Clinical trial 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)
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastatic Urothelial Carcinoma
Locally Advanced Urothelial Carcinoma
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)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2024-07-03
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Part 1 is non-randomized open-label. Part 2 is randomized open-label.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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 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.

Primary outcomes:
measure: Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)
timeFrame: Up to 21 days
measure: Part 1: Percentage of Participants Who Experienced At Least One Adverse Event (AE)
timeFrame: Up to ~3 years
measure: Part 1: Percentage of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to ~2 years
measure: Part 2: Percentage of Participants with DLT
timeFrame: Up to 21 days
measure: Part 2: Percentage of Participants Who Experienced At Least One AE
timeFrame: Up to ~3 years
measure: Part 2: Percentage of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to ~2 years
measure: Part 2: Objective Response Rate (ORR)
timeFrame: Up to ~3 years
Secondary outcomes:
measure: Part 1: ORR
timeFrame: Up to ~3 years
measure: Part 2: Duration of Response (DOR)
timeFrame: Up to ~3 years
measure: Part 1: Maximum Serum Concentration (Cmax) of Sacituzumab Tirumotecan-Antibody-Drug Conjugate (ADC)
timeFrame: 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
measure: Part 1: Serum Trough Concentration (Ctrough) of Sacituzumab Tirumotecan-ADC
timeFrame: 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
measure: Part 1: Cmax of Free Payload for Sacituzumab Tirumotecan
timeFrame: 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
measure: Part 1: Ctrough of Free Payload for Sacituzumab Tirumotecan
timeFrame: 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
measure: Part 1: Cmax of Enfortumab Vedotin-ADC
timeFrame: 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
measure: Part 1: Ctrough of Enfortumab Vedotin-ADC
timeFrame: 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
measure: Part 1: Cmax of Free Payload for Enfortumab Vedotin
timeFrame: 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
measure: Part 1: Ctrough of Free Payload for Enfortumab Vedotin
timeFrame: 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
measure: Part 1: Incidence of Antidrug Antibodies (ADA) to Sacituzumab Tirumotecan
timeFrame: 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
measure: Part 1: Incidence of ADA to Enfortumab Vedotin
timeFrame: Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4 and 8
measure: Part 2: Cmax of Sacituzumab Tirumotecan-ADC
timeFrame: 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
measure: Part 2: Ctrough of Sacituzumab Tirumotecan-ADC
timeFrame: 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
measure: Part 2: Cmax of Free Payload for Sacituzumab Tirumotecan
timeFrame: 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
measure: Part 2: Ctrough of Free Payload for Sacituzumab Tirumotecan
timeFrame: 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
measure: Part 2: Cmax of Enfortumab Vedotin-ADC
timeFrame: Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8
measure: Part 2: Ctrough of Enfortumab Vedotin-ADC
timeFrame: Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8
measure: Part 2: Cmax of Free Payload for Enfortumab Vedotin
timeFrame: Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8
measure: Part 2: Ctrough of Free Payload for Enfortumab Vedotin
timeFrame: Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8
measure: Part 2: Cmax of Pembrolizumab-ADC
timeFrame: 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
measure: Part 2: Ctrough of Pembrolizumab-ADC
timeFrame: 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
measure: Part 2: Cmax of Free Payload for Pembrolizumab
timeFrame: 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
measure: Part 2: Ctrough of Free Payload for Pembrolizumab
timeFrame: 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
measure: Part 2: Incidence of ADA to Sacituzumab Tirumotecan
timeFrame: 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
measure: Part 2: Incidence of ADA to Enfortumab Vedotin
timeFrame: Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8
measure: Part 2: Incidence of ADA to Pembrolizumab
timeFrame: 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
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco HDFCCC ( Site 4044)
state: California
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center ( Site 4011)
state: Indiana
city: Boston
country: United States
facility: Dana-Farber Cancer Institute ( Site 4047)
state: Massachusetts
city: Saint Louis
country: United States
facility: Siteman Cancer Center ( Site 4038)
state: Missouri
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai ( Site 4018)
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic-Taussig Cancer Center ( Site 4036)
state: Ohio
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute-HCI Clinical Trials Office ( Site 4041)
state: Utah
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus ( Site 4105)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 4106)
state: Ontario
city: Pierre-Benite
country: France
facility: Centre Hospitalier Lyon Sud ( Site 4606)
state: Rhone-Alpes
city: Haifa
country: Israel
facility: Rambam Health Care Campus ( Site 4501)
city: Petah Tikva
country: Israel
facility: Rabin Medical Center-Oncology ( Site 4504)
city: Ramat Gan
country: Israel
facility: Sheba Medical Center-ONCOLOGY ( Site 4503)
city: Milano
country: Italy
facility: Ospedale San Raffaele-Oncologia Medica ( Site 4403)
state: Lombardia
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori ( Site 4405)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System-Medical oncology ( Site 4903)
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center-Department of Oncology ( Site 4901)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 4902)
city: Amsterdam
country: Netherlands
facility: Nederlands Kanker Instituut - Antoni van Leeuwenhoek - NKI-AVL ( Site 4302)
state: Noord-Holland
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron-Oncology ( Site 4767)
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos ( Site 4765)
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital-Clinical Trial Center ( Site 4803)
city: London
country: United Kingdom
facility: St Bartholomew s Hospital ( Site 4206)
state: London, City Of
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: