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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)

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ClinicalTrials.gov Identifier: NCT03615326
Recruitment Status : Recruiting
First Posted : August 3, 2018
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE July 31, 2018
First Posted Date  ICMJE August 3, 2018
Last Update Posted Date March 15, 2019
Actual Study Start Date  ICMJE October 5, 2018
Estimated Primary Completion Date June 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03615326 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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  ICMJE Interventional
Study Phase Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Gastric Neoplasms
  • Gastroesophageal Junction Adenocarcinoma
Intervention  ICMJE
  • 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 * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 31, 2018)
732
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date March 20, 2024
Estimated Primary Completion Date June 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 72 hours prior to randomization or treatment allocation
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 7 months after the last dose of trial treatment
  • 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  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE 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
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03615326
Other Study ID Numbers  ICMJE 3475-811
2018-000224-34 ( EudraCT Number )
MK-3475-811 ( Other Identifier: Merck Protocol 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
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP