A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents 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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 160
- 试验地点
- 95
- 主要终点
- Safety Lead-in Phase: Number of Participants Who Experienced an Adverse Event (AE)
研究概览
简要总结
This is a phase 1/2, multicenter, open-label umbrella platform study that will evaluate the safety and tolerability of investigational agents 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 investigational agents in combination with chemotherapy and immunotherapy. There is no formal hypothesis in this study.
详细描述
The master protocol is MK-3475-U06.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 first-line (1L) gastroesophageal adenocarcinoma
- •Is not expected to require tumor resection during the treatment course
- •Tumor tissue must be confirmed as negative for human epidermal growth factor receptor 2 (HER2) expression as classified by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines
- •Core/excisional biopsy of a tumor lesion not previously irradiated has been provided
- •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 blinded independent central review (BICR)
- •Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to the first dose of study intervention
- •Has a life expectancy of at least 6 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 allocation/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
排除标准
- •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/gastroesophageal junction (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
- •Has history of human immunodeficiency virus (HIV) infection with Kaposi's sarcoma and/or Multicentric Castleman's Disease
- •Has received prior treatment with a trophoblast antigen 2 (TROP2)-targeted or anti-human epidermal growth factor receptor 3 (HER3) targeted agents
- •Has received prior treatment with a topoisomerase I inhibitor-based antibody-drug conjugate (ADC) and/or a topoisomerase I inhibitor-based chemotherapy
- •Has received prior systemic anticancer therapy 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, patritumab deruxtecan, 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 interstitial lung disease (ILD)/pneumonitis irrespective of steroid use, or current ILD, or suspected ILD, or ILD that cannot be ruled out by imaging at Screening
- •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 or a known history of hepatitis B and/or C infection
- •Has history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's ability to cooperate with the requirements of the study
- •Has gastrointestinal (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
- •Has not adequately recovered from major surgery or has ongoing surgical complications
研究组 & 干预措施
Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy
Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Leucovorin (Drug)
Pembrolizumab plus Patritumab Deruxtecan plus Chemotherapy
Participants will receive patritumab deruxtecan via IV infusion on Days 1 and 22 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: 5-Fluorouracil (5-FU) (Drug)
Pembrolizumab plus Chemotherapy
Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle (Q6W) 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-Fluorouracil (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).
干预措施: Capecitabine (Drug)
Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy
Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Sacituzumab Tirumotecan (sac-TMT) (Biological)
Pembrolizumab plus Chemotherapy
Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle (Q6W) 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-Fluorouracil (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).
干预措施: 5-Fluorouracil (5-FU) (Drug)
Pembrolizumab plus Chemotherapy
Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle (Q6W) 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-Fluorouracil (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).
干预措施: Oxaliplatin (Drug)
Pembrolizumab plus Chemotherapy
Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle (Q6W) 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-Fluorouracil (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).
干预措施: Pembrolizumab (Biological)
Pembrolizumab plus Chemotherapy
Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle (Q6W) 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-Fluorouracil (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).
干预措施: Levoleucovorin (Drug)
Pembrolizumab plus Chemotherapy
Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle (Q6W) 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-Fluorouracil (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).
干预措施: Leucovorin (Drug)
Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy
Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: 5-Fluorouracil (5-FU) (Drug)
Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy
Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Levoleucovorin (Drug)
Pembrolizumab plus Patritumab Deruxtecan plus Chemotherapy
Participants will receive patritumab deruxtecan via IV infusion on Days 1 and 22 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Levoleucovorin (Drug)
Pembrolizumab plus Patritumab Deruxtecan plus Chemotherapy
Participants will receive patritumab deruxtecan via IV infusion on Days 1 and 22 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Patritumab Deruxtecan (Biological)
Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy
Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Pembrolizumab (Biological)
Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy
Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Capecitabine (Drug)
Pembrolizumab plus Patritumab Deruxtecan plus Chemotherapy
Participants will receive patritumab deruxtecan via IV infusion on Days 1 and 22 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Capecitabine (Drug)
Pembrolizumab plus Patritumab Deruxtecan plus Chemotherapy
Participants will receive patritumab deruxtecan via IV infusion on Days 1 and 22 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Leucovorin (Drug)
Pembrolizumab plus Patritumab Deruxtecan plus Chemotherapy
Participants will receive patritumab deruxtecan via IV infusion on Days 1 and 22 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W 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 2400 mg/m^2 IV once Q2W AND leucovorin 400 mg/m^2 via IV infusion Q2W OR levoleucovorin 200 mg/m^2 Q2W.
干预措施: Pembrolizumab (Biological)
结局指标
主要结局
Safety Lead-in Phase: Number of Participants Who Experienced an Adverse Event (AE)
时间窗: 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.
Safety Lead-in Phase: Number of Participants Who Experience One or More Dose-Limiting Toxicities (DLTs)
时间窗: Up to approximately 28 days
DLTs are defined as any treatment-emergent adverse events (TEAEs) not attributable to disease or disease-related processes that occur during the DLT evaluation period and are a Grade 3 or higher according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) Version 5.0. 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)
时间窗: 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.
Safety Lead-in Phase: Number of Participants Who Discontinued Study Intervention Due to an AE
时间窗: 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 Blinded Independent Central Review (BICR)
时间窗: 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.
次要结局
- Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR(Up to approximately 55 months)
- Number of Participants Who Experience an Adverse Event (AE)(Up to approximately 55 months)
- Number of Participants Who Discontinue Study Treatment Due to an AE(Up to approximately 55 months)
- Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR(Up to approximately 55 months)
- Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR(Up to approximately 55 months)
- Overall Survival (OS)(Up to approximately 55 months)
- Number of Participants Who Experience an Adverse Event (AE)(Up to approximately 55 months)
- Number of Participants Who Discontinue Study Treatment Due to an AE(Up to approximately 55 months)
- Incidence of Antidrug Antibodies (ADA) to investigational agents - (sacituzumab tirumotecan (sac-TMT, MK-2870) and patritumab deruxtecan (HER3-DXd))(At designated timepoints up to approximately 55 months)