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)
Overview
- Phase
- Phase 3
- Intervention
- Enfortumab Vedotin
- Conditions
- Ureteral Cancer
- Sponsor
- Astellas Pharma Global Development, Inc.
- Enrollment
- 608
- Locations
- 182
- Primary Endpoint
- Overall Survival (OS)
- Status
- Completed
- Last Updated
- 3 months ago
Overview
Brief Summary
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
Japan PMDA has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan. Participants considered an adult according to local regulation at the time of obtaining informed consent participated in the study.
Investigators
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 × 10\^9/L
Exclusion Criteria
- •Subject has preexisting sensory or motor neuropathy Grade ≥
- •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.
Arms & Interventions
Arm A: Enfortumab Vedotin 1.25 mg/kg
Participants 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.
Intervention: Enfortumab Vedotin
Arm B: Chemotherapy
Participants 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.
Intervention: Docetaxel
Arm B: Chemotherapy
Participants 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.
Intervention: Vinflunine
Arm B: Chemotherapy
Participants 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.
Intervention: Paclitaxel
Cross-over Extension (COE)
Eligible participants from chemotherapy arm who met the criteria for COE will receive 1.25 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 until discontinuation criteria is met.
Intervention: Enfortumab Vedotin
Outcomes
Primary Outcomes
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)
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 Outcomes
- Change From Baseline to Week 12 in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)(Baseline and week 12)
- Duration of Response (DOR) as Per RECIST V1.1(From date of first objective response until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months))
- Number of Participants With ECOG Performance Status(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))
- Progression Free Survival on Study Therapy (PFS1) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)(From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months))
- Overall Response Rate (ORR) as Per RECIST V1.1(From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months))
- Number of Participants With Treatment Emergent Adverse Events(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))
- Disease Control Rate (DCR) as Per RECIST V1.1(From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months))
- 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)(Baseline and week 12)