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 MedDRA version: 21.1 Level: LLT Classification code 10077840 Term: Urothelial cancer of rena
Conditions
Sponsors
Seagen Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Patients must have histologically documented locally advanced or metastatic urothelial (previously known as transitional cell) cancer (ie, cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous differentiation or mixed cell types are eligible. Patients with locally advanced disease that is resectable with curative intent are ineligible. 2.Patients in Cohort K must be eligible for CPI therapy. 3. Cohort-specific eligibility: Randomized Cohort K (EV Mono arm and EV+Pembro arm): Patients must be ineligible for cisplatin-based chemotherapy at the time of enrollment due to at least 1 of the following criteria: i. Glomerular filtration rate (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) ii. ECOG performance status of <= 2 (refer to inclusion criterion #6 for additional criteria for subjects with ECOG 2) iii. NCI CTCAE Version 4.03 Grade =2 hearing loss iv. NYHA Class III heart failure Patients must not have received prior systemic treatment for locally advanced or metastatic disease. Patients may not have previously received adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization. 4. Minimum age of 18 years 5. Patients must have measurable disease according to RECIST Version 1.1 (Eisenhauer 2009). Lesions in a prior irradiated field must have progressed to be considered measurable. 6. An ECOG performance status of 0, 1, or 2 . • 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 7. Anticipated life expectancy of =3 months as assessed by the investigator. 8. Have adequate organ function as defined in the following table. Specimens must be collected within 7 days prior to the start of study treatment. 9. A female subject of childbearing potential is anyone born female who has experienced menarche and who has not undergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person over age 45 in the absence of other biological, physiological, or pharmacological causes. 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 3 days prior to Day 1. 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. A male subject who can father children is anyone born male who has testes and who has not undergone surgical sterilization (eg, vasectomy followed by a clinical test proving that the procedure was effective). Male subjects who can f
Exclusion criteria
Exclusion criteria: 1. Received any prior treatment with a CPI. A CPI is defined as a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). Patients in Expansion Cohort F may have previously received treatment with a CPI. 2. Received any prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists). 3. Ongoing sensory or motor neuropathy Grade 2 or higher. 4. Active central nervous system [CNS] metastases. Patients with treated CNS metastases are permitted on study if all the following are true: a. CNS metastases have been clinically stable for at least 6 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis. b. If requiring steroid treatment for CNS metastases, the patient is on a stable dose 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. 7. Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer. 8. 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. Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ (eg, breast carcinoma, cervical cancer) who have undergone potentially curative therapy are not excluded. Patients with low-risk prostate cancer (T1-T2a, Gleason score =6, and prostate specific antigen [PSA] <10 ng/mL) either treated with definite intent any time prior to screening or untreated in active surveillance are not excluded. 9. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of first dose of enfortumab vedotin. Routine antimicrobial prophylaxis is permitted. 10. Patients with a positive hepatitis B surface antigen and/or antihepatitis B core antibody; patients with a negative polymerase chain reaction (PCR) assay are permitted with either universal prophylaxis or the use of a pre-emptive approach. The approach will be selected in accordance with regional or national guidelines for patients who receive anticancer therapies. 11. Active hepatitis C infection or known human immunodeficiency virus (HIV) infection. Patients who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks. No HIV testing is required unless mandated by local health authority. 12. Patients with active tuberculosis. 13. 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 NYHA Class III–IV (see Appendix E) within 6 months prior to the first dose of enfortumab vedotin. Patients with NYHA Class III are permitted in Cohort K. 14. Radiotherapy or major surgery within 2 weeks prior to first dose of study drug. Patient must
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the antitumor activity of enfortumab vedotin monotherapy or enfortumab vedotin in combination with pembrolizumab as measured by ORR per RECIST Version 1.1 by blinded independent central review (BICR) ;Secondary Objective: -To assess the ORR per RECIST Version 1.1 by investigator assessment -To assess the DOR per RECIST Version 1.1 by BICR and investigator assessment -To assess the DCR per RECIST Version 1.1 by BICR and investigator assessment -To assess the PFS on study therapy per RECIST Version 1.1 by BICR and investigator assessment -To assess OS -To assess the safety and tolerability of EV monotherapy or enfortumab vedotin in combination with pembrolizumab Additional/Exploratory: -To assess: -PK and the incidence of ATA - Nectin-4 and PD-L1 expression levels - biomarkers of biological activity and disease resistance, and their potential associations with clinical outcome measures - the PFS on subsequent therapy (PFS2) by investigator assessment - the impact on quality of life (QoL) and symptoms, including pain, from the patient perspective - the ORR, DOR, DCR, and PFS on study therapy per iRECIST for EV in combination with pembrolizumab (EV+Pembro arm) by investigator assessment;Primary end point(s): ORR (confirmed) per RECIST Version 1.1 by BICR;Timepoint(s) of evaluation of this end point: Every 9 weeks starting from Cycle 1 Day 1 through EOT and for up to one year, then every 12 weeks. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • ORR (confirmed) per RECIST Version 1.1 by investigator assessment • DOR per RECIST Version 1.1 by BICR • DOR per RECIST Version 1.1 by investigator assessment • DCR per RECIST Version 1.1 by BICR • DCR per RECIST Version 1.1 by investigator assessment • PFS per RECIST Version 1.1 by BICR • PFS per RECIST Version 1.1 by investigator • OS • Type, incidence, severity, seriousness, and relatedness of AEs • Type, incidence, and severity of laboratory abnormalities Corresponding Additional/Exploratory Endpoints • Selected plasma or serum PK parameters of enfortumab vedotin, MMAE, and TAb • Incidence of ATA to enfortumab vedotin • Exploratory biomarkers of clinical activity, including relationship of Nectin-4 expression and PD-L1 expression status to response • PFS2 by investigator assessment • Change from baseline in PRO assessments of the EQ-5D-5L, EORTC QLQ-C30, and BPI-SF For the EV+Pembro arm: • ORR (confirmed) per iRECIST by investigator assessment • DOR per iRECIST by investigator assessment • DCR per iRECIST by investigator assessment • PFS per iRECIST by investigator assessment ;Timepoint(s) of evaluation of this end point: Following documentation of PFS2, patients will enter the survival follow-up period and be followed every 12 weeks for survival status until death, study closure, or withdrawal of consent, whichever occurs first. | — |
Countries
Canada, France, Italy, Spain, United States
Contacts
Public ContactSeagen Clinical Trial Information
Seagen Inc.
Outcome results
None listed