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 sacituzumab tirumotecan (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
This is a substudy of the master protocol MK-3475-U06 (KEYMAKER-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
- Participants with gastroesophageal adenocarcinoma that is known to be human epidermal growth factor receptor 2 (HER2)/neu positive are excluded. Participants with unknown HER2 status are eligible.
- 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.
- Human Immunodeficiency Virus (HIV)-infected participants must have well controlled HIV on 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 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 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) and HCV (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid) infection
- History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
- Has severe hypersensitivity (Grade ≥3) to sacituzumab tirumotecan, 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 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. Sacituzumab Tirumotecan + Paclitaxel Paclitaxel Following a 28-day run-in with sacituzumab tirumotecan 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 sacituzumab tirumotecan at selected dose IV infusion on days 1, 15, 29 of every 6-week cycle until discontinuation. Sacituzumab Tirumotecan + Paclitaxel Sacituzumab Tirumotecan Following a 28-day run-in with sacituzumab tirumotecan 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 sacituzumab tirumotecan at selected dose IV infusion on days 1, 15, 29 of every 6-week cycle until discontinuation. Sacituzumab Tirumotecan + Paclitaxel Rescue Medications Following a 28-day run-in with sacituzumab tirumotecan 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 sacituzumab tirumotecan 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 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.
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.
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.
Objective Response Rate (ORR) Up to ~28 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.
- Secondary Outcome Measures
Name Time Method Progression Free Survival (PFS) Up to ~50 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.
Overall Survival (OS) Up to ~50 months OS is defined as the time from the date of randomization to the date of death from any cause. OS will be presented.
Duration of Response (DOR) Up to ~50 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.
Percentage of Particiapants who Experience an AE During the Efficacy Phase Up to ~50 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.
Percentage of Participants who Discontinue Study Intervention Due to an AE During the Efficacy Phase Up to ~50 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 sacituzumab tirumotecan anti-drug antibody (ADA) Up to ~50 months In participants treated with sacituzumab tirumotecan the immunogenicity of sacituzumab tirumotecan ADA response will be evaluated with validated immunogenicity assays.
Trial Locations
- Locations (42)
University of Arizona Cancer Center-University of Arizona Cancer Center ( Site 8927)
🇺🇸Tucson, Arizona, United States
UCLA Hematology/Oncology - Santa Monica ( Site 8905)
🇺🇸Los Angeles, California, 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 ( Site 8907)
🇺🇸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
Scroll for more (32 remaining)University of Arizona Cancer Center-University of Arizona Cancer Center ( Site 8927)🇺🇸Tucson, Arizona, United StatesStudy CoordinatorContact888-577-8839