A Phase 1b/2 Study of MEDI4736 in Combination With Tremelimumab, MEDI4736 Monotherapy, and Tremelimumab Monotherapy in Subjects With Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 114
- 试验地点
- 29
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Phase 1b
研究概览
简要总结
This is a randomized, multicenter, open-label, dose-exploration and dose-expansion study to evaluate the safety, tolerability, antitumor activity, PK, pharmacodynamics, and immunogenicity of MEDI4736 in combination with tremelimumab, MEDI4736 monotherapy or tremelimumab monotherapy in participants with metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female participants
- •18 years and older
- •Histological or cytological confirmation of metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma
- •Participants must have received and have progressed, or are refractory to standard regimens
- •Participants must have at least one lesion amenable to biospy
排除标准
- •Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment
- •Previous immunotherapy
- •Concurrent or prior use of immunosuppressive medication with 14 days
- •Active or prior documented autoimmune or inflammatory disease within 3 years with some exceptions
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Phase 1b
时间窗: Day 1 up to 90 days after the last dose (approximately 4 years and one month)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1b
时间窗: From first dose of Study drug (Day 1) through 28 days after the administration of MEDI4736 and tremelimumab
A DLT was defined as any Grade 3 or higher toxicity that occurs during the DLT evaluation period (From first dose of Study drug \[Day 1\] through 28 days after the administration of MEDI4736 and tremelimumab). The DLTs are: any Grade 4 immune-related adverse event (irAE), any Grade \>=3 non-irAE, \>= Grade 3 colitis, Grade 3 or 4 noninfectious pneumonitis irrespective of duration, Grade 2 pneumonitis, liver transaminase elevation \> 8 × upper limit of normal (ULN) or total bilirubin \> 5 × ULN. Immune-related AEs are defined as AEs of an immune nature (ie, inflammatory) in the absence of a clear alternative etiology.
Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs in Phase 1b
时间窗: Day 1 up to 90 days after the last dose (approximately 4 years and one month)
Number of participants with clinical laboratory abnormalities reported as TEAEs are reported. Clinical laboratory abnormalities are defined as any abnormal findings in analysis of serum chemistry, hematology, and urine.
Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs in Phase 1b
时间窗: Day 1 up to 90 days after the last dose (approximately 4 years and one month)
Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal findings in the vital signs parameters (temperature, blood pressure \[BP\], pulse rate \[or pulse oximetry at screening\], and respiratory rate). Abnormal physical examinations are defined as any abnormal impact on measurements of height and weight.
Number of Participants With Abnormal Electrocardiograms Reported as TEAEs in Phase 1b
时间窗: Day 1 up to 90 days after the last dose (approximately 4 years and one month)
Number of participants with abnormal electrocardiograms (ECGs) reported as TEAEs are reported. Abnormal ECGs are defined as any abnormal findings in heart rate, PR, RR, QRS and QT intervals from the primary lead of the digital 12-lead ECG.
Percentage of Participants With Objective Response (OR) in Phase 2
时间窗: From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 months post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month)
OR: best overall response (BOR) of confirmed complete response (CR) or partial response (PR) per RECIST v1.1. BOR: best response (CR, PR, stable disease \[SD\], progressive disease \[PD\], and not evaluable) among all overall responses recorded from date of randomization for Arm A, B, C participants or date of first dose of study drug for Arms D, E participants until progression, or last evaluable disease assessment or discontinuation from the study, whichever occurred first. CR: disappearance of all target/non-target lesions; PR: at least 30% decrease in sum of diameters (SOD) of target lesions from baseline; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD from smallest SOD on study; PD: at least 20% increase in SOD of target lesions from smallest sum on study (at least 5mm), appearance of one or more new lesions, substantial worsening in non-target disease, increase in tumor burden leading to discontinuation of therapy.
Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline in Phase 1b
时间窗: Baseline (Day 1)
The ECOG scale of performance status describes the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. ECOG Performance Status Scorings are: 0= fully active, able to carry on all pre-disease performance without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (for example, light house work, office work); 2= ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3= capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed or chair; 5= dead. The baseline performance status of participants is presented.
Progression Free Survival at 6 (PFS-6) Month in Phase 2
时间窗: From Day 1 upto 6 months
The PFS-6 is the 6-month progression-free survival rate, which was the percentage of participants who were progression free and alive at 6 months. PFS was defined as the time from the date of first dose of study drug for Arm A, B, and C participants or the date of first dose of study drug for Arm D and Arm E participants to the earlier of the dates of the first objective documentation of radiographic disease progression (per RECIST v1.1) or death due to any cause. PFS was censored at the date of their last evaluable tumor assessment. Kaplan Meier method was used to evaluate PFS-6.
次要结局
- Percentage of Participants With Objective Response in Phase 1b(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 months post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))
- Duration of Stable Disease (DSD) in Phase 1b(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 months post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))
- Median Best Percentage Change From Baseline of the Sum of Longest Diameters (SLD) of Target Lesions in Phase 1b(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 months post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))
- Percentage of Participants With Disease Control at 16 Weeks in Phase 1b(From Day 1 up to 16 weeks)
- Percentage of Participants With Disease Control at 24 Weeks in Phase 1b(From Day 1 up to 24 weeks)
- Progression Free Survival at 6 Month in Phase 1b(From Day 1 upto 6 months)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Phase 2(Day 1 up to 90 days after the last dose (approximately 4 years and one month))
- Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline in Phase 2(Baseline (Day 1))
- Percentage of Participants With Disease Control at 16 Weeks in Phase 2(From Day 1 up to 16 weeks)
- Median Best Percentage Change From Baseline of the Sum of Longest Diameters (SLD) of Target Lesions in Phase 2(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 month post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))
- Percentage of Participants With Objective Response With Positive Interferon Gamma (IFN-γ) Gene Expression in Phase 2(Day 1 through Day 30 post EOT (approximately 4 years and one month))
- Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs in Phase 2(Day 1 up to 90 days after the last dose (approximately 4 years and one month))
- Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs in Phase 2(Day 1 up to 90 days after the last dose (approximately 4 years and one month))
- Number of Participants With Abnormal Electrocardiograms Reported as TEAEs in Phase 2(Day 1 up to 90 days after the last dose (approximately 4 years and one month))
- Percentage of Participants With Disease Control at 24 Weeks in Phase 2(From Day 1 up to 24 weeks)
- Overall Survival at 12 Months in Phase 2(From Day 1 up to 12 months)
- Percentage of Participants With Objective Response in Phase 2 by Programmed Death-ligand (PD-L1) Status(Day 1 through Day 30 post EOT (approximately 4 years and one month))
- Duration of Response (DoR) in Phase 2(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 month post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))
- Time to Response (TTR) in Phase 2(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 month post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))
- Duration of Stable Disease in Phase 2(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 month post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))
- Percentage of Participants With Progression Free Survival (PFS) at 6 Month With Positive IFN-γ Gene Expression in Phase 2(Day 1 through Day 30 post EOT (approximately 4 years and one month))
- Progression Free Survival in Phase 2(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 month post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))
- Progression Free Survival at 9 Month (PFS-9) in Phase 2(From Day 1 up to 9 months)
- Overall Survival (OS) in Phase 2(From Day 1 up to End of the Treatment (EOT), 90 days post-EOT, every 3 months (Q3M) after Day 90 post-EOT up to 12 month post-EOT, and every 6 months after month 12 post-EOT (approximately up to 4 years and one month))