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NCT02340975

A Phase 1b/2 Study of MEDI4736 With Tremelimumab, MEDI4736 or Tremelimumab Monotherapy in Gastric or GEJ Adenocarcinoma

Completed Phase 1, PHASE2 Results posted Last updated 9 June 2020
What this trial tests

Phase 1, PHASE2 trial testing MEDI4736 + tremelimumab in Gastric or Gastroesophageal Junction Adenocarcinoma in 114 participants. Completed in 29 April 2019.

Timeline
31 March 2015
Primary endpoint
29 April 2019
29 April 2019

Quick facts

Lead sponsorMedImmune LLC
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment114
Start date31 March 2015
Primary completion29 April 2019
Estimated completion29 April 2019
Sites28 locations across Japan, Taiwan, South Korea, Canada, Singapore, United States

Drugs / interventions tested

Conditions studied

Sponsor

MedImmune LLC — full company profile →

Who can join

Adults 18 to 99, any sex, with Gastric or Gastroesophageal Junction Adenocarcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Phase 1b Primary · 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

TEAEs
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)6
TESAEs
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)2
Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1b Primary · 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 cle

GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs in Phase 1b Primary · 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.

Anaemia
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Lymphopenia
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Haemoglobin decreased
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Prothrombin time prolonged
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Activated partial thromboplastin time prolonged
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Blood alkaline phosphatase increased
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Blood bilirubin increased
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Gamma-glutamyltransferase increased
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)2
Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs in Phase 1b Primary · 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.

Pyrexia
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Weight decreased
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Number of Participants With Abnormal Electrocardiograms Reported as TEAEs in Phase 1b Primary · 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.

GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)1
Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline in Phase 1b Primary · 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= ca

ECOG 0
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)4
ECOG 1
GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)2
Percentage of Participants With Objective Response (OR) in Phase 2 Primary · 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 lesio

GroupValue95% CI
Phase 2 Arm A-(M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)11.12.4 – 29.2
Phase 2 Arm B-M10 mg/kg (Q2W)00.0 – 14.2
Phase 2 Arm C-T10 mg/kg (Q4W)8.30.2 – 38.5
Phase 2 Arm D-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)4.00.1 – 20.4
Phase 2 Arm E-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)15.83.4 – 39.6
Progression Free Survival at 6 (PFS-6) Month in Phase 2 Primary · 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.

GroupValue95% CI
Phase 2 Arm A-(M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)12.13.1 – 27.9
Phase 2 Arm B-M10 mg/kg (Q2W)NANA – NA
Phase 2 Arm C-T10 mg/kg (Q4W)23.33.6 – 52.9
Phase 2 Arm D-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)12.53.1 – 28.7
Phase 2 Arm E-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)5.30.4 – 21.4
Percentage of Participants With Objective Response in Phase 1b Secondary · 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 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

GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)00.0 – 45.9
Duration of Stable Disease (DSD) in Phase 1b Secondary · 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)

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.

GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)5.43.5 – 7.4
Median Best Percentage Change From Baseline of the Sum of Longest Diameters (SLD) of Target Lesions in Phase 1b Secondary · 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)

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.

GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)17.7-3.2 – 115.1
Percentage of Participants With Disease Control at 16 Weeks in Phase 1b Secondary · From Day 1 up to 16 weeks

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.

GroupValue95% CI
Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)33.34.3 – 77.7

Adverse events — posted to ClinicalTrials.gov

Time frame: Day 1 up to 90 days after the last dose (approximately 4 years and one month). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)
Serious: 2/6 (33%)
Deaths: 6/6
Phase 2 Arm A-(M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)
Serious: 14/27 (52%)
Deaths: 23/27
Phase 2 Arm B-M10 mg/kg (Q2W)
Serious: 16/24 (67%)
Deaths: 21/24
Phase 2 Arm C-T10 mg/kg (Q4W)
Serious: 10/12 (83%)
Deaths: 7/12
Phase 2 Arm D-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)
Serious: 15/25 (60%)
Deaths: 21/25
Phase 2 Arm E-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)
Serious: 12/19 (63%)
Deaths: 13/19

Serious adverse events (81 terms)

