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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)

NCT03615326

Description:

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).

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-811
  • SECONDARY ID: 2018-000224-34
  • SECONDARY ID: MK-3475-811
  • NCT ID: NCT03615326

Conditions

  • Gastric Neoplasms
  • Gastroesophageal Junction Adenocarcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda®, MK-3475Pembrolizumab +Trastuzumab + Chemotherapy
PlaceboPlacebo +Trastuzumab + Chemotherapy
CisplatinPembrolizumab +Trastuzumab + Chemotherapy
5-FUPembrolizumab +Trastuzumab + Chemotherapy
OxaliplatinPembrolizumab +Trastuzumab + Chemotherapy
CapecitabinePembrolizumab +Trastuzumab + Chemotherapy
S-1Pembrolizumab +Trastuzumab + Chemotherapy
TrastuzumabHerceptin®Pembrolizumab +Trastuzumab + Chemotherapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab +Trastuzumab + ChemotherapyExperimentalParticipants 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).
  • Cisplatin
  • 5-FU
  • Oxaliplatin
  • Capecitabine
  • S-1
Placebo +Trastuzumab + ChemotherapyActive ComparatorParticipants 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).
  • Cisplatin
  • 5-FU
  • Oxaliplatin
  • Capecitabine
  • S-1

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 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])
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS) per RECIST 1.1 assessed by BICR
Time Frame:Up to 4 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR) per RECIST 1.1 assessed by BICR
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Duration of Response (DOR) per RECIST 1.1 assessed by BICR
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Adverse Events (AE)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Treatment Discontinuations Due to AEs
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • programmed cell death receptor 1 (PD-1)
  • programmed cell death ligand 1 (PD-L1)
  • anti-PD-1
  • anti PD-1
  • GEJ
  • Gastric Cancer

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