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)
- Conditions
- Gastroesophageal JunctionGastroesophageal AdenocarcinomaEsophageal NeoplasmsEsophageal Cancer
- Interventions
- Biological: Sacituzumab Tirumotecan (sac-TMT)
- Registration Number
- NCT06469944
- Lead Sponsor
- Merck Sharp & Dohme LLC
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 130
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)
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pembrolizumab plus Chemotherapy Pembrolizumab Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of CAPOX chemotherapy (capecitabine 1000 mg/m\^2 orally twice daily for 14 days every 3 weeks (Q3W) and oxaliplatin 130 mg/m\^2 via IV infusion Q3W) OR mFOLFOX6 chemotherapy (oxaliplatin 85 mg/m\^2 via IV infusion Q3W; 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once every 2 weeks (Q2W); and leucovorin 400 mg/m\^2 via IV infusion Q2W OR levoleucovorin 200 mg/m\^2 Q2W). Pembrolizumab plus Chemotherapy Capecitabine Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of CAPOX chemotherapy (capecitabine 1000 mg/m\^2 orally twice daily for 14 days every 3 weeks (Q3W) and oxaliplatin 130 mg/m\^2 via IV infusion Q3W) OR mFOLFOX6 chemotherapy (oxaliplatin 85 mg/m\^2 via IV infusion Q3W; 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once every 2 weeks (Q2W); and leucovorin 400 mg/m\^2 via IV infusion Q2W OR levoleucovorin 200 mg/m\^2 Q2W). Pembrolizumab plus Chemotherapy Leucovorin Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of CAPOX chemotherapy (capecitabine 1000 mg/m\^2 orally twice daily for 14 days every 3 weeks (Q3W) and oxaliplatin 130 mg/m\^2 via IV infusion Q3W) OR mFOLFOX6 chemotherapy (oxaliplatin 85 mg/m\^2 via IV infusion Q3W; 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once every 2 weeks (Q2W); and leucovorin 400 mg/m\^2 via IV infusion Q2W OR levoleucovorin 200 mg/m\^2 Q2W). Pembrolizumab plus Chemotherapy Levoleucovorin Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of CAPOX chemotherapy (capecitabine 1000 mg/m\^2 orally twice daily for 14 days every 3 weeks (Q3W) and oxaliplatin 130 mg/m\^2 via IV infusion Q3W) OR mFOLFOX6 chemotherapy (oxaliplatin 85 mg/m\^2 via IV infusion Q3W; 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once every 2 weeks (Q2W); and leucovorin 400 mg/m\^2 via IV infusion Q2W OR levoleucovorin 200 mg/m\^2 Q2W). Pembrolizumab plus Chemotherapy 5-FU Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of CAPOX chemotherapy (capecitabine 1000 mg/m\^2 orally twice daily for 14 days every 3 weeks (Q3W) and oxaliplatin 130 mg/m\^2 via IV infusion Q3W) OR mFOLFOX6 chemotherapy (oxaliplatin 85 mg/m\^2 via IV infusion Q3W; 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once every 2 weeks (Q2W); and leucovorin 400 mg/m\^2 via IV infusion Q2W OR levoleucovorin 200 mg/m\^2 Q2W). Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy Pembrolizumab Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 of each 6 week cycle until discontinuation, pembrolizumab 400 mg via IV injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of capecitabine 1000 mg/m\^2 orally twice daily for 14 days Q3W OR 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once Q2W. Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy Sacituzumab Tirumotecan (sac-TMT) Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 of each 6 week cycle until discontinuation, pembrolizumab 400 mg via IV injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of capecitabine 1000 mg/m\^2 orally twice daily for 14 days Q3W OR 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once Q2W. Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy Capecitabine Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 of each 6 week cycle until discontinuation, pembrolizumab 400 mg via IV injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of capecitabine 1000 mg/m\^2 orally twice daily for 14 days Q3W OR 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once Q2W. Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy 5-FU Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 of each 6 week cycle until discontinuation, pembrolizumab 400 mg via IV injection on day 1 of every 6 week cycle for up to 18 cycles (up to \~2 years) AND investigator's choice of capecitabine 1000 mg/m\^2 orally twice daily for 14 days Q3W OR 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once Q2W.
- Primary Outcome Measures
Name Time Method Safety Lead-in Phase: Number of Participants Who Discontinued Study Intervention Due to an AE Up to approximately 28 days An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
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) Up to approximately 28 months ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by BICR will be presented.
Safety Lead-in Phase: Number of Participants Who Experience One or More Dose-Limiting Toxicities (DLTs) Up to approximately 28 days DLTs are defined as any drug-related adverse event (AE) according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) Version 5.0, observed during the DLT evaluation period that results in a change to a given dose or a delay in initiating the next cycle. The percentage of participants who experience at least one DLT will be reported.
Safety Lead-in Phase: Number of Participants Who Experienced an Adverse Event (AE) Up to approximately 28 days An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
- Secondary Outcome Measures
Name Time Method Number of Participants Who Discontinue Study Treatment Due to an AE Up to approximately 55 months An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR Up to approximately 55 months PFS is defined as the time from randomization to the first documented progressive disease (PD) or death from any cause, whichever occurs first. 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. PFS as assessed by BICR will be presented.
Number of Participants Who Experience an Adverse Event (AE) Up to approximately 55 months An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Incidence of Antidrug Antibodies (ADA) to sacituzumab tirumotecan (sac-TMT, MK-2870) 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) Blood samples collected at designated timepoints will be used to determine the ADA response to sac-TMT. The incidence of ADAs over time will be presented.
Overall Survival (OS) Up to approximately 55 months OS is defined as the time from randomization to the date of death from any cause.
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR Up to approximately 55 months For participants who demonstrate 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 RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until 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 BICR will be presented.
Trial Locations
- Locations (37)
The 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army ( Site 5501)
🇨🇳Fuzhou, Fujian, China
Liga Norte Riograndense Contra o Câncer ( Site 6303)
🇧🇷Natal., Rio Grande Do Norte, Brazil
Hospital Nossa Senhora da Conceição ( Site 6301)
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Centro de Investigación del Maule ( Site 6408)
🇨🇱Talca, Maule, Chile
Columbia University Irving Medical Center-CUIMC Herbert Irving Comprehensive Cancer Center Clinical ( Site 6907)
🇺🇸New York, New York, United States
University of Arizona Cancer Center-University of Arizona Cancer Center ( Site 6927)
🇺🇸Tucson, Arizona, United States
IRCCS - Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"-Oncologia Medica ( Site 5207)
🇮🇹Meldola, Emilia-Romagna, Italy
Norton Hospital-Norton Cancer Institute - Downtown ( Site 6900)
🇺🇸Louisville, Kentucky, United States
The Cancer and Hematology Centers ( Site 6912)
🇺🇸Grand Rapids, Michigan, United States
Hematology-Oncology Associates of Central NY, P.C. ( Site 6925)
🇺🇸East Syracuse, New York, United States
UPMC Hillman Cancer Center-UPMC ( Site 6904)
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas MD Anderson Cancer Center ( Site 6920)
🇺🇸Houston, Texas, United States
FALP-UIDO ( Site 6400)
🇨🇱Santiago, Region M. De Santiago, Chile
Centro de Oncología de Precisión-Oncology ( Site 6404)
🇨🇱Santiago, Region M. De Santiago, Chile
Clínica UC San Carlos de Apoquindo ( Site 6405)
🇨🇱Santiago, Region M. De Santiago, Chile
Bradfordhill-Clinical Area ( Site 6401)
🇨🇱Santiago, Region M. De Santiago, Chile
Bradford Hill Norte ( Site 6407)
🇨🇱Antofagasta, Chile
Beijing Cancer hospital-Digestive Oncology ( Site 5500)
🇨🇳Beijing, Beijing, China
The First Affiliated hospital of Xiamen University ( Site 5503)
🇨🇳XiaMen, Fujian, China
Henan Cancer Hospital ( Site 5504)
🇨🇳Zhengzhou, Henan, China
The First Affiliated Hospital of Nanchang University ( Site 5514)
🇨🇳Nanchang, Jiangxi, China
Xinjiang Medical University Cancer Hospital - Urumqi ( Site 5506)
🇨🇳Urumqi, Xinjiang, China
Sir Run Run Shaw Hospital of Zhejiang University School of Medicine ( Site 5510)
🇨🇳Hangzhou, Zhejiang, China
CHU-BREST Cavale Blanche ( Site 5104)
🇫🇷Brest, Finistere, France
CIC. ( Site 5100)
🇫🇷Lille, Nord, France
Pitie Salpetriere University Hospital-Hepato-Gastro-Enterology ( Site 5102)
🇫🇷Paris, France
Facharztzentrum Eppendorf-Facharztzentrum Eppendorf ( Site 6807)
🇩🇪Hamburg, Germany
Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 5200)
🇮🇹Milan, Lombardia, Italy
Asan Medical Center-Department of Oncology ( Site 5901)
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center-Division of Hematology/Oncology ( Site 5900)
🇰🇷Seoul, Korea, Republic of
Oslo universitetssykehus, Radiumhospitalet ( Site 6501)
🇳🇴Oslo, Norway
Hôpitaux Universitaires de Genève (HUG) ( Site 6701)
🇨🇭Genève, Geneve, Switzerland
Kantonsspital Graubünden-Medizin ( Site 6700)
🇨🇭Chur, Grisons, Switzerland
China Medical University Hospital ( Site 6007)
🇨🇳Taichung, Taiwan
National Cheng Kung University Hospital ( Site 6001)
🇨🇳Tainan, Taiwan
National Taiwan University Hospital-Oncology ( Site 6000)
🇨🇳Taipei, Taiwan
Taipei Veterans General Hospital ( Site 6005)
🇨🇳Taipei, Taiwan