Metastatic Urothelial Carcinoma, Locally Advanced Urothelial Carcinoma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1(PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Brief 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.
Detailed description
The master study for this substudy is MK-3475-U04/KEYMAKER-U04. The master study will not be screening any participants and will not be registered. As of Amendment 5, Part 2 will not be conducted. No participants will be enrolled in Part 2, and no data for Part 2 will be collected.
Interventions
BIOLOGICALSacituzumab tirumotecan
IV infusion at different dose levels
BIOLOGICALEnfortumab Vedotin
IV infusion at different dose levels
BIOLOGICALPembrolizumab
200 mg IV infusion
Participants are allowed to take supportive care measures at the discretion of the investigator. Prophylactic supportive care measures may include but are not limited to antiemetic agents, antidiarrheal agents, granulocyte and erythroid growth factors, and blood transfusions.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part 1 is non-randomized open-label. Part 2 is randomized open-label (as of Amendment 5, Part 2 will not be conducted).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The main inclusion criteria include but are not limited to the following: * Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC). * 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. * Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement are eligible. * PART 1 ONLY: Participants must have received platinum-based chemotherapy for treatment of la/mUC. * PART 1 ONLY: Participants must not have received \>2 lines of therapy for la/mUC. Platinum-based chemotherapy followed by avelumab maintenance is considered 2 lines of therapy. * PART 2 ONLY: Participants must not have received prior systemic therapy for la/mUC.
Exclusion criteria
The main
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants with Dose-limiting toxicities (DLT) | Up to 21 days | 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. |
| Part 1: Percentage of Participants Who Experienced At Least One Adverse Event (AE) | Up to ~3 years | 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. |
| Part 1: Percentage of Participants Who Discontinued Study Treatment Due to an AE | Up to ~2 years | 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. |
| Part 2: Percentage of Participants with DLT | Up to 21 days | 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. |
| Part 2: Percentage of Participants Who Experienced At Least One AE | Up to ~3 years | 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. |
| Part 2: Percentage of Participants Who Discontinued Study Treatment Due to an AE | Up to ~2 years | 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. |
| Part 2: Objective Response Rate (ORR) | Up to ~3 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: ORR | Up to ~3 years | 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. |
| Part 2: Duration of Response (DOR) | Up to ~3 years | 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. |
| Part 1: Maximum Serum Concentration (Cmax) of Sacituzumab Tirumotecan-Antibody-Drug Conjugate (ADC) | 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 | Blood samples collected at designated time points will be used to determine the Cmax of sacituzumab tirumotecan-ADC in Part 1. |
| Part 1: Serum Trough Concentration (Ctrough) of Sacituzumab Tirumotecan-ADC | 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 | Blood samples collected at designated time points will be used to determine the Ctrough of sacituzumab tirumotecan-ADC in Part 1. |
| Part 1: Cmax of Free Payload for Sacituzumab Tirumotecan | 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 | Blood samples collected at designated time points will be used to determine the Cmax of free payload for sacituzumab tirumotecan in Part 1. |
| Part 1: Ctrough of Free Payload for Sacituzumab Tirumotecan | 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 | Blood samples collected at designated time points will be used to determine the Ctrough of free payload for sacituzumab tirumotecan in Part 1. |
| Part 1: Cmax of Enfortumab Vedotin-ADC | 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 | Blood samples collected at designated time points will be used to determine the Cmax of enfortumab vedotin-ADC in Part 1. |
| Part 1: Ctrough of Enfortumab Vedotin-ADC | 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 | Blood samples collected at designated time points will be used to determine the Ctrough of enfortumab vedotin-ADC in Part 1. |
| Part 1: Cmax of Free Payload for Enfortumab Vedotin | 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 | Blood samples collected at designated time points will be used to determine the Cmax of free payload for EV in Part 1. |
| Part 1: Ctrough of Free Payload for Enfortumab Vedotin | 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 | Blood samples collected at designated time points will be used to determine the Ctrough of free payload for EV in Part 1. |
| Part 1: Incidence of Antidrug Antibodies (ADA) to Sacituzumab Tirumotecan | 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 | 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. |
| Part 1: Incidence of ADA to Enfortumab Vedotin | Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4 and 8 | 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. |
| Part 2: Cmax of Sacituzumab Tirumotecan-ADC | 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 | Blood samples collected at designated time points will be used to determine the Cmax of sacituzumab tirumotecan-ADC in Part 2. |
| Part 2: Ctrough of Sacituzumab Tirumotecan-ADC | 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 | Blood samples collected at designated time points will be used to determine the Ctrough of sacituzumab tirumotecan-ADC in Part 2. |
| Part 2: Cmax of Free Payload for Sacituzumab Tirumotecan | 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 | Blood samples collected at designated time points will be used to determine the Cmax of free payload for sacituzumab tirumotecan in Part 2. |
| Part 2: Ctrough of Free Payload for Sacituzumab Tirumotecan | 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 | Blood samples collected at designated time points will be used to determine the Ctrough of free payload for sacituzumab tirumotecan in Part 2. |
| Part 2: Cmax of Enfortumab Vedotin-ADC | Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 | Blood samples collected at designated time points will be used to determine the Cmax of enfortumab vedotin-ADC in Part 2. |
| Part 2: Ctrough of Enfortumab Vedotin-ADC | Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 | Blood samples collected at designated time points will be used to determine the Ctrough of enfortumab vedotin-ADC in Part 2. |
| Part 2: Cmax of Free Payload for Enfortumab Vedotin | Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 | Blood samples collected at designated time points will be used to determine the Cmax of free payload for EV in Part 2. |
| Part 2: Ctrough of Free Payload for Enfortumab Vedotin | Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 | Blood samples collected at designated time points will be used to determine the Ctrough of free payload for EV in Part 2. |
| Part 2: 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 | Blood samples collected at designated time points will be used to determine the Cmax of pembrolizumab-ADC. |
| Part 2: 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 | Blood samples collected at designated time points will be used to determine the Ctrough of pembrolizumab-ADC. |
| Part 2: 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 | Blood samples collected at designated time points will be used to determine the Cmax of free payload for pembrolizumab. |
| Part 2: 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 | Blood samples collected at designated time points will be used to determine the Ctrough of free payload for pembrolizumab. |
| Part 2: Incidence of ADA to Sacituzumab Tirumotecan | 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 | 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. |
| Part 2: Incidence of ADA to Enfortumab Vedotin | Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 | 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. |
| Part 2: Incidence of ADA to Pembrolizumab | 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 | Blood samples collected at designated timepoints will be used to determine the ADA response to pembrolizumab. The incidence of ADAs over time be presented. |
Countries
Canada, France, Israel, Italy, Netherlands, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Outcome results
None listed