A randomized, double-blind, phase 3 clinical study of Pembrolizumab (MK-3475) plus chemotherapy compared to placebo plus chemotherapy as first-line therapy in patients with untreated, locally advanced, unresectable or metastatic HER2-negative adenocarcinoma of the stomach or gastroesophageal junction (KEYNOTE-859)
Summary description of the study
The immune system plays an important role in controlling tumors. Pembrolizumab is an antibody that blocks or ends the inhibition of the immune system by the tumor, thereby enhancing the body's ability to fight the tumor. In this study, the efficacy and safety of Pembrolizumab in combination with standard chemotherapy and standard chemotherapy alone are examined and compared. The primary endpoints are the overall survival rate and progression-free survival of the two groups. The total duration of the study is a maximum of 5 years (2 years of treatment with the study medication; followed by monitoring with the possibility, under certain circumstances, of receiving further treatment if there is a recurrence of the disease).
(BASEC)
Intervention under investigation
Approximately 780 patients are expected to participate in this study. After careful eligibility assessment, medical history collection, and detailed explanation, the participant will be enrolled in the study and randomly assigned to one of the two treatment arms (treatment with Pembrolizumab and chemotherapy or treatment with placebo and chemotherapy). The probability of being assigned to the Pembrolizumab treatment group is 50%. Neither the study physician nor the participant knows which group the patient is assigned to and thus whether Pembrolizumab or placebo is administered (the study is termed "double-blind" regarding Pembrolizumab). For standard chemotherapy, 2 different treatments are available, which will be administered at the discretion of the investigator: Participants receive intravenous Pembrolizumab or placebo (depending on the assigned group) every three weeks plus standard chemotherapy for a total of 35 cycles. During this period, their health status will be regularly monitored for any changes in the tumor through imaging studies. Various measures and examinations may occur during study visits: discussion of well-being and current medication, intravenous therapy, imaging procedures (CT and/or MRI scans), electrocardiogram (ECG), samples of blood, urine, or tissue, hearing test (when administering cisplatin), eye examinations (when administering 5-fluorouracil), questionnaires, and examination of vital signs (pulse, blood pressure, etc.). If a deterioration of the disease is detected in imaging studies, the further course of action will be discussed with the patient. After complete treatment or after study discontinuation for reasons other than disease progression, participants enter the follow-up phase, during which they will be contacted every 12 weeks in the first year, every 6 months in years 2-5, and then annually to assess their health status. Under certain circumstances, a study participant may also receive further treatment with Pembrolizumab in the event of disease recurrence (every three weeks for up to 17 cycles).
(BASEC)
Disease under investigation
This study includes patients with untreated, locally advanced, unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction. Stomach cancer is the fifth most common cancer worldwide and the third most deadly cancer. Until now, chemotherapy was considered the standard therapy for this type of carcinoma. Clinical research data show that Pembrolizumab combined with standard chemotherapy may improve the treatment of locally advanced, unresectable, and/or metastatic tumors.
(BASEC)
• Diagnosis of locally advanced, unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction • HER2 negative tumor • Measurable tumor disease by imaging and available tumor tissue for analyses (BASEC)
Exclusion criteria
• Squamous cell carcinoma or undifferentiated gastric cancer • The metastatic tumor has already been treated (a prior neoadjuvant or adjuvant chemotherapy is not an exclusion criterion, provided it was at least 6 months ago) • Diagnosed immunodeficiency, long-term systemic steroid treatment (daily >10 mg prednisone or equivalent) or any other form of immunosuppressive treatment within 7 days prior to the first administration of the study medication (BASEC)
Trial sites
Bellinzona, Chur, Luzern, Zurich
(BASEC)
Sponsor
MSD Merck Sharp & Dohme AG
(BASEC)
Contact
Contact Person Switzerland
Klaudia Georgi
+41 58 618 33 88
klaudia.georgi@cluttermsd.comMSD Merck Sharp & Dohme AG
(BASEC)
General Information
Merck Sharp & Dohme LLC
(ICTRP)
Scientific Information
Merck Sharp & Dohme LLC
(ICTRP)
Name of the authorising ethics committee (for multicentre studies, only the lead committee)
Ethics Committee Zurich
(BASEC)
Date of authorisation
23.01.2019
(BASEC)
ICTRP Trial ID
NCT03675737 (ICTRP)
Official title (approved by ethics committee)
Phase 3, randomized, double-blind clinical study of pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy as first-line treatment in participants with HER2 negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (KEYNOTE-859) (BASEC)
Academic title
A Phase 3, Randomized, Double-blind Clinical Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy as First-line Treatment in Participants With HER2 Negative, Previously Untreated, Unresectable or Metastatic Gastric Orgastroesophageal Junction Adenocarcinoma (KEYNOTE-859) (ICTRP)
Public title
Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Participants Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-859/KEYNOTE-859) (ICTRP)
Disease under investigation
Stomach Neoplasms (ICTRP)
Intervention under investigation
Biological: Pembrolizumab;Drug: Cisplatin;Drug: 5-fluorouracil;Drug: oxaliplatin;Drug: capecitabine;Drug: Placebo for Pembrolizumab (ICTRP)
Type of trial
Interventional (ICTRP)
Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator). (ICTRP)
Inclusion/Exclusion criteria
Gender: All
Maximum age: N/A
Minimum age: 18 Years
Inclusion Criteria
- Has histologically or cytologically confirmed diagnosis of locally advanced
unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma
with known programmed cell death ligand 1 (PD-L1) expression status
- Has human epidermal growth factor receptor 2 (HER2) negative cancer
- Male participants must agree to use contraception during the treatment period and
through 95 days after the last dose of chemotherapy, refrain from donating sperm,
and be abstinent from heterosexual intercourse, as their preferred and usual
lifestyle, and agree to remain abstinent or must agree to use contraception per
study protocol unless confirmed to be azoospermic during this period
- Female participants who are not pregnant, not breastfeeding, and at least one of the
following conditions applies: not a woman of childbearing potential (WOCBP) OR is a
WOCBP who agrees to use contraception or be abstinent from heterosexual intercourse,
as their preferred and usual lifestyle, during the treatment period and through 180
days after the last dose of chemotherapy or through 120 days after the last dose of
pembrolizumab, whichever is last, and agrees not to donate eggs to others or
freeze/store for her own use for the purpose of reproduction during this period
- Has measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1
(RECIST 1.1) as assessed by investigator assessment
- Has provided archival tumor tissue sample or newly obtained core or excisional
biopsy of a tumor lesion not previously irradiated
- Has provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis
- Has provided tumor tissue sample for microsatellite instability (MSI) biomarker
analysis
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within
3 days prior to the start of study intervention
- Has adequate organ function as demonstrated by laboratory testing within 10 days
prior to the start of study treatment
Exclusion Criteria
- Has squamous cell or undifferentiated gastric cancer
- Has had major surgery, open biopsy, or significant traumatic injury within 28 days
prior to randomization, anticipation of the need for major surgery during the course
of study intervention, or has not recovered adequately from the toxicity and/or
complications from previous surgery
- Has preexisting peripheral neuropathy >Grade 1
- Is a WOCBP who has a positive urine pregnancy test within 24 hours for urine or
within 72 hours for serum prior to randomization or treatment allocation
- Has had previous therapy for locally advanced, unresectable or metastatic
gastric/GEJ cancer. Participants may have received prior neoadjuvant and/or adjuvant
therapy as long as it was completed =6 months prior to randomization
- Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1 or
anti-programmed cell death ligand 2 (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, CD137)
- Has received prior systemic anticancer therapy including investigational agents
within 4 weeks prior to randomization or has not recovered from all adverse events
(AEs) due to any previous therapies to =Grade 1 or baseline
- Has received prior radiotherapy within 2 weeks prior to study start or has not
recovered from all previous radiation-related toxicities, required corticosteroids,
and have not had radiation pneumonitis. A 1-week washout is permitted for palliative
radiation (=2 weeks of radiotherapy) to non-central nervous system (CNS) disease
- Has received a live or live-attenuated vaccine within 30 days prior to the first
dose of study treatment
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose
of study treatment
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to the first dose
of study treatment
- Has a known additional malignancy that is progressing or has required active
treatment within the past 5 years with the exception of basal cell carcinoma of the
skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast
carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
- Has known active CNS metastases and/or carcinomatous meningitis
- Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients
- Has an active autoimmune disease that has required systemic treatment in past 2
years
- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) infection
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (defined as Hepatitis C virus [HCV]
ribonucleic acid [RNA] detected qualitatively) infection
- Has a known history of active tuberculosis
- Has hypokalemia (serum potassium less than the lower limit of normal)
- Has hypomagnesemia (serum magnesium less than the lower limit of normal)
- Has hypocalcemia (serum calcium less than the lower limit of normal)
- Has a history or current evidence of any condition (eg, known deficiency of the
enzyme dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality that
might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator
- Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study
- Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 180 days
after the last dose of chemotherapy or through 120 days after the last dose of
pembrolizumab, whichever is last
- Has had an allogenic tissue/solid organ transplant
- Has a known severe hypersensitivity (= Grade 3) to any of the study chemotherapy
agents (including, but not limited to, infusional 5-fluorouracil or oral
capecitabine) and/or to any of their excipients
- For participants taking cisplatin: has Grade =2 audiometric hearing loss (ICTRP)
not available
Primary and secondary end points
Overall Survival (OS) in All Participants;Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) =1;Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) =10 (ICTRP)
Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants;Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) =1;Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) =10;Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants;Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) =1;Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) =10;Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants;Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) =1;Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) =10;Number of Participants Who Experienced an Adverse Event (AE);Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE) (ICTRP)
Registration date
not available
Incorporation of the first participant
not available
Secondary sponsors
not available
Additional contacts
Medical Director, Merck Sharp & Dohme LLC (ICTRP)
Secondary trial IDs
MK-3475-859, KEYNOTE-859, JAPIC-CTI, 2018-001757-27, 3475-859 (ICTRP)
Results-Individual Participant Data (IPD)
not available
Further information on the trial
https://clinicaltrials.gov/ct2/show/NCT03675737 (ICTRP)
Results of the trial
Results summary
not available
Link to the results in the primary register
not available