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)

Phase 2Active Not RecruitingNCT06483334

Merck Sharp & Dohme LLC38 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metastatic Urothelial Carcinoma Locally Advanced Urothelial Carcinoma

Interventions

Sacituzumab tirumotecanBIOLOGICAL

IV infusion at different dose levels

Enfortumab VedotinBIOLOGICAL

IV infusion at different dose levels

PembrolizumabBIOLOGICAL

200 mg IV infusion

Supportive care measuresDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 exclusion criteria include but are not limited to the following: * Known additional malignancy that is progressing or has required active treatment within the past 3 years. * Known active central nervous system metastases and/or carcinomatous meningitis. * Has Grade ≥2 peripheral neuropathy. * Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing. * Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea). * Has uncontrolled, significant cardiovascular disease or cerebrovascular disease and/or serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention. * Has active keratitis or corneal ulcerations. Superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator. * Has a history of uncontrolled diabetes. * Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. * Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. * PART 2 ONLY: Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before 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. * PART 2 ONLY: Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy. * Is human immunodeficiency virus (HIV)-infected and has a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease. * Has active Hepatitis B or Hepatitis C virus infection. * Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. * Has an active infection requiring systemic therapy. * PART 2 ONLY: History of allogeneic tissue/solid organ transplant. * Has not adequately recovered from major surgery or has ongoing surgical complications.

Locations (25)

University of California San Francisco HDFCCC ( Site 4044)

San Francisco, California, United States

University of Chicago Medical Center ( Site 4037)

Chicago, Illinois, United States

Indiana University Melvin and Bren Simon Cancer Center ( Site 4011)

Indianapolis, Indiana, United States

Dana-Farber Cancer Institute ( Site 4047)

Boston, Massachusetts, United States

Siteman Cancer Center ( Site 4038)

St Louis, Missouri, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Up to ~3 years

Part 1: Percentage of Participants Who Discontinued Study Treatment Due to an AE

Time frame: 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.

Time frame: Up to 21 days

Part 2: Percentage of Participants Who Experienced At Least One AE

Time frame: Up to ~3 years

Part 2: Percentage of Participants Who Discontinued Study Treatment Due to an AE

Time frame: 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.

Time frame: Up to ~3 years

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Icahn School of Medicine at Mount Sinai ( Site 4018)

New York, New York, United States

Cleveland Clinic-Taussig Cancer Center ( Site 4036)

Cleveland, Ohio, United States

Huntsman Cancer Institute-HCI Clinical Trials Office ( Site 4041)

Salt Lake City, Utah, United States

The Ottawa Hospital - General Campus ( Site 4105)

Ottawa, Ontario, Canada

Princess Margaret Cancer Centre ( Site 4106)

Toronto, Ontario, Canada

...and 15 more locations

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.

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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