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NCT Number: NCT06483334

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)

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.

Active, Not Recruiting

This study is active but is not currently recruiting participants.

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Key information

Conditions

Metastatic Urothelial Carcinoma Carcinoma Carcinoma, Transitional Cell Locally Advanced Urothelial Carcinoma Neoplasms Neoplasms by Histologic Type Neoplasms, Glandular and Epithelial Parkinson Disease 4, Autosomal Dominant Lewy Body

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

The Ottawa Hospital - General Campus ( Site 4105), Ottawa, Ontario, Canada

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Sacituzumab tirumotecan

Biological

IV infusion at different dose levels

Other names: MK-2870, SKB264

Enfortumab Vedotin

Biological

IV infusion at different dose levels

Other names: PADCEV™

Pembrolizumab

Biological

200 mg IV infusion

Other names: MK-3475, KEYTRUDA

Supportive care measures

Drug

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.

Primary outcomes

  1. Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)

    Time frame: 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.

  2. Part 1: Percentage of Participants Who Experienced At Least One Adverse Event (AE)

    Time frame: 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.

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

    Time frame: 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.

  4. Part 2: Percentage of Participants with DLT

    Time frame: 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.

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

    Time frame: 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.

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

    Time frame: 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.

  7. Part 2: Objective Response Rate (ORR)

    Time frame: 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 outcomes

  1. Part 1: ORR

    Time frame: 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.

  2. Part 2: Duration of Response (DOR)

    Time frame: 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.

  3. Part 1: Maximum Serum Concentration (Cmax) of Sacituzumab Tirumotecan-Antibody-Drug Conjugate (ADC)

    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

    Blood samples collected at designated time points will be used to determine the Cmax of sacituzumab tirumotecan-ADC in Part 1.

  4. Part 1: Serum Trough Concentration (Ctrough) of Sacituzumab Tirumotecan-ADC

    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

    Blood samples collected at designated time points will be used to determine the Ctrough of sacituzumab tirumotecan-ADC in Part 1.

  5. Part 1: Cmax of Free Payload for Sacituzumab Tirumotecan

    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

    Blood samples collected at designated time points will be used to determine the Cmax of free payload for sacituzumab tirumotecan in Part 1.

  6. Part 1: Ctrough of Free Payload for Sacituzumab Tirumotecan

    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

    Blood samples collected at designated time points will be used to determine the Ctrough of free payload for sacituzumab tirumotecan in Part 1.

  7. Part 1: Cmax of Enfortumab Vedotin-ADC

    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

    Blood samples collected at designated time points will be used to determine the Cmax of enfortumab vedotin-ADC in Part 1.

  8. Part 1: Ctrough of Enfortumab Vedotin-ADC

    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

    Blood samples collected at designated time points will be used to determine the Ctrough of enfortumab vedotin-ADC in Part 1.

  9. Part 1: Cmax of Free Payload for Enfortumab Vedotin

    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

    Blood samples collected at designated time points will be used to determine the Cmax of free payload for EV in Part 1.

  10. Part 1: Ctrough of Free Payload for Enfortumab Vedotin

    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

    Blood samples collected at designated time points will be used to determine the Ctrough of free payload for EV in Part 1.

  11. Part 1: Incidence of Antidrug Antibodies (ADA) to Sacituzumab Tirumotecan

    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

    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.

  12. Part 1: Incidence of ADA to Enfortumab Vedotin

    Time frame: 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.

  13. Part 2: Cmax of Sacituzumab Tirumotecan-ADC

    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

    Blood samples collected at designated time points will be used to determine the Cmax of sacituzumab tirumotecan-ADC in Part 2.

  14. Part 2: Ctrough of Sacituzumab Tirumotecan-ADC

    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

    Blood samples collected at designated time points will be used to determine the Ctrough of sacituzumab tirumotecan-ADC in Part 2.

  15. Part 2: Cmax of Free Payload for Sacituzumab Tirumotecan

    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

    Blood samples collected at designated time points will be used to determine the Cmax of free payload for sacituzumab tirumotecan in Part 2.

  16. Part 2: Ctrough of Free Payload for Sacituzumab Tirumotecan

    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

    Blood samples collected at designated time points will be used to determine the Ctrough of free payload for sacituzumab tirumotecan in Part 2.

  17. Part 2: Cmax of Enfortumab Vedotin-ADC

    Time frame: 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.

  18. Part 2: Ctrough of Enfortumab Vedotin-ADC

    Time frame: 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.

  19. Part 2: Cmax of Free Payload for Enfortumab Vedotin

    Time frame: 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.

  20. Part 2: Ctrough of Free Payload for Enfortumab Vedotin

    Time frame: 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.

  21. Part 2: 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

    Blood samples collected at designated time points will be used to determine the Cmax of pembrolizumab-ADC.

  22. Part 2: 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

    Blood samples collected at designated time points will be used to determine the Ctrough of pembrolizumab-ADC.

  23. Part 2: 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

    Blood samples collected at designated time points will be used to determine the Cmax of free payload for pembrolizumab.

  24. Part 2: 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

    Blood samples collected at designated time points will be used to determine the Ctrough of free payload for pembrolizumab.

  25. Part 2: Incidence of ADA to Sacituzumab Tirumotecan

    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

    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.

  26. Part 2: Incidence of ADA to Enfortumab Vedotin

    Time frame: 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.

  27. Part 2: Incidence of ADA to Pembrolizumab

    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

    Blood samples collected at designated timepoints will be used to determine the ADA response to pembrolizumab. The incidence of ADAs over time be presented.

Sponsors and collaborators

Lead sponsor

Merck Sharp & Dohme LLC

Industry

Registry information

Official study title

A Phase 1/2 Randomized, Umbrella Study to Evaluate the Efficacy and Safety of MK-2870 Plus Enfortumab Vedotin (EV) With and Without Pembrolizumab, as Treatment for Participants With Advanced Urothelial Carcinoma (KEYMAKER-U04): Substudy 04C

Important dates

Study start
2024
Primary completion
2028
Study completion
2028
First posted
Jul 3, 2024
Registry last updated
Feb 18, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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