Clinical trial NCT06469944: Substudy 06C: A Study of Sacituzumab Tirumotecan (MK-2870) With Pembrolizumab (MK-3475) and Chemotherapy in Participants With First-Line Locally Advanced Unresectable/Metastatic Gastroesophageal Adenocarcinoma (MK-3475-06C/KEYMAKER-U06)
Official title: A Phase 1/2 Open-Label, Umbrella Platform Design Study of MK-2870 With Pembrolizumab (MK-3475) and Chemotherapy in Participants With 1L Locally Advanced Unresectable/Metastatic Gastroesophageal Adenocarcinoma (Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, and Esophageal Adenocarcinoma): Substudy 06C
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Gastroesophageal Junction
Gastroesophageal Adenocarcinoma
Esophageal Neoplasms
Esophageal Cancer
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: 2024-06-24
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase 1/2, multicenter, open-label umbrella platform study that will evaluate the safety and tolerability of sacituzumab tirumotecan with pembrolizumab and fluoropyrimidine chemotherapy for the first-line (1L) treatment of participants with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric, gastroesophageal junction, or esophageal adenocarcinoma.

This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to evaluate the safety and tolerability, and to establish a recommended Phase 2 dose (RP2D) for sacituzumab tirumotecan in combination with chemotherapy and immunotherapy. There is no formal hypothesis in this study.

Detailed description: The master protocol is MK-3475-U06.

Eligibility criteria: Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

* Has histologically and/or cytologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic 1L gastroesophageal adenocarcinoma
* Has gastroesophageal adenocarcinoma that is known to be human epidermal growth factor receptor 2 (HER2)/neu-positive are excluded. HER2 status is not required if HER2/neu testing is not mandatory per local standard of care (SOC)
* Is not expected to require tumor resection during the treatment course
* Has not had prior systemic therapy administered in the recurrent or metastatic setting
* Has provided an archival tumor tissue sample or most recently obtained core, or incisional, or excisional biopsy for a tumor lesion
* Participants who have adverse events (AEs) due to previous anticancer therapies must have recovered to \<Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible
* Has adequate organ function
* Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as determined by the local site investigator/radiology assessment and verified by blind independent review committee (BICR)
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 3 days before allocation/randomization.
* Has a life expectancy of at least 6 months
* Who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.
* Who has history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.
* Human immunodeficiency virus (HIV)-infected participants must have well-controlled HIV on antiretroviral therapy (ART)

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

* Has squamous cell or undifferentiated gastroesophageal cancer.
* Has had previous therapy for locally advanced unresectable or metastatic gastric/GEJ/esophageal adenocarcinoma
* Has experienced weight loss \>20% over 3 months before the first dose of study intervention
* Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing
* Has Grade \>2 peripheral neuropathy
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease within 6 months preceding study intervention
* Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Has received prior treatment with a trophoblast antigen 2 (TROP2)-targeted antibody-drug conjugate (ADC)
* Has received prior treatment with a topoisomerase I inhibitor-based ADC and/or a topoisomerase I inhibitor-based chemotherapy
* Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention
* Has received prior therapy with an anti-Programmed Cell Death Protein 1 (PD-1), anti-Programmed Cell Death-Ligand 1 (PD-L1), anti-Programmed Cell Death-Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR)
* Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation related toxicities, requiring corticosteroids
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
* Has received a strong inducer/inhibitor of CYP3A4 that cannot be discontinued
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
* Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
* Has known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has Severe hypersensitivity (≥Grade 3) to pembrolizumab, sacituzumab tirumotecan, or other biologic therapy, chemotherapy (ie, oxaliplatin, fluorouracil, capecitabine), leucovorin, levoleucovorin, or any of their excipients
* Has active autoimmune disease that has required systemic treatment in the past 2 years
* Has history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
* Has an active infection requiring systemic therapy
* Has concurrent active hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] positive and/or detectable HBV DNA) and hepatitis C virus (defined as anti-hepatitis C virus \[HCV\] Ab positive and detectable HCV ribonucleic acid \[RNA\] infection
* Has GI obstruction, poor oral intake, or difficulty in taking oral medication
* Has poorly controlled diarrhea
* Has had a major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention
* Has history of allogeneic tissue/solid organ transplant
* Have not adequately recovered from major surgery or have ongoing surgical complications

Primary outcomes:
measure: Safety Lead-in Phase: Number of Participants Who Experience One or More Dose-Limiting Toxicities (DLTs)
timeFrame: Up to approximately 28 days
measure: Safety Lead-in Phase: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 28 days
measure: Safety Lead-in Phase: Number of Participants Who Discontinued Study Intervention Due to an AE
timeFrame: Up to approximately 28 days
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blind Independent Review Committee (BICR)
timeFrame: Up to approximately 28 months
Secondary outcomes:
measure: Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 55 months
measure: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 55 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 55 months
measure: Number of Participants Who Experience an Adverse Event (AE)
timeFrame: Up to approximately 55 months
measure: Number of Participants Who Discontinue Study Treatment Due to an AE
timeFrame: Up to approximately 55 months
measure: Incidence of Antidrug Antibodies (ADA) to sacituzumab tirumotecan (sac-TMT, MK-2870)
timeFrame: Predose on Cycle 1 Days 1, 15, and 29; Cycle 2 Days 1, 15, and 29; Cycle 3 Days 1 and 15; Cycle 4 Days 1 and 29; and Cycle 5 Day 15 (each cycle length = 6 weeks)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center-University of Arizona Cancer Center ( Site 6927)
state: Arizona
city: Louisville
country: United States
facility: Norton Hospital-Norton Cancer Institute - Downtown ( Site 6900)
state: Kentucky
city: Grand Rapids
country: United States
facility: The Cancer and Hematology Centers ( Site 6912)
state: Michigan
city: East Syracuse
country: United States
facility: Hematology-Oncology Associates of Central NY, P.C. ( Site 6925)
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center-CUIMC Herbert Irving Comprehensive Cancer Center Clinical ( Site 6907)
state: New York
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center-UPMC ( Site 6904)
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center ( Site 6920)
state: Texas
city: Natal.
country: Brazil
facility: Liga Norte Riograndense Contra o Câncer ( Site 6303)
state: Rio Grande Do Norte
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceição ( Site 6301)
state: Rio Grande Do Sul
city: Puerto Montt
country: Chile
facility: Clínica Puerto Montt ( Site 6409)
state: Los Lagos
city: Talca
country: Chile
facility: Centro de Investigación del Maule ( Site 6408)
state: Maule
city: Santiago
country: Chile
facility: FALP-UIDO ( Site 6400)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Centro de Oncología de Precisión-Oncology ( Site 6404)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Clínica UC San Carlos de Apoquindo ( Site 6405)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Bradfordhill-Clinical Area ( Site 6401)
state: Region M. De Santiago
city: Antofagasta
country: Chile
facility: Bradford Hill Norte ( Site 6407)
city: Beijing
country: China
facility: Beijing Cancer hospital-Digestive Oncology ( Site 5500)
state: Beijing
city: Fuzhou
country: China
facility: The 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army ( Site 5501)
state: Fujian
city: XiaMen
country: China
facility: The First Affiliated hospital of Xiamen University ( Site 5503)
state: Fujian
city: Zhengzhou
country: China
facility: Henan Cancer Hospital ( Site 5504)
state: Henan
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University ( Site 5514)
state: Jiangxi
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center ( Site 5513)
state: Shanghai
city: Urumqi
country: China
facility: Xinjiang Medical University Cancer Hospital - Urumqi ( Site 5506)
state: Xinjiang
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital of Zhejiang University School of Medicine ( Site 5510)
state: Zhejiang
city: Brest
country: France
facility: CHU-BREST Cavale Blanche ( Site 5104)
state: Finistere
city: Lille
country: France
facility: CIC. ( Site 5100)
state: Nord
city: Paris
country: France
facility: Pitie Salpetriere University Hospital-Hepato-Gastro-Enterology ( Site 5102)
city: Hamburg
country: Germany
facility: Facharztzentrum Eppendorf-Facharztzentrum Eppendorf ( Site 6807)
city: Meldola
country: Italy
facility: IRCCS - Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"-Oncologia Medica ( Site 5207)
state: Emilia-Romagna
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 5200)
state: Lombardia
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center-Department of Oncology ( Site 5901)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center-Division of Hematology/Oncology ( Site 5900)
city: Oslo
country: Norway
facility: Oslo universitetssykehus, Radiumhospitalet ( Site 6501)
city: Genève
country: Switzerland
facility: Hôpitaux Universitaires de Genève (HUG) ( Site 6701)
state: Geneve
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden-Medizin ( Site 6700)
state: Grisons
city: Taichung
country: Taiwan
facility: China Medical University Hospital ( Site 6007)
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital ( Site 6001)
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital-Oncology ( Site 6000)
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital ( Site 6005)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: