Pembrolizumab, Trastuzumab, Fluorouracil, and Combination Chemotherapy as First Line Therapy in Treating Patients with HER2-Positive Stage IV Esophagogastric Cancer
- Patient must have pathologically or cytologically Memorial Sloan-Kettering Cancer Center (MSKCC) confirmed esophageal, gastric or gastroesophageal junction (GEJ) adenocarcinoma by the enrolling institution
- Patients must have esophageal, gastric or gastroesophageal adenocarcinoma with HER2 overexpression and/or amplification as determined by next generation sequencing assay, immunohistochemistry (IHC 3+) or fluorescent in situ hybridization (FISH+ is defined as HER2:CEP17 ratio >= 2.0); MSKCC or enrolling institution confirmation of HER2 status is not mandatory prior to enrollment and treatment on study; for patients with outside HER2 testing, if sufficient tissue is available HER2 testing will be repeated at MSKCC or the enrolling institution for purpose of analysis and will not impact the patient's eligibility
- Additional available archival tumor tissue in the form of 15-20 unstained slides should be submitted to MSKCC for future correlative analysis, but will not be required prior registration; Note: if tissue is depleted, patient will still be eligible after discussion with the MSK principal investigator (PI)
- Patients may have received no prior chemotherapy for stage IV disease; patients may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) if more than 6 months have elapsed between the end of adjuvant therapy and registration
- Patients must have disease that can be evaluated radiographically; this may be measurable disease or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Patient must have a normal left ventricular ejection fraction (LVEF) (>= 53%); if a patient has a borderline LVEF (40-52%) they may be considered after consultation with cardiology and study PI and treated per the guidelines
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 10 days of treatment initiation)
- Platelets >= 100,000/mcL (within 10 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 10 days of treatment initiation)
- Serum creatinine OR measured or calculated (creatinine clearance should be calculated per institutional standard) creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x institutional upper limit of normal (ULN) OR (measured via 24-hour urine collection) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 10 days of treatment initiation)
- Serum total bilirubin =< 1.5 x ULN (1.5 mg/dL or 25.65 umol/L) OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN; except patients with Gilbert's disease (=< 3 x ULN) (within 10 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN or =< 5 x ULN for subjects with liver metastases (within 10 days of treatment initiation)
- Albumin >= 3 mg/dL (within 10 days of treatment initiation)
- Prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
- Peripheral neuropathy =< grade 1
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent *Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves‘ disease; rheumatoid arthritis, hypophysitis, uveitis) within the past 3 years prior to the start of treatment; the following are exceptions to this criterion: * Subjects with vitiligo or alopecia * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface agent [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [HCV RNA] [qualitative] is detected)
- Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
- Is unwilling to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study
- Has active or clinically significant cardiac disease including: * Congestive heart failure - New York Heart Association (NYHA) > class II * Active coronary artery disease * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin * Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before initiation, or myocardial infarction within 6 months before initiation
I. To determine the efficacy of pembrolizumab in combination with trastuzumab and capecitabine/fluorouracil (5-FU) and oxaliplatin/cisplatin and in patients with stage IV HER2-positive esophagogastric (EG) