Substudy 06D: Combination Therapies in Second Line (2L) Gastroesophageal Adenocarcinoma (MK-3475-06D/Keymaker-U06)
- Conditions
- Gastroesophageal AdenocarcinomaEsophageal NeoplasmsGastroesophageal JunctionEsophageal Cancer
- Interventions
- Registration Number
- NCT06445972
- 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 efficacy of MK-2870 plus paclitaxel versus Ramucirumab plus paclitaxel, for the treatment of participants with advanced or metastatic gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, or esophageal adenocarcinoma who have failed 1 prior line of therapy. This is an estimation study, and no formal hypothesis testing will be performed.
- Detailed Description
The master protocol is MK-3475-U06.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 90
The main inclusion criteria include but are not limited to the following:
- Has histologically and/or cytologically confirmed diagnosis of previously treated, 2L (received first line (1L) treatment) gastric adenocarcinoma, GEJ adenocarcinoma, or esophageal adenocarcinoma
- Has metastatic disease or locally advanced, unresectable disease
- Has experienced documented objective radiographic or clinical disease progression during or after 1L therapy containing any platinum/fluoropyrimidine doublet with or without immunotherapy
- Has gastroesophageal adenocarcinoma that is not human epidermal growth factor receptor 2 (HER2)/neu positive
- Has provided an archival tumor tissue sample or most recently obtained core, incisional, or excisional biopsy of a tumor lesion
- AEs due to previous anticancer therapies must be ≤Grade 1 or baseline (except alopecia and vitiligo). Endocrine-related AEs adequately treated with hormone replacement are acceptable.
- Has Eastern Cooperative Oncology Group performance status of 0 or 1
- Has a life expectancy of at least 3 months
- Participants 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
- Participants with history of Hepatitis C Virus (HCV) infection are eligible if HCV viral load is undetectable at screening
- HIV-infected participants must have well controlled Human Immunodeficiency Virus (HIV) on ART (Antiretroviral Therapy)
The main exclusion criteria include but are not limited to the following:
- Has squamous cell or undifferentiated gastroesophageal cancer
- Has experienced weight loss >20% over 3 months before the first dose of study intervention
- Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or 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 a serious or nonhealing wound or peptic ulcer or bone fracture within 28 days prior to randomization
- Has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea)
- Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
- Has experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization
- Has uncontrolled arterial hypertension ≥150/≥90 mm mercury (Hg)
- Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment
- Has undergone major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization or planned major surgery following initiation of study treatment
- Is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin or similar agents
- Is receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs) or other antiplatelet agents
- Has a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to randomization
- Has significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal (GI) tract within 3 months prior to study entry
- Has history of GI perforation and/or fistulae within 6 months prior to randomization
- HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
- Has received prior treatment with a trophoblast cell-surface antigen 2 (TROP2)-targeted antibody-drug conjugate (ADC), topoisomerase 1 inhibitor-based ADC and/or a topoisomerase 1 inhibitor-based chemotherapy
- Has received any previous systemic therapy targeting vascular endothelial growth factor (VEGF) or the vascular endothelial growth factor receptor (VEGFR) signaling pathways
- Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study drug intervention
- 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. Administration of killed vaccines is allowed
- Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
- Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has an active infection requiring systemic therapy
- Has a concurrent active HBV (defined as HBsAg positive and/or detectable HBV deoxyribonucleic acid (DNA)) and HCV (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid (RNA)) infection
- History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
- Has severe hypersensitivity (Grade ≥3) to MK-2870, any of its excipients and/or to another biologic therapy
- Has not adequately recovered from major surgery or have ongoing surgical complications
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description MK-2870 + Paclitaxel MK-2870 Following a 28-day run-in with MK-2870 at 3 mg/kg and 4 mg/kg IV infusion on Days 1 and 15 of a 6-week cycle plus paclitaxel at 80 mg/M\^2 IV infusion on days 1, 8 and 15 of a 4-week cycle, participants will receive paclitaxel at 80 mg/M\^2 IV infusion on days 1, 8, 15 of each 4-week cycle (3 weeks on and 1 week off) up to \~60 weeks plus MK-2870 at selected dose IV infusion on days 1, 15, 29 of every 6-week cycle until discontinuation. Ramucirumab + Paclitaxel Ramucirumab Participants will receive ramucirumab at 8mg/kg via intravenous (IV) infusion on days 1 and 15 of each 4-week cycle for up to \~60 weeks plus paclitaxel at 80 mg/M\^2 via IV infusion on Days 1, 8, and 15 of each 4-week cycle (3 weeks on and 1 week off) for up to \~60 weeks. Ramucirumab + Paclitaxel Paclitaxel Participants will receive ramucirumab at 8mg/kg via intravenous (IV) infusion on days 1 and 15 of each 4-week cycle for up to \~60 weeks plus paclitaxel at 80 mg/M\^2 via IV infusion on Days 1, 8, and 15 of each 4-week cycle (3 weeks on and 1 week off) for up to \~60 weeks. MK-2870 + Paclitaxel Paclitaxel Following a 28-day run-in with MK-2870 at 3 mg/kg and 4 mg/kg IV infusion on Days 1 and 15 of a 6-week cycle plus paclitaxel at 80 mg/M\^2 IV infusion on days 1, 8 and 15 of a 4-week cycle, participants will receive paclitaxel at 80 mg/M\^2 IV infusion on days 1, 8, 15 of each 4-week cycle (3 weeks on and 1 week off) up to \~60 weeks plus MK-2870 at selected dose IV infusion on days 1, 15, 29 of every 6-week cycle until discontinuation.
- Primary Outcome Measures
Name Time Method Percentage of Participants who Discontinue Study Intervention Due to an AE During the Safety Lead-In Phase Up to ~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. The percentage of participants who discontinued study intervention due to an AE will be presented.
Percentage of Particiapants who Experience an Adverse Event (AE) During the Safety Lead-In Phase Up to ~60 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. The percentage of participants who discontinued study intervention due to an AE will be presented.
Objective Response Rate (ORR) Up to ~30 months ORR is defined as the percentage of participants with 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 Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.
Percentage of Participants who Experience Dose Limiting Toxicities (DLTs) During the Safety Lead-In Phase Up to ~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 presented.
- Secondary Outcome Measures
Name Time Method Percentage of Participants who Discontinue Study Intervention Due to an AE During the Efficacy Phase Up to ~52 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. The percentage of participants who discontinued study intervention due to an AE will be presented.
Incidence of MK-2870 anti-drug antibody (ADA) Up to ~52 months In participants treated with MK-2870 the immunogenicity of MK-2870 ADA response will be evaluated iwith validated immunogenicity assays.
Duration of Response (DOR) Up to ~52 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 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 BICR will be presented.
Overall Survival (OS) Up to ~52 months OS is defined as the time from the date of randomization to the date of death from any cause. OS will be presented.
Progression Free Survival (PFS) Up to ~52 months PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as assessed by RECIST 1.1. PD is defined as ≥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 ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.
Percentage of Particiapants who Experience an AE During the Efficacy Phase Up to ~52 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. The percentage of participants who discontinued study intervention due to an AE will be presented.
Trial Locations
- Locations (37)
University of Arizona Cancer Center-University of Arizona Cancer Center ( Site 8927)
🇺🇸Tucson, Arizona, United States
Norton Cancer Institute - Downtown ( Site 8900)
🇺🇸Louisville, Kentucky, United States
The Cancer and Hematology Centers ( Site 8912)
🇺🇸Grand Rapids, Michigan, United States
Hematology-Oncology Associates of Central NY, P.C. ( Site 8925)
🇺🇸East Syracuse, New York, United States
Columbia University Irving Medical Center-CUIMC Herbert Irving Comprehensive Cancer Center Clinical
🇺🇸New York, New York, United States
UPMC Hillman Cancer Center-UPMC ( Site 8904)
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas MD Anderson Cancer Center ( Site 8920)
🇺🇸Houston, Texas, United States
Liga Norte Riograndense Contra o Câncer ( Site 8303)
🇧🇷Natal., Rio Grande Do Norte, Brazil
Hospital Nossa Senhora da Conceição ( Site 8301)
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Centro de Investigación del Maule ( Site 8408)
🇨🇱Talca, Maule, Chile
FALP-UIDO ( Site 8400)
🇨🇱Santiago, Region M. De Santiago, Chile
Centro de Oncología de Precisión-Oncology ( Site 8404)
🇨🇱Santiago, Region M. De Santiago, Chile
Clínica UC San Carlos de Apoquindo ( Site 8405)
🇨🇱Santiago, Region M. De Santiago, Chile
Bradfordhill-Clinical Area ( Site 8401)
🇨🇱Santiago, Region M. De Santiago, Chile
Beijing Cancer hospital-Digestive Oncology ( Site 7500)
🇨🇳Beijing, Beijing, China
The 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army ( Si
🇨🇳Fuzhou, Fujian, China
Henan Cancer Hospital ( Site 7504)
🇨🇳Zhengzhou, Henan, China
The First Affiliated Hospital of Nanchang University ( Site 7514)
🇨🇳Nanchang, Jiangxi, China
The First Affiliated hospital of Xiamen University ( Site 7503)
🇨🇳XiaMen, Fujian, China
Fudan University Shanghai Cancer Center ( Site 7513)
🇨🇳Shanghai, Shanghai, China
Xinjiang Medical University Cancer Hospital - Urumqi ( Site 7506)
🇨🇳Urumqi, Xinjiang, China
Sir Run Run Shaw Hospital of Zhejiang University School of Medicine ( Site 7510)
🇨🇳Hangzhou, Zhejiang, China
Centre Hospitalier Régional Universitaire de Brest - Hôpital-Institut de cancérologie et hématologi
🇫🇷Brest, Finistere, France
CIC. ( Site 7100)
🇫🇷Lille, Nord, France
Pitie Salpetriere University Hospital-Hepato-Gastro-Enterology ( Site 7102)
🇫🇷Paris, France
Facharztzentrum Eppendorf-Facharztzentrum Eppendorf ( Site 8807)
🇩🇪Hamburg, Germany
IRCCS - Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"-Oncologia Medica ( Site 72
🇮🇹Meldola, Emilia-Romagna, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 7200)
🇮🇹Milan, Lombardia, Italy
Asan Medical Center-Department of Oncology ( Site 7901)
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center-Division of Hematology/Oncology ( Site 7900)
🇰🇷Seoul, Korea, Republic of
Oslo universitetssykehus, Radiumhospitalet ( Site 8501)
🇳🇴Oslo, Norway
Hôpitaux Universitaires de Genève (HUG) ( Site 8701)
🇨🇭Genève, Geneve, Switzerland
Kantonsspital Graubünden-Medizin ( Site 8700)
🇨🇭Chur, Grisons, Switzerland
China Medical University Hospital ( Site 8007)
🇨🇳Taichung, Taiwan
National Cheng Kung University Hospital ( Site 8001)
🇨🇳Tainan, Taiwan
National Taiwan University Hospital-Oncology ( Site 8000)
🇨🇳Taipei, Taiwan
Taipei Veterans General Hospital ( Site 8005)
🇨🇳Taipei, Taiwan