study if all of the following are true:
- Subjects with ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to ≤ Grade 1 or returned to baseline.
- 8a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis;
- 8b) the subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment);
- 8c) subject does not have leptomeningeal disease.
- 20a. Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
- 20b. Brief (<7 days) use of systemic corticosteroids is allowed when use is considered standard of care.
- 20c. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will not be excluded.
- 20d. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded.
- 20e. Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome will not be excluded.
- Subjects with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
- Subjects who have received a prior allogeneic stem cell or solid organ transplant.
- Subjects who have received a live attenuated vaccine within 30 days prior to randomization (see protocol).
- Subjects with active tuberculosis.
- Subjects with another underlying medical condition that, in the opinion of the investigator, would impair the ability of the subject to receive or tolerate the planned treatment and follow-up; any known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 28 Feb 2020 | 30 |
 Czechia | Not Recruiting | 28 Feb 2020 | 20 |
 Denmark | Not Recruiting | 28 Feb 2020 | 20 |
 France | Not Recruiting | 28 Feb 2020 | 140 |
 Germany | Not Recruiting | 28 Feb 2020 | 71 |
 Hungary | Not Recruiting | 28 Feb 2020 | 27 |
 Italy | Not Recruiting | 28 Feb 2020 | 160 |
 The Netherlands | Not Recruiting | 28 Feb 2020 | — |
 Poland | Not Recruiting | 28 Feb 2020 | 15 |
 Spain | Not Recruiting | 28 Feb 2020 | 148 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 200 | 105 | PRD4323105 |
Cisplatin 1 mg/ml Concentrate for Solution for Infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 70 | 18 | PRD1951570 |
CARBOPLATINE ACCORD 10 mg/ml, solution pour perfusion | Comparator | SOLUTION POUR PERFUSION | INTRAVENOUS | 400 | 18 | PRD415296 |
Gemcitabin AqVida 38 mg/ml Pulver zur Herstellung einer Infusionslösung | Comparator | PULVER ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS | 1000 | 18 | PRD1744676 |
CISPLATINE ACCORD 1 mg/ml, solution à diluer pour perfusion | Comparator | SOLUTION À DILUER POUR PERFUSION | INTRAVENOUS | 70 | 18 | PRD415238 |
Padcev 30 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1.25 | 9999999 | PRD9634494 |
Carboplatin 10 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 400 | 18 | PRD2005389 |