Phase 3 Randomized Study of Enfortumab Vedotin Versus Chemotherapy in Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma
- Trial ID
- 2024-517571-20-00
- Protocol
- 7465-CL-0301
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **overall survival** (OS) of subjects with locally advanced or metastatic **urothelial cancer** treated with enfortumab vedotin (EV) to the OS of subjects treated with chemotherapy. This is clinically relevant as it aims to determine the efficacy of EV in extending the lifespan of patients with this aggressive form of cancer, potentially offering a more effective treatment option compared to standard chemotherapy.
Secondary objectives include:
- Comparing progression-free survival on study therapy (PFS1) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 of subjects treated with EV to those treated with chemotherapy.
- Comparing the overall response rate (ORR) per RECIST V1.1 of EV to chemotherapy.
- Evaluating the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy.
- Comparing the disease control rate (DCR) per RECIST V1.1 of EV to chemotherapy.
- Assessing the safety and tolerability of EV.
- Assessing quality of life (QOL) and Patient Reported Outcomes (PRO) parameters.
These secondary objectives are crucial for understanding the broader impact of EV on disease progression, patient quality of life, and treatment safety, providing a comprehensive evaluation of its potential benefits over existing chemotherapy options.
Participants
The clinical trial involves a total of **244 participants** diagnosed with **locally advanced or metastatic urothelial cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of urothelial carcinoma and a history of treatment with a platinum-containing regimen. The trial population is characterized by individuals who have experienced disease progression or relapse during or after treatment with checkpoint inhibitors. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The study includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Key inclusion criteria ensure that participants have adequate baseline laboratory values and are not concurrently participating in another interventional study.
Plans and Procedures
The clinical trial is designed as an open-label, randomized, Phase 3 study to evaluate the efficacy of **enfortumab vedotin** compared to chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer. The primary objective is to compare the overall survival of subjects treated with enfortumab vedotin to those receiving chemotherapy. The trial is expected to run from June 27, 2018, to February 24, 2025, with participants involved for a maximum treatment period of one year. The study employs a randomized, controlled design, ensuring that participants are randomly assigned to either the test group receiving enfortumab vedotin or the control group receiving chemotherapy, which includes agents such as **docetaxel**, **paclitaxel**, and **vinflunine**. All treatments are administered via intravenous use.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed urothelial carcinoma and prior treatment history. Following the screening, participants will attend regular follow-up visits to monitor treatment response and safety, including assessments of overall survival, progression-free survival, and objective response rates. Secondary endpoints include safety variables, quality of life, and patient-reported outcomes. The end-of-study visit will conclude the participant's involvement, where final assessments and data collection will occur.
Participant involvement is expected to last up to one year, with conditions for early termination including withdrawal of consent, adverse events, or disease progression that necessitates discontinuation of the study drug. The trial's rigorous methodology and structured visit schedule are designed to ensure the collection of comprehensive data to evaluate the efficacy and safety of enfortumab vedotin in comparison to standard chemotherapy regimens.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Enfortumab vedotin** is the experimental medication used in this study. It is a **biologic** agent provided as a **concentrate for solution for infusion**. The dosage is calculated based on body weight, with a maximum daily dose of 1.25 mg/kg. The route of administration is **intravenous use**, and the treatment period is limited to one cycle. This medication is developed by Astellas Pharma Global Development, Inc.
**Docetaxel** is one of the comparator treatments in this trial. It is a **chemical** compound administered in a pharmaceutical form identified as PHF00230MIG. The maximum daily dose is 75 mg/m², and it is also administered via **intravenous use**. The treatment period is restricted to one cycle, and the medication is subject to secondary packaging and clinical trial labeling modifications.
Another comparator treatment is **Paclitaxel**, which is also a **chemical** compound provided in the same pharmaceutical form as Docetaxel, PHF00230MIG. The maximum daily dose for Paclitaxel is 175 mg/m², administered through **intravenous use**. Similar to Docetaxel, the treatment period is one cycle, and it undergoes secondary packaging and clinical trial labeling changes.
**Vinflunine** serves as an additional comparator treatment. It is a **chemical** compound with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 320 mg/m², administered via **intravenous use**. The treatment period is limited to one cycle, and the medication is subject to secondary packaging and clinical trial labeling modifications.
All treatments are administered under strict compliance monitoring to ensure adherence to dosing schedules and to evaluate participant compliance throughout the trial. The study aims to compare the overall survival of subjects with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin against those treated with the aforementioned chemotherapy agents.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **overall survival (OS)** in subjects with locally advanced or metastatic urothelial cancer. This primary endpoint will compare the OS of subjects treated with enfortumab vedotin to those treated with chemotherapy. Secondary endpoints include progression-free survival (PFS1) by RECIST V1.1, overall response rate (ORR) defined as complete response (CR) plus partial response (PR) by RECIST V1.1, disease control rate (DCR) defined as CR plus PR plus stable disease (SD) by RECIST V1.1, and duration of response (DOR) by RECIST V1.1. Additionally, safety variables such as adverse events (AEs), laboratory tests, vital sign measurements, 12-lead ECG, and Eastern Cooperative Oncology Group Performance Status (ECOG PS) will be monitored. Quality of life (QOL) and patient-reported outcomes (PRO) will be assessed using the QLQ-C30 and EQ-5D-5L instruments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
- Subject is legally an adult according to local regulation at the time of signing informed consent.
- Subject has histologically or cytologically confirmed urothelial carcinoma. 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 CPI (anti-PD1 or anti-PD-L1) for locally advanced or metastatic disease. Subjects who discontinued CPI treatment due to toxicity are eligible provided that they 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 they have progressed/relapsed during or after their 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 × 10^9/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 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 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 his 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 his 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. Waivers to the inclusion criteria will NOT be allowed.
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). Patients 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 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). Note: after vinflunine cap is reached, subjects who have received both docetaxel and paclitaxel will be excluded.
- 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., HBsAg reactive) or active hepatitis C (e.g., HCV 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 (including histidine, trehalose dihydrate, and polysorbate 20); OR subject has known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells.
- Subject has known hypersensitivity to the following: docetaxel, Paclitaxel, vinflunine or to any of the other excipients listed in product label.
- Subject has known active keratitis or corneal ulcerations. Subject with superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
- Subject has other 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.
- 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. Waivers to the exclusion criteria will NOT be allowed.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Portugal | Not Recruiting | 27 Jun 2018 | 15 |
 Spain | Not Recruiting | 27 Jun 2018 | 65 |
Sites & Investigators
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 |
|---|---|---|---|---|---|---|
enfortumab vedotin | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1.25 | 1 | PRD11581759 |
VINFLUNINE | Comparator | PHF00230MIG | INTRAVENOUS USE | 320 | 1 | SCP8210253 |
DOCETAXEL | Comparator | PHF00230MIG | INTRAVENOUS USE | 75 | 1 | SCP126226 |
PACLITAXEL | Comparator | PHF00230MIG | INTRAVENOUS USE | 175 | 1 | SCP129816 |