Phase 3 Randomized Double-Blind Study of Pembrolizumab Plus Chemotherapy Versus Placebo Plus Chemotherapy in HER2-Negative Advanced Gastric or GEJ Adenocarcinoma
- Trial ID
- 2023-508890-10-00
- Protocol
- MK3475-859
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind clinical study is to compare the **overall survival (OS)** of participants with HER2 negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma following administration of pembrolizumab versus placebo, each combined with chemotherapy. This objective is clinically relevant as it aims to determine the efficacy of pembrolizumab in extending the lifespan of patients with advanced gastric cancer, a condition with limited treatment options and poor prognosis.
Secondary objectives include:
- Comparing the **progression-free survival (PFS)** per RECIST 1.1, as assessed by blinded independent central review (BICR), following administration of pembrolizumab versus placebo when each is combined with chemotherapy.
- Comparing the **overall response rate (ORR)** per RECIST 1.1, as assessed by BICR, following administration of pembrolizumab versus placebo when each is combined with chemotherapy.
- Describing the **duration of response (DOR)** per RECIST 1.1, as assessed by BICR, following administration of pembrolizumab versus placebo when each is combined with chemotherapy in participants with Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10, PD-L1 CPS ≥1, and in all participants.
- Evaluating the **safety and tolerability** of pembrolizumab plus chemotherapy versus placebo plus chemotherapy.
Participants
The clinical trial involves a total of **1297 participants** diagnosed with **gastric and gastric esophageal junction (GEJ) adenocarcinoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, with known PD-L1 expression status and adequate organ function. The trial excludes vulnerable populations. Participants are required to have a measurable disease per RECIST 1.1 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Lifestyle considerations include the use of contraception and abstinence from heterosexual intercourse as a preferred and usual lifestyle during the treatment period, with specific guidelines for both male and female participants regarding reproductive health. The trial does not include individuals with HER2 positive cancer, and participants must provide tumor tissue samples for biomarker analysis.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, controlled study designed to evaluate the efficacy and safety of **pembrolizumab** in combination with chemotherapy compared to a placebo with chemotherapy in participants with HER2 negative, previously untreated, unresectable, or metastatic gastric or gastroesophageal junction adenocarcinoma. The trial aims to assess the overall survival (OS) as the primary endpoint, with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) as assessed by blinded independent central review (BICR) using RECIST 1.1 criteria. The estimated duration of the trial is from November 2018 to March 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically confirmed diagnosis, adequate organ function, and known PD-L1 expression status. Following successful screening, participants will be randomized to receive either pembrolizumab or placebo in combination with chemotherapy. The treatment period will involve regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 157 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants are required to adhere to specific contraceptive measures during the study and for a defined period after the last dose of study medication to ensure safety and compliance with the study protocol.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed as KEYTRUDA, which is a **biological** agent used in the study. Pembrolizumab is provided as a 25 mg/mL concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 10,400 mg over a treatment period of 157 days. Pembrolizumab is produced by Merck Sharp & Dohme B.V. and is identified by the sponsor product code MK-3475.
The trial also includes a **placebo** for pembrolizumab, which serves as a comparator in the study. The placebo is administered in the same manner as pembrolizumab, via intravenous infusion, although specific details regarding its pharmaceutical form are not available.
**Capecitabine** is another agent used in the trial, classified as a **chemical** compound. It is administered orally, with a maximum daily dose of 2000 mg/m² and a total maximum dose of 980,000 mg/m² over a 105-day treatment period. The pharmaceutical form is denoted as PHF00009MIG.
**Fluorouracil**, also a **chemical** compound, is administered via intravenous infusion. The maximum daily dose is 800 mg/m², with a total maximum dose of 140,000 mg/m² over a 105-day treatment period. The pharmaceutical form is identified as PHF00231MIG.
**Oxaliplatin** is included in the trial as a **chemical** agent, administered through intravenous infusion. The maximum daily dose is 130 mg/m², with a total maximum dose of 4,550 mg/m² over a 105-day treatment period. The pharmaceutical form is PHF00230MIG.
**Cisplatin** is another **chemical** compound used in the study, administered via intravenous infusion. The maximum daily dose is 80 mg/m², with a total maximum dose of 2,800 mg/m² over a 105-day treatment period. The pharmaceutical form is PHF00015MIG.
Efficacy
The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints focus on overall survival (OS) in all participants, as well as in participants with programmed death-ligand 1 (PD-L1) combined positive score (CPS) of ≥1 and ≥10. Secondary endpoints include progression-free survival (PFS) and objective response rate (ORR) as per RECIST 1.1, assessed by blinded independent central review (BICR) in all participants and in those with PD-L1 CPS of ≥1 and ≥10. Additionally, duration of response (DOR) will be evaluated under the same conditions. The trial will also monitor the number of participants who experience adverse events (AEs) and those who discontinue study treatment due to AEs.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with known 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 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 07 Nov 2018 | 17 |
 Denmark | Not Recruiting | 07 Nov 2018 | 10 |
 France | Not Recruiting | 07 Nov 2018 | 52 |
 Germany | Not Recruiting | 07 Nov 2018 | 12 |
 Ireland | Not Recruiting | 07 Nov 2018 | 30 |
 Italy | Not Recruiting | 07 Nov 2018 | 18 |
 Poland | Not Recruiting | 07 Nov 2018 | 62 |
 Spain | Not Recruiting | 07 Nov 2018 | 67 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo for pembrolizumab | Placebo | N/A | — | — | — | N/A |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 157 | PRD4323105 |
CAPECITABINE | Other | PHF00009MIG | ORAL USE | 2000 | 105 | SCP131876 |
FLUOROURACIL | Other | PHF00231MIG | INTRAVENOUS INFUSION | 800 | 105 | SCP1165178 |
OXALIPLATIN | Other | PHF00230MIG | INTRAVENOUS INFUSION | 130 | 105 | SCP128961 |
CISPLATIN | Other | PHF00015MIG | INTRAVENOUS INFUSION | 80 | 105 | SCP134220 |