urothelial cancer
Conditions
Interventions
Enfortumab vedotin plus pembrolizumab:Subjects in Arm A will receive enfortumab vedotin at 1.25 mg/kg, administered as an intravenous (IV) infusion on Days 1 and 8 of every 3-week cycle, and pembroliz
Gemcitabine plus either cisplatin or carboplatin:Subjects in Arm B will receive gemcitabine at 1,000 mg/m2 as an IV infusion on Days 1 and 8 of every 3 week cycle. Cisplatin (70 mg/m2) or carboplatin
Sponsors
Beijing Cancer Hospital/Sun Yat-sen Memorial Hospital, Sun Yat-sen University
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
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 (Appendix J): 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: (1) Subjects that received neoadjuvant chemotherapy with recurrence >;12 months from completion of therapy are permitted; (2) 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 investigators judgment; Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria: (1) GFR = 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 investigators clinical judgment; (2) ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects); (3) NCI CTCAE Grade >= 2 audiometric hearing loss; (4) NYHA Class III heart failure; 5. Subjects must be aged 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 (see Section 7.5); 7. Subjects must have an ECOG Performance Status score of 0, 1, or 2 (see Appendix B for conversion of performance status using Karnofsky, if applicable); Subjects with ECOG performance status of 2 must additionally meet the following criteria: (1) Hemoglobin >= 10 g/dL; (2) GFR >= 50 mL/min; (3) 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; 9. A female subject of childbearing potential is anyone born female who has experienced menarche and who has not undergone surgical sterilization (e.g., 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: (1) Agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug; (2) Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [beta-hCG]) within 1 day prior to administration of study drug. Female subjects with false positive results and documented verification of negative pregnancy st
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 (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab); 3. Subjects who have previously 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); 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 (ongoing hormonal/anti hormonal treatment, eg, for breast cancer, is allowed, provided that the subject is eligible per exclusion criteria 14); 5. Subjects with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) >= 8% or HbA1c 7% to 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. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type (if complete resection was performed) are allowed. (1) A history of prostate cancer (T2NXMX or lower with Gleason score <= 7) treated with definitive intent (surgically or with radiati
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR);overall survival; | — |
Secondary
| Measure | Time frame |
|---|---|
| objective response rate per RECIST v1.1 by blinded independent central review (BICR);objective response rate per RECIST v1.1 by investigator assessment;duration of response per RECIST v1.1 by blinded independent central review (BICR);duration of response per RECIST v1.1 by investigator assessment;disease control rate per RECIST v1.1 by blinded independent central review (BICR);disease control rate per RECIST v1.1 by investigator assessment;progression-free survival per RECIST v1.1 by investigator assessment;Change from baseline in patient-reported outcome (PRO) assessments of the EuroQOL 5-dimensions (EQ-5D-5L), European Organisation for Researchand Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30), and Brief Pain Inventory–Short Form (BPI-SF);Type, incidence, relatedness, severity and seriousness of adverse events (AEs);Type, incidence and severity of laboratory abnormalities;Treatment discontinuation rate due to adverse event;Selected plasma or serum pharmacokinetic parameters of enfortumab vedotin, monomethyl auristatin E (MMAE) and pembrolizumab;Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin and pembrolizumab; | — |
Countries
China
Contacts
Public ContactJian Huang
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
Outcome results
None listed