Pembrolizumab/Placebo Plus Trastuzumab Plus Chemotherapy in Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-811/KEYNOTE-811)

• ClinicalTrials.gov Identifier: NCT03615326
• Recruitment Status: Active, not recruiting
• First Posted: August 3, 2018
• Last Update Posted: July 22, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: July 31, 2018
• First Posted Date: August 3, 2018
• Last Update Posted Date: July 22, 2022
• Actual Study Start Date: October 5, 2018
• Estimated Primary Completion Date: December 15, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 6, 2021)

• Progression Free Survival (PFS) per RECIST 1.1 assessed by BICR [ Time Frame: Up to approximately 4 years ]
  PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. PFS will be determined for each treatment arm.
• Overall Survival (OS) [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from randomization to death due to any cause. OS will be determined for each treatment arm.

Original Primary Outcome Measures (submitted: July 31, 2018)

• Progression Free Survival (PFS) per RECIST 1.1 assessed by BICR [ Time Frame: Up to 4 years ]
  PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. PFS will be determined for each treatment arm.
• Overall Survival (OS) [ Time Frame: Up to 5 years ]
  OS is defined as the time from randomization to death due to any cause. OS will be determined for each treatment arm.

Current Secondary Outcome Measures (submitted: July 6, 2021)

• Objective Response Rate (ORR) per RECIST 1.1 assessed by BICR [ Time Frame: Up to approximately 5 years ]
  ORR is defined as the percentage of participants who have a Complete Response ([CR], disappearance of all evidence of disease) or Partial Response ([PR], regression of measurable disease and no new sites) per RECIST 1.1 as assessed by BICR. ORR will be determined for each treatment arm.
• Duration of Response (DOR) per RECIST 1.1 assessed by BICR [ Time Frame: Up to approximately 5 years ]
  For participants who demonstrate CR or PR, DOR is defined as the time from first response (CR or PR) to subsequent disease progression or death from any cause, whichever occurs first. DOR will be determined for each treatment arm.
• Adverse Events (AE) [ Time Frame: Up to approximately 5 years ]
  An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. 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 treatment. The number of participants who experience an AE will be reported for each treatment arm.
• Treatment Discontinuations Due to AEs [ Time Frame: Up to approximately 5 years ]
  An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. 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 treatment. The number of participants who discontinue study treatment due to an AE will be reported for each treatment arm.

Original Secondary Outcome Measures (submitted: July 31, 2018)

• Objective Response Rate (ORR) per RECIST 1.1 assessed by BICR [ Time Frame: Up to 5 years ]
  ORR is defined as the percentage of participants who have a Complete Response ([CR], disappearance of all evidence of disease) or Partial Response ([PR], regression of measurable disease and no new sites) per RECIST 1.1 as assessed by BICR. ORR will be determined for each treatment arm.
• Duration of Response (DOR) per RECIST 1.1 assessed by BICR [ Time Frame: Up to 5 years ]
  For participants who demonstrate CR or PR, DOR is defined as the time from first response (CR or PR) to subsequent disease progression or death from any cause, whichever occurs first. DOR will be determined for each treatment arm.
• Adverse Events (AE) [ Time Frame: Up to 5 years ]
  An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. 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 treatment. The number of participants who experience an AE will be reported for each treatment arm.
• Treatment Discontinuations Due to AEs [ Time Frame: Up to 5 years ]
  An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. 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 treatment. The number of participants who discontinue study treatment due to an AE will be reported for each treatment arm.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pembrolizumab/Placebo Plus Trastuzumab Plus Chemotherapy in Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-811/KEYNOTE-811)
• Official Title: A Phase III, Randomized, Double-blind Trial Comparing Trastuzumab Plus Chemotherapy and Pembrolizumab With Trastuzumab Plus Chemotherapy and Placebo as First-line Treatment in Participants With HER2 Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (KEYNOTE 811)
• Brief Summary: The study will compare the efficacy and safety of pembrolizumab plus trastuzumab in combination with standard of care (SOC) chemotherapy versus trastuzumab in combination with SOC chemotherapy in participants with HER2-positive gastric cancer. The primary hypotheses of the study are that pembrolizumab plus trastuzumab in combination with chemotherapy is superior to trastuzumab plus chemotherapy in terms of 1) progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR), and 2) overall survival (OS).
• Detailed Description: Pembrolizumab (200 mg) or placebo will be administered intravenously [IV] on day 1 of each 3-week cycle. Trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance dose) will be administered IV on day 1 of each 3-week cycle. SOC chemotherapy for the global cohort will either be FP (80 mg/m^2 cisplatin administered IV on Day 1 of each 3-week cycle and 800 mg/m^2 5-fluorouracil [5-FU] administered IV on Days 1-5 of each 3-week cycle) or CAPOX (1000 mg/m^2 capecitabine administered orally twice daily [BID] on days 1-14 of each 3-week cycle and 130 mg/m^2 oxaliplatin administered IV on Day 1 of each 3-week cycle). A Japan cohort will receive SOX chemotherapy consisting of S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine [CDHP], and potassium oxonate [Oxo]) administered orally BID according to Body Surface Area (BSA) on Days 1-14 of each 3-week cycle and oxaliplatin (130 mg/m^2) administered IV on Day 1 each 3-week cycle.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Gastric Neoplasms
• Gastroesophageal Junction Adenocarcinoma

Intervention

• Biological: Pembrolizumab
  200 mg on Day 1 of each 3-week cycle as an IV infusion.
  Other Names:

  • Keytruda®
  • MK-3475
• Biological: Placebo
  Solution for IV infusion on Day 1 of each 3-week cycle.
• Drug: Cisplatin
  80 mg/m^2 on Day 1 of each 3-week cycle as an IV infusion, administered as part of FP chemotherapy regimen.
• Drug: 5-FU
  800 mg/m^2/day continuous on Days 1-5 of each 3-week cycle (120 hours or per local standard), administered as part of FP chemotherapy regimen.
• Drug: Oxaliplatin
  130 mg/m^2 on Day 1 of each 3-week cycle over 2 hours as an IV infusion, administered as part of CAPOX chemotherapy regimen and as part of SOX chemotherapy regimen.
• Drug: Capecitabine
  1000 mg/m^2 as oral capsules BID on Days 1-14 of each 3-week cycle, administered as part of CAPOX chemotherapy regimen.
• Drug: S-1
  Combination product of tegafur, CDHP, and Oxo. Oral capsules BID on Days 1-14 of each 3-week cycle based on body surface area (BSA): <1.25 m^2 BSA =40 mg, 1.25 to <1.5 m^2 BSA=50 mg, ≥1.5 m^2 BSA=60 mg. Administered as part of SOX chemotherapy regimen.
• Biological: Trastuzumab
  8 mg/kg loading dose and then 6 mg/kg maintenance dose administered IV on day 1 of each 3-week cycle.
  Other Name: Herceptin®

Study Arms

• Experimental: Pembrolizumab +Trastuzumab + Chemotherapy
  Participants receive 200 mg pembrolizumab IV every 3 weeks (Q3W) plus trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance thereafter) IV Q3W in combination with FP or CAPOX chemotherapy (Global Cohort) or SOX chemotherapy (Japan cohort).
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Cisplatin
  • Drug: 5-FU
  • Drug: Oxaliplatin
  • Drug: Capecitabine
  • Drug: S-1
  • Biological: Trastuzumab
• Active Comparator: Placebo +Trastuzumab + Chemotherapy
  Participants receive matched placebo to pembrolizumab IV Q3W plus trastuzumab (8mg/kg loading dose, 6mg/kg maintenance thereafter) IV Q3W in combination with FP or CAPOX chemotherapy (Global Cohort) or SOX chemotherapy (Japan cohort).
  Interventions:

  • Biological: Placebo
  • Drug: Cisplatin
  • Drug: 5-FU
  • Drug: Oxaliplatin
  • Drug: Capecitabine
  • Drug: S-1
  • Biological: Trastuzumab

Publications *

• Janjigian YY, Kawazoe A, Yanez P, Li N, Lonardi S, Kolesnik O, Barajas O, Bai Y, Shen L, Tang Y, Wyrwicz LS, Xu J, Shitara K, Qin S, Van Cutsem E, Tabernero J, Li L, Shah S, Bhagia P, Chung HC. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021 Dec;600(7890):727-730. doi: 10.1038/s41586-021-04161-3. Epub 2021 Dec 15.
• Chung HC, Bang YJ, S Fuchs C, Qin SK, Satoh T, Shitara K, Tabernero J, Van Cutsem E, Alsina M, Cao ZA, Lu J, Bhagia P, Shih CS, Janjigian YY. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol. 2021 Feb;17(5):491-501. doi: 10.2217/fon-2020-0737. Epub 2020 Nov 10.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 31, 2018): 732
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2024
• Estimated Primary Completion Date: December 15, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic HER2 positive gastric or GEJ adenocarcinoma
• HER2-positive defined as either immunohistochemistry (IHC) 3+ or IHC 2+ in combination with in-situ hybridization positive (ISH+) or fluorescent in-situ hybridization (FISH), as assessed by central review on primary or metastatic tumor
• Has measurable disease as defined by RECIST 1.1 as determined by the site investigator
• Male participants must agree to use approved contraception
• Female participants who are not pregnant or breastfeeding, and who are either not a woman of childbearing potential (WOCBP), or are a WOCBP who agrees to use approved contraception
• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to the first dose of trial treatment
• Has a life expectancy of greater than 6 months
• Has adequate organ function

Exclusion Criteria:

• Has had previous therapy for locally advanced unresectable or metastatic gastric/GEJ cancer
• Has had major surgery, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study treatment
• Has had radiotherapy within 14 days of randomization
• Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active autoimmune disease that has required systemic treatment in past 2 years
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis)
• Has an active infection requiring systemic therapy
• Has poorly controlled diarrhea
• Accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment. If the participant is receiving diuretic drugs for other reasons, it is acceptable
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Has peripheral neuropathy > Grade 1
• Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
• A WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization or treatment allocation
• Has active or clinically significant cardiac disease
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab, trastuzumab, study chemotherapy agents and/or to any excipients, murine proteins, or platinum-containing products
• Has had an allogeneic tissue/solid organ transplant
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, Cluster of Differentiation 137 [CD137])

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Chile, China, France, Germany, Guatemala, Ireland, Israel, Italy, Japan, Korea, Republic of, New Zealand, Poland, Russian Federation, Spain, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03615326
• Other Study ID Numbers: 3475-811; MK-3475-811 ( Other Identifier: Merck Protocol Number ); 184142 ( Registry Identifier: JAPAC-CTI ); 2018-000224-34 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: July 2022