Locally advanced/unresectable or metastatic urothelial carcinoma previously untreated for their advanced disease MedDRA version: 20.0 Level: LLT Classification code 10064467 Term: Urothelial carcinoma System Organ Class: 100000004864
Conditions
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. The participants must have histologically documented, la/mUC (ie, cancer of the bladder, renal pelvis, ureter, or urethra). Histology will be confirmed locally. • Participants with mixed histology are eligible provided the urothelial component is =50% (and 12 months from completion of therapy are permitted. 4. Participants must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable. 5. Participants who have AEs due to previous anticancer therapies must have recovered to =Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have <Grade 2 neuropathy are eligible. 6. Is male or female, and =18 years at the time the participant provides documented informed consent for the study. 7. If male, agrees to the following during the intervention period and for at least 180 days after the last dose of EV: • Refrains from donating sperm PLUS either: • Abstains from heterosexual intercourse as their preferred and usual lifestyle and agrees to remain abstinent OR • Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below: - Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. - Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Not a WOCBP OR • A WOCBP and: - Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, during the intervention period and for at least 120 days (MK-4280A, MK-7684A, or pembrolizumab) or 180 days (EV) after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her ow
Exclusion criteria
Exclusion criteria: 1. Known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy. 2. Participants with treated CNS metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of =10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease. 3. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, LAG3, TIGIT, OX-40, CD137). Exception includes participants who received neo-adjuvant or adjuvant anti-PD-1 or PD-L1 therapy for an earlier disease stage (eg, MIUC) with recurrence >12 months from completion of therapy. 4. Received therapy with hematopoietic growth factor such as G-CSF or GM-CSF within 14 days prior to randomization. 5. Received prior systemic anticancer therapy including investigational agents (including EV or other MMAE-based ADCs) within 3 years prior to randomization. Exception includes participants that received neoadjuvant or adjuvant chemotherapy or anti-PD-1/L1 therapy for an earlier disease stage (eg, MIUC). 6. Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. 7. Has received an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention administration. 8. Ongoing sensory or motor neuropathy Grade 2 or higher. 9. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency. 10. Severe hypersensitivity (=Grade 3) to mAb (including pembrolizumab) and/or any of their excipients. 11. Known severe hypersensitivity (=Grade 3) to any excipient contained in the drug formulation of EV (including histidine, trehalose dihydrate, and polysorbate 20). 12. Active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator. 13. Active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid). 14. A history of uncontrolled diabetes. Uncontrolled diabetes is defined as HbA1c =8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. 15. A history of (noninfectious) pneumonitis that required steroids or has current pneumonitis. 16. An active infection (viral, bacterial, or fungal) requiring systemic therapy. Participant may be rescreened after resolution of the infection. 17. A known history of HIV infection. No HIV testing is required unless mandated by local health authority. 18. Hepatitis B (defined as HBsAg reactive) or hepatitis C virus (defined as HCV RNA qualitative is dete
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. Part 1: To evaluate ORR in participants treated with MK-4280A plus EV (Arm A), MK-7684A plus EV (Arm B), and pembrolizumab plus EV (Arm C) per RECIST 1.1 by BICR. 2. Part 1: To evaluate the safety and tolerability in participants treated with MK-4280A plus EV (Arm A), MK-7684A plus EV (Arm B), and pembrolizumab plus EV (Arm C). 3. Part 2: To compare EV plus MK-4280A (Arm A) and/or EV plus MK-7684A (Arm B) to EV plus pembrolizumab (Arm C) with respect to PFS per RECIST 1.1 by BICR.;Secondary Objective: 1. Part 1: To evaluate PFS in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B), & pembrolizumab + EV (Arm C) per RECIST 1.1 by BICR 2. Part 2: To compare EV + MK-4280A (Arm A) and/or EV + MK-7684A (Arm B) versus EV + pembrolizumab (Arm C) with respect to OS 3. Part 2: To evaluate ORR in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B), & pembrolizumab + EV (Arm C) per RECIST 1.1 by BICR 4. Part 2: To evaluate safety and tolerability in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B), & pembrolizumab + EV (Arm C) 5. Part 1 and Part 2: To evaluate DOR in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B), and pembrolizumab + EV (Arm C) per RECIST 1.1 by BICR 6. Part 1 and Part 2: To evaluate changes in patient-reported outcomes from baseline and TTD using the EORTC QLQ-C30 instrument and EQ-5D-5L in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B) & pembrolizumab + EV (Arm C);Primary end point(s): 1. Part 1: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by Blinded Independent Central Review (BICR) 2. Part 1: Percentage of Participants Who Experienced At Least One Adverse Event (AE) 3. Part 1: Percentage of Participants Who Discontinued Study Treatment Due to an AE 4. Part 1: Percentage of Participants Who Experienced at Least One Dose-Limiting Toxicity (DLT) 5. Part 2: Progression Free Su | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Part 1: Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR 2. Part 2: Overall Survival (OS) 3. Part 2: ORR per RECIST 1.1 as assessed by BICR 4. Part 2: Percentage of Participants Who Experienced At Least One AE 5. Part 2: Percentage of Participants Who Discontinued Study Treatment Due to an AE 6. Part 2: Percentage of Participants Who Experienced at Least One DLT 7. Part 1: Duration of Response (DOR) per RECIST 1.1 as assessed by BICR 8. Part 2: DOR per RECIST 1.1 as assessed by BICR 9. Part 1: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score 10. Part 1: Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale (Items 1-5) Combined Score 11. Part 1: Change from Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) 12. Part 1: Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score 13. Part 1: TTD in the EORTC QLQ-C30 Physical Functioning Scale (Items 1-5) Combined Score 14. Part 1: TTD in the EQ-5D-5L VAS 15. Part 2: Change from Baseline in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score 16. Part 2: Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale (Items 1-5) Combined Score 17. Part 2: Change from Baseline in EQ-5D-5L VAS 18. Part 2: Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score 19. Part 2: TTD in the EORTC QLQ-C30 Physical Functioning Scale (Items 1-5) Combined Score 20. Part 2: TTD in the EQ-5D-5L VAS;Timepoint(s) of evaluation of this end point: 1. Up to approximately 4 years 2. Up to approximately 4 years 3. Up to approximately 4 years 4. Up to approximately 4 years 5. Up to approximately 4 years 6. Up to approximately 21 | — |
Countries
Australia, Canada, Chile, France, Israel, Italy, Korea, Republic of, Netherlands, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactInvestigación Clínica
Merck Sharp & Dohme de España S.A.
Outcome results
None listed