Urothelial cancer MedDRA version: 20.0 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10046723 Term: Urothelial carcinoma ureter System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10046728 Term: Urothelial carcinoma urethra System Organ Class: 100000004864
Conditions
Sponsors
Seagen Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subjects must have histologically documented, unresectable locally advanced or metastatic urothelial carcinoma (i.e., 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. a. 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 3. Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: a. Subjects that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted b. Subjects that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted 4. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator’s judgment. a. Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria: 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 ii. ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects) iii. NCI CTCAE Grade =2 audiometric hearing loss iv. NYHA Class III heart failure 5. Subjects must be age 18 years or older. 6. 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. 7. Subjects must have an ECOG Performance Status score of 0, 1, or 2. a. Subjects with ECOG performance status of 2 must additionally meet the following criteria: i. Hemoglobin =10 g/dL ii. GFR =50 mL/min iii. May not have NYHA Class III heart failure 8. Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 3 (see protocol) 9. Female subjects of childbearing potential must meet the following conditions: · Agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug. · Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [ß-hCG]) within 1 day prior to administration of the study drug. Female subjects with false positive results and documented verification of negative pregnancy status are eligible for participation. · 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. · 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. 10. Male subjects who can father children,
Exclusion criteria
Exclusion criteria: 1. Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs. 2. 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. 3. Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor. 4. 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. 5. Subjects with uncontrolled diabetes. 6. Subjects with an estimated life expectancy 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. 14. 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 (eligible exceptions see protocol). 15. 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. 16. Subjects who have received radiotherapy within 2 weeks prior to randomization. 17. Subjects who have received major surgery within 4 weeks prior to randomization. 18. Subjects with known severe (= Grade 3) hypersensitivity to any excipient contained in the drug formulations of enfortumab vedotin, pembrolizumab, the platinum agent selected by the investigator or gemcitabine. 19. Subjects with active keratitis or corneal ulcerations. 20. History of autoimmune disease that has required systemic tre
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - To compare PFS between the experimental arm (enfortumab vedotin + pembrolizumab [Arm A] and the control arm (gemcitabine + cisplatin or carboplatin [Arm B]) by blinded independent central review (BICR) - To compare overall survival (OS) between the experimental arm (Arm A) and the control arm (Arm B);Secondary Objective: - To compare ORR between the experimental arm (Arm A) and the control arm (Arm B) by BICR - To compare time to pain progression (TTPP) from the subject perspective between the experimental arm (Arm A) and the control arm (Arm B) - To compare average change in pain from the subject perspective between the experimental arm (Arm A) and the control arm (Arm B) - To evaluate PFS between the experimental arm (Arm A) and the control arm (Arm B) by investigator assessment - To evaluate ORR between the experimental arm (Arm A) and the control arm (Arm B) by investigator assessment - To evaluate DOR between the experimental arm (Arm A) and the control arm (Arm B) - To evaluate DCR between the experimental arm (Arm A) and the control arm (Arm B) - To evaluate the impact of study treatment on quality of life (QOL), functioning, and symptoms from the subject perspective - To evaluate the safety profile of each treatment regimen;Primary end point(s): ? PFS per RECIST v1.1 by BICR ? OS;Timepoint(s) of evaluation of this end point: Response assessments should be performed every 9 weeks (±1-week) timed from the randomization date until 18 months after randomization, then every 12 weeks (±1-week) thereafter. Survival status will be updated every 12 weeks (±1-week) until death, withdrawal of consent, or study closure, whichever occurs first. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): ? ORR per RECIST v1.1 by BICR ? TTPP ? Mean change from baseline in worst pain at Week 26 ? PFS per RECIST v1.1 by investigator assessment ? ORR per RECIST v1.1 by investigator assessment ? DOR per RECIST v1.1 by BICR ? DOR per RECIST v1.1 by investigator assessment ? DCR per RECIST v1.1 by BICR ? DCR per RECIST v1.1 by investigator assessment ? Mean scores and change 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), visual analogue scale (VAS), and utility scores ? Type, incidence, relatedness, severity and seriousness of AEs ? Type, incidence and severity of laboratory abnormalities ? Treatment discontinuation rate due to AEs;Timepoint(s) of evaluation of this end point: Response assessments should be performed every 9 weeks (±1-week) timed from the randomization date until 18 months after randomization, then every 12 weeks (±1-week) thereafter. | — |
Countries
Argentina, Australia, Belgium, Canada, China, Czechia, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Serbia, Singapore, Spain, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactSeagen Trial Information
Seagen Trial Information Support
Outcome results
None listed