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

NCT02340975 | Completed Phase 1 Results

• 1 other identifier: D4190C00021
• Study Type: interventional
• Target: 114
• Locations: 6 countries
• Sites: 28

Brief Summary

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.

Conditions

Gastric or Gastroesophageal Junction Adenocarcinoma

Keywords

Gastric Adenocarcinoma; Gastroesophageal Junction Adenocarcinoma; Immunotherapy; Antibodies, Monoclonal; Tremelimumab; MEDI4736

Outcome Measures

Primary Outcomes (8)

• 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.

  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.

  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.

  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

  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.

  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.

  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.

  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.

  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.

  From Day 1 upto 6 months

Secondary Outcomes (24)

• 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

Study Arms (6)

Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)

EXPERIMENTAL

Participants in second-line therapy with gastric or gastroesophageal junction (GEJ) adenocarcinoma will receive intravenous (IV) infusion of 20 mg/kg MEDI4736 every 4 weeks (Q4W) for 4 months (up to 4 doses) in combination with IV 1 mg/kg tremelimumab Q4W for 4 months (up to 4 doses in total). Thereafter, participants will receive MEDI4736 monotherapy (10 mg/kg) every 2 weeks (Q2W) to complete a total of 12 months of therapy (up to 18 additional doses).

Biological: MEDI4736 + tremelimumab

Phase 2 Arm A-(M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)

EXPERIMENTAL

Participants in second-line therapy with metastatic or recurrent gastric or GEJ adenocarcinoma will receive IV infusion of 20 mg/kg MEDI4736 Q4W for 4 months (up to 4 doses) in combination with IV 1 mg/kg tremelimumab Q4W for 4 months (up to 4 doses in total). Thereafter, participants will receive MEDI4736 monotherapy (10 mg/kg) every 2 weeks (Q2W) to complete a total of 12 months of therapy (up to 18 additional doses).

Biological: MEDI4736 + tremelimumab

Phase 2 Arm B-M10 mg/kg (Q2W)

EXPERIMENTAL

Participants in second-line therapy with metastatic or recurrent gastric or GEJ adenocarcinoma will receive IV infusion of 10 mg/kg MEDI4736 Q2W for 12 months (up to 26 doses).

Biological: MEDI4736

Phase 2 Arm C-T10 mg/kg (Q4W)

EXPERIMENTAL

Participants in second-line therapy with metastatic or recurrent gastric or GEJ adenocarcinoma will receive IV infusion of 10 mg/kg tremelimumab Q4W for 7 doses and then Q12W for 2 doses for 12 months (for a total of up to 9 doses).

Biological: Tremelimumab

Phase 2 Arm D-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)

EXPERIMENTAL

Participants in third-line therapy with metastatic or recurrent gastric or GEJ adenocarcinoma will receive IV infusion of 20 mg/kg MEDI4736 Q4W for 4 months (up to 4 doses) in combination with IV 1 mg/kg tremelimumab Q4W for 4 months (up to 4 doses in total). Thereafter, participants will receive MEDI4736 monotherapy (10 mg/kg) every 2 weeks (Q2W) to complete a total of 12 months of therapy (up to 18 additional doses).

Biological: MEDI4736+tremelimumab

Phase 2 Arm E-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)

EXPERIMENTAL

Participants in second and third-line therapy with metastatic or recurrent gastric or GEJ adenocarcinoma and a positive IFN-γ gene expression signature will receive IV infusion of 20 mg/kg MEDI4736 Q4W for 4 months (up to 4 doses) in combination with IV 1 mg/kg tremelimumab Q4W for 4 months (up to 4 doses in total). Thereafter, participants will receive MEDI4736 monotherapy (10 mg/kg) every 2 weeks (Q2W) to complete a total of 12 months of therapy (up to 18 additional doses).

Biological: MEDI4736 + tremelimumab

Interventions

MEDI4736 + tremelimumab BIOLOGICAL

MEDI4736 will be administered by IV infusion in combination with tremelimumab.

Phase 1b-M20 mg/kg (Q4W) + T 1 mg/kg (Q4W) Fw M10 mg/kg (Q2W)

MEDI4736 BIOLOGICAL

MEDI4736 will be administered by IV infusion.

Phase 2 Arm B-M10 mg/kg (Q2W)

Tremelimumab BIOLOGICAL

Tremelimumab will be administered by IV infusion.

Phase 2 Arm C-T10 mg/kg (Q4W)

MEDI4736+tremelimumab BIOLOGICAL

MEDI4736 will be administered by IV infusion in combination with tremelimumab.

Phase 2 Arm D-M20 mg/kg (Q4W) + T1 mg/kg Fw M10 mg/kg (Q2W)

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female participants
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• MedImmune LLC: lead

Study Sites (28)

Research Site

Los Angeles, California, 90033, United States

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Santa Monica, California, 90404, United States

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New Haven, Connecticut, 06520, United States

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Tampa, Florida, 33612, United States

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Chicago, Illinois, 60637, United States

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Baltimore, Maryland, 21231, United States

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New York, New York, 10032, United States

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New York, New York, 10065, United States

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New York, New York, 10116, United States

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Cleveland, Ohio, 44106, United States

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Portland, Oregon, 97213, United States

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Philadelphia, Pennsylvania, 19111, United States

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Greenville, South Carolina, 29605, United States

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Nashville, Tennessee, 37203, United States

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Houston, Texas, 77030, United States

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Montreal, Quebec, H4A 3J1, Canada

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Kawasaki-shi, 216-8511, Japan

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Kōtoku, 135-8550, Japan

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Osaka, 541-8567, Japan

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Singapore, 119082, Singapore

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Singapore, 308433, Singapore

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Seongnam-si, 13620, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Seoul, 06351, South Korea

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Taipei, 100, Taiwan

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Taipei, 11217, Taiwan

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Taoyuan District, 333, Taiwan

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Related Links

• Redacted D4190C00021 SAP v3.0 final
• Protocol D4190C00021\_Redacted\_Final\_April2020\_Redacted

MeSH Terms

Interventions

durvalumab; tremelimumab

Results Point of Contact

• Title: Shahram Rahimian
• Organization: MedImmune, LLC

information.center@astrazeneca.com

+1-800-236-9933

Study Officials

• MedImmune, LLC MedImmune, LLC

  MedImmune LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2015
• First Posted: January 19, 2015
• Study Start: March 31, 2015
• Primary Completion: April 29, 2019
• Study Completion: April 29, 2019
• Last Updated: June 9, 2020
• Results First Posted: May 11, 2020

Record last verified: 2020-05

Locations

CA (1); KR (4); US (15); SG (2); JP (3); TW (3)