A Study of Efficacy and Safety of Sacituzumab Tirumotecan (MK-2870) Plus Enfortumab Vedotin (EV) With and Without Pembrolizumab in Advanced Urothelial Carcinoma (MK-3475-04C/KEYMAKER-U04)
NCT Number: NCT06483334
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1|PHASE2
Conditions: Metastatic Urothelial Carcinoma|Locally Advanced Urothelial Carcinoma
Interventions: BIOLOGICAL: Sacituzumab tirumotecan|BIOLOGICAL: Enfortumab Vedotin|BIOLOGICAL: Pembrolizumab
Sponsor: Merck Sharp & Dohme LLC
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 98
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-07-17
Completion Date: 2028-07-28
Locations: Cleveland Clinic-Taussig Cancer Center ( Site 4036), Cleveland, Ohio, 44195, United States|Rambam Health Care Campus ( Site 4501), Haifa, 3109601, Israel|Rabin Medical Center-Oncology ( Site 4504), Petah Tikva, 4941492, Israel|Asan Medical Center-Department of Oncology ( Site 4901), Seoul, 05505, Korea, Republic of|Samsung Medical Center ( Site 4902), Seoul, 06351, Korea, Republic of

Summary:
This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the safety and preliminary efficacy of sacituzumab tirumotecan plus enfortumab vedotin (EV). Part 2 will be based on Part 1 results and will evaluate the efficacy, pharmacokinetics, and safety of sacituzumab tirumotecan plus EV in combination with pembrolizumab in participants with advanced urothelial carcinoma.

Primary Outcome Measures: Part 1: Percentage of Participants with Dose-limiting toxicities (DLT), A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0). The number of participants who experience a DLT in Part 1 will be reported., Up to 21 days|Part 1: Percentage of Participants Who Experienced At Least One Adverse Event (AE), An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 1 will be reported., Up to ~3 years|Part 1: Percentage of Participants Who Discontinued Study Treatment Due to an AE, An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study treatment due to an AE in Part 1 will be reported., Up to ~2 years|Part 2: Percentage of Participants with DLT, A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the NCI CTCAE 5.0. The number of participants who experience a DLT in Part 2 will be reported., Up to 21 days|Part 2: Percentage of Participants Who Experienced At Least One AE, An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 2 will be reported., Up to ~3 years|Part 2: Percentage of Participants Who Discontinued Study Treatment Due to an AE, An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study treatment due to an AE in Part 2 will be reported., Up to ~2 years|Part 2: Objective Response Rate (ORR), ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) (disappearance of all target lesions) or partial response (PR) (at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by investigator. ORR will be reported for participants in Part 2., Up to ~3 years
Secondary Outcome Measures: Part 1: ORR, ORR is defined as the percentage of participants who achieve a confirmed CR or PR per RECIST 1.1 as assessed by investigator. ORR will be reported for participants in Part 1., Up to ~3 years|Part 2: Duration of Response (DOR), For participants who demonstrate confirmed CR or PR per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by investigator will be presented., Up to ~3 years|Part 1: Maximum Serum Concentration (Cmax) of Sacituzumab Tirumotecan-Antibody-Drug Conjugate (ADC), Blood samples collected at designated time points will be used to determine the Cmax of sacituzumab tirumotecan-ADC in Part 1., Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 1: Serum Trough Concentration (Ctrough) of Sacituzumab Tirumotecan-ADC, Blood samples collected at designated time points will be used to determine the Ctrough of sacituzumab tirumotecan-ADC in Part 1., Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 1: Cmax of Free Payload for Sacituzumab Tirumotecan, Blood samples collected at designated time points will be used to determine the Cmax of free payload for sacituzumab tirumotecan in Part 1., Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 1: Ctrough of Free Payload for Sacituzumab Tirumotecan, Blood samples collected at designated time points will be used to determine the Ctrough of free payload for sacituzumab tirumotecan in Part 1., Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 1: Cmax of Enfortumab Vedotin-ADC, Blood samples collected at designated time points will be used to determine the Cmax of enfortumab vedotin-ADC in Part 1., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8|Part 1: Ctrough of Enfortumab Vedotin-ADC, Blood samples collected at designated time points will be used to determine the Ctrough of enfortumab vedotin-ADC in Part 1., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8|Part 1: Cmax of Free Payload for Enfortumab Vedotin, Blood samples collected at designated time points will be used to determine the Cmax of free payload for EV in Part 1., Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8|Part 1: Ctrough of Free Payload for Enfortumab Vedotin, Blood samples collected at designated time points will be used to determine the Ctrough of free payload for EV in Part 1., Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8|Part 1: Incidence of Antidrug Antibodies (ADA) to Sacituzumab Tirumotecan, Blood samples collected at designated timepoints will be used to determine the ADA response to sacituzumab tirumotecan. The incidence of ADAs over time in Part 1 will be presented., Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 1: Incidence of ADA to Enfortumab Vedotin, Blood samples collected at designated timepoints will be used to determine the ADA response to sacituzumab tirumotecan. The incidence of ADAs over time in Part 1 will be presented., Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4 and 8|Part 2: Cmax of Sacituzumab Tirumotecan-ADC, Blood samples collected at designated time points will be used to determine the Cmax of sacituzumab tirumotecan-ADC in Part 2., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Ctrough of Sacituzumab Tirumotecan-ADC, Blood samples collected at designated time points will be used to determine the Ctrough of sacituzumab tirumotecan-ADC in Part 2., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Cmax of Free Payload for Sacituzumab Tirumotecan, Blood samples collected at designated time points will be used to determine the Cmax of free payload for sacituzumab tirumotecan in Part 2., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Ctrough of Free Payload for Sacituzumab Tirumotecan, Blood samples collected at designated time points will be used to determine the Ctrough of free payload for sacituzumab tirumotecan in Part 2., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Cmax of Enfortumab Vedotin-ADC, Blood samples collected at designated time points will be used to determine the Cmax of enfortumab vedotin-ADC in Part 2., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8|Part 2: Ctrough of Enfortumab Vedotin-ADC, Blood samples collected at designated time points will be used to determine the Ctrough of enfortumab vedotin-ADC in Part 2., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8|Part 2: Cmax of Free Payload for Enfortumab Vedotin, Blood samples collected at designated time points will be used to determine the Cmax of free payload for EV in Part 2., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8|Part 2: Ctrough of Free Payload for Enfortumab Vedotin, Blood samples collected at designated time points will be used to determine the Ctrough of free payload for EV in Part 2., Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8|Part 2: Cmax of Pembrolizumab-ADC, Blood samples collected at designated time points will be used to determine the Cmax of pembrolizumab-ADC., Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Ctrough of Pembrolizumab-ADC, Blood samples collected at designated time points will be used to determine the Ctrough of pembrolizumab-ADC., Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Cmax of Free Payload for Pembrolizumab, Blood samples collected at designated time points will be used to determine the Cmax of free payload for pembrolizumab., Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Ctrough of Free Payload for Pembrolizumab, Blood samples collected at designated time points will be used to determine the Ctrough of free payload for pembrolizumab., Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Incidence of ADA to Sacituzumab Tirumotecan, Blood samples collected at designated timepoints will be used to determine the ADA response to sacituzumab tirumotecan. The incidence of ADAs over time in Part 2 will be presented., Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose|Part 2: Incidence of ADA to Enfortumab Vedotin, Blood samples collected at designated timepoints will be used to determine the ADA response to EV. The incidence of ADAs over time in Part 2 will be presented., Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8|Part 2: Incidence of ADA to Pembrolizumab, Blood samples collected at designated timepoints will be used to determine the ADA response to pembrolizumab. The incidence of ADAs over time be presented., Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose