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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
114
MEDI4736 will be administered by IV infusion in combination with tremelimumab.
MEDI4736 will be administered by IV infusion in combination with tremelimumab.
MEDI4736 will be administered by IV infusion.
Research Site
Los Angeles, California, United States
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Phase 1b
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.
Time frame: Day 1 up to 90 days after the last dose (approximately 4 years and one month)
Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1b
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.
Time frame: From first dose of Study drug (Day 1) through 28 days after the administration of MEDI4736 and tremelimumab
Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs in Phase 1b
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.
Time frame: 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 1b
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Tremelimumab will be administered by IV infusion.
MEDI4736 will be administered by IV infusion in combination with tremelimumab.
MEDI4736 will be administered by IV infusion in combination with tremelimumab.
Research Site
Santa Monica, California, United States
Research Site
New Haven, Connecticut, United States
Research Site
Tampa, Florida, United States
Research Site
Chicago, Illinois, United States
Research Site
Baltimore, Maryland, United States
Research Site
New York, New York, United States
Research Site
New York, New York, United States
Research Site
New York, New York, United States
Research Site
Cleveland, Ohio, United States
...and 18 more locations
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.
Time frame: 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 1b
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.
Time frame: 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 1b
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.
Time frame: Baseline (Day 1)
Percentage of Participants With Objective Response (OR) in Phase 2
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.
Time frame: 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)
Progression Free Survival at 6 (PFS-6) Month in Phase 2
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.
Time frame: From Day 1 upto 6 months
Percentage of Participants With Objective Response in Phase 1b
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 of participants or date of first dose of study drug 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.
Time frame: 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
The DSD was defined as the time from the date of first dose of study treatment for Phase 1b until the first date of documented PD (per RECIST v1.1), or death due to any cause, whichever occurred first. PD is at least a 20% increase in sum of diameters 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. Kaplan Meier method was used to evaluate DSD.
Time frame: 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
Best percentage change from baseline of the SLD of target lesions per RECIST v1.1 was derived as the biggest decease or the smallest increase from baseline on the SLD among all post-baseline disease assessment including unscheduled assessments. Best percent change is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction.
Time frame: 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
The disease control rate at 16 weeks was defined as the percentage of participants who achieved a BOR of confirmed CR, confirmed PR, or had SD with duration of SD for a minimum duration of 110 days, following the date of first dose of study drug. The DC was defined as a BOR of confirmed CR, confirmed PR or SD per RECIST v1.1. 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.
Time frame: From Day 1 up to 16 weeks
Percentage of Participants With Disease Control at 24 Weeks in Phase 1b
The disease control rate at 24 weeks was defined as the percentage of participants who achieved a BOR of confirmed CR, confirmed PR, or had SD with duration of SD for a minimum duration of 166 days, following the date of first dose of study drug. The DC was defined as a BOR of confirmed CR, confirmed PR or SD per RECIST v1.1. 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.
Time frame: From Day 1 up to 24 weeks
Progression Free Survival at 6 Month in Phase 1b
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 Phase 1b 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.
Time frame: 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
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.
Time frame: 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 in Phase 2
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.
Time frame: 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
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.
Time frame: 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
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.
Time frame: 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
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.
Time frame: Baseline (Day 1)
Percentage of Participants With Disease Control at 16 Weeks in Phase 2
The disease control rate at 16 weeks was defined as the percentage of participants who achieved a BOR of confirmed CR, confirmed PR, or had SD with duration of SD for a minimum duration of 110 days, following the date of randomization for Arm A, B, and C participants and the date of first dose of study drug for Arm D and E participants. The DC was defined as a BOR of confirmed CR, confirmed PR or SD per RECIST v1.1. 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.
Time frame: From Day 1 up to 16 weeks
Percentage of Participants With Disease Control at 24 Weeks in Phase 2
The disease control rate at 24 weeks was defined as the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or had SD with duration of SD for a minimum duration of 166 days, following the date of randomization for Arm A, B, and C participants and the date of first dose of study drug for Arm D and E participants. The DC was defined as a BOR of confirmed CR, confirmed PR or SD per RECIST v1.1. 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.
Time frame: From Day 1 up to 24 weeks
Duration of Response (DoR) in Phase 2
The DoR was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression according to RECIST v1.1 that occurred subsequently after response or death due to any cause, 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. Kaplan Meier method was used to evaluate DoR.
Time frame: 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
TTR: time from date of randomization of participants for Arm A, B, and C or date of first dose of study drug for Arm D and Arm E until first documented OR per RECIST v1.1. OR: BOR of confirmed CR or PR per RECIST v1.1. BOR: best response (CR, PR, SD, PD, and not evaluable) among all overall responses recorded from date of randomization/date of first dose of study drug 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 SOD of target lesions from baseline; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD from smallest SOD; PD: at least 20% increase in SOD of target lesions from smallest sum (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. Kaplan Meier method used to evaluate TTR.
Time frame: 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
The DSD was defined as the time from the date of randomization for Arm A, B, and C participants or the date of first dose of study drug for Arm D and Arm E participants until the first date of documented PD (per RECIST v1.1), or death due to any cause, whichever occurred first. PD is at least a 20% increase in sum of diameters of target lesions from smallest sum on study (at least 5 mm), appearance of one or more new lesions, substantial worsening in non-target disease, increase in tumor burden leading to discontinuation of therapy. Kaplan Meier method was used to evaluate DSD.
Time frame: 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)
Median Best Percentage Change From Baseline of the Sum of Longest Diameters (SLD) of Target Lesions in Phase 2
Best percentage change from baseline of the SLD of target lesions per RECIST v1.1 was derived as the biggest decease or the smallest increase from baseline on the SLD among all post-baseline disease assessment including unscheduled assessments. Best percent change is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction.
Time frame: 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 in Phase 2
The PFS was defined as the time from the date of randomization for Arm A, B, and C participants or the date of first dose of study treatment for Arm D and 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.
Time frame: 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
The PFS-9 is the 9-month progression-free survival rate, which was the percentage of participants who were progression free and alive at 9 months. PFS was defined as the time from the date of first dose of study drug for Arm A, B, C participants or the date of first dose of study drug for Arm D and 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.
Time frame: From Day 1 up to 9 months
Overall Survival (OS) in Phase 2
The OS was defined as the time from date of randomization for Arm A, B, and C participants or the date of first dose of study drug for Arm D and Arm E participants until death due to any cause. OS was censored at last known alive date. Kaplan Meier method was used to evaluate OS. Kaplan Meier method was used to evaluate OS.
Time frame: 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)
Overall Survival at 12 Months in Phase 2
The OS was defined as the time from date of randomization for Arm A, B, and C participants or the date of first dose of study drug for Arm D and Arm E participants until 12 months. OS was censored at last known alive date. Kaplan Meier method was used to evaluate OS. Kaplan Meier method was used to evaluate OS and 95% confidence interval.
Time frame: From Day 1 up to 12 months
Percentage of Participants With Objective Response With Positive Interferon Gamma (IFN-γ) Gene Expression in Phase 2
Percentage of participants with OR with positive IFN-γ gene expression is reported. OR: BOR of confirmed CR or PR per RECIST v1.1. BOR: best response (CR, PR, SD, 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.
Time frame: Day 1 through Day 30 post EOT (approximately 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
Percentage of participants with PFS at 6 month with positive IFN-γ gene expression is reported. 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.
Time frame: Day 1 through Day 30 post EOT (approximately 4 years and one month)
Percentage of Participants With Objective Response in Phase 2 by Programmed Death-ligand (PD-L1) Status
Percentage of participants with objective response in Phase 2 by programmed death-ligand (PD-L1) status is reported. PD-L1 is a protein that may be found on some normal cells and in higher-than-normal amounts on some types of cancer cells. It plays a role in regulating the immune response against some types of cancers and therefore, is the target for some anticancer drugs. PD-L1 status was based on the percentage of tumor cells from baseline tumor tissue samples with PD-L1 membrane staining: PD-L1 high if \>= 1% tumor cells (better response), PD-L1 low/neg if \< 1% tumor cells (low response).
Time frame: Day 1 through Day 30 post EOT (approximately 4 years and one month)