ReactionSystemPhase 1b-M20 mg/kg (Q4W) +…Phase 2 Arm A-(M20 mg/kg (…Phase 2 Arm B-M10 mg/kg (Q…Phase 2 Arm C-T10 mg/kg (Q…Phase 2 Arm D-M20 mg/kg (Q…Phase 2 Arm E-M20 mg/kg (Q…
ColitisGastrointestinal disorders
DysphagiaGastrointestinal disorders
Abdominal distensionGastrointestinal disorders
Abdominal painGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
Large intestinal obstructionGastrointestinal disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
PyrexiaGeneral disorders
PneumoniaInfections and infestations
Decreased appetiteMetabolism and nutrition disorders
Mental status changesPsychiatric disorders
Acute kidney injuryRenal and urinary disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
AnaemiaBlood and lymphatic system disorders
Cardiac failure congestiveCardiac disorders
Sinus tachycardiaCardiac disorders
Adrenal insufficiencyEndocrine disorders
HypophysitisEndocrine disorders
AscitesGastrointestinal disorders
ConstipationGastrointestinal disorders
Gastric perforationGastrointestinal disorders
Gastrointestinal haemorrhageGastrointestinal disorders
HaematemesisGastrointestinal disorders
MelaenaGastrointestinal disorders
Other adverse events (168 terms — click to expand)

ReactionSystemPhase 1b-M20 mg/kg (Q4W) +…Phase 2 Arm A-(M20 mg/kg (…Phase 2 Arm B-M10 mg/kg (Q…Phase 2 Arm C-T10 mg/kg (Q…Phase 2 Arm D-M20 mg/kg (Q…Phase 2 Arm E-M20 mg/kg (Q…
FatigueGeneral disorders
Decreased appetiteMetabolism and nutrition disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
AnaemiaBlood and lymphatic system disorders
ConstipationGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
HyperglycaemiaMetabolism and nutrition disorders
InsomniaPsychiatric disorders
Abdominal painGastrointestinal disorders
AstheniaGeneral disorders
Oedema peripheralGeneral disorders
PyrexiaGeneral disorders
Back painMusculoskeletal and connective tissue disorders
CoughRespiratory, thoracic and mediastinal disorders
PruritusSkin and subcutaneous tissue disorders
Weight decreasedInvestigations
HypoalbuminaemiaMetabolism and nutrition disorders
HyponatraemiaMetabolism and nutrition disorders
HypotensionVascular disorders
HypothyroidismEndocrine disorders
AscitesGastrointestinal disorders
RashSkin and subcutaneous tissue disorders
Sinus tachycardiaCardiac disorders
Abdominal discomfortGastrointestinal disorders
Abdominal distensionGastrointestinal disorders
Abdominal pain upperGastrointestinal disorders
DysphagiaGastrointestinal disorders
Aspartate aminotransferase increasedInvestigations
Blood thyroid stimulating hormone increasedInvestigations
International normalised ratio increasedInvestigations
Lipase increasedInvestigations
DehydrationMetabolism and nutrition disorders
HypocalcaemiaMetabolism and nutrition disorders
HypomagnesaemiaMetabolism and nutrition disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Muscular weaknessMusculoskeletal and connective tissue disorders
Musculoskeletal chest painMusculoskeletal and connective tissue disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders

Most-reported serious reactions: Colitis, Dysphagia, Abdominal distension, Abdominal pain, Diarrhoea, Large intestinal obstruction, Nausea, Vomiting.

Data from ClinicalTrials.gov NCT02340975 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions.
    Yi M, Zheng X, Niu M, Zhu S, et al · · 2022 · cited 1018× · PMID 35062949 · DOI 10.1186/s12943-021-01489-2
  2. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
    Wu M, Huang Q, Xie Y, Wu X, et al · · 2022 · cited 336× · PMID 35279217 · DOI 10.1186/s13045-022-01242-2
  3. Durvalumab: First Global Approval.
    Syed YY. · · 2017 · cited 130× · PMID 28643244 · DOI 10.1007/s40265-017-0782-5
  4. Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma.
    Kelly RJ, Lee J, Bang YJ, Almhanna K, et al · · 2020 · cited 103× · PMID 31676670 · DOI 10.1158/1078-0432.ccr-19-2443
  5. PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy.
    Long J, Lin J, Wang A, Wu L, et al · · 2017 · cited 77× · PMID 28774337 · DOI 10.1186/s13045-017-0511-2
  6. The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials.
    Saeed A, Park R, Sun W. · · 2021 · cited 74× · PMID 33436042 · DOI 10.1186/s13045-021-01034-0
  7. The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability <i>vs</i>. PD-L1.
    Jin Z, Yoon HH. · · 2016 · cited 72× · PMID 27747091 · DOI 10.21037/jgo.2016.08.06
  8. Tumor immune response and immunotherapy in gastric cancer.
    Kwak Y, Seo AN, Lee HE, Lee HS. · · 2020 · cited 68× · PMID 31674166 · DOI 10.4132/jptm.2019.10.08

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Data sources for this page

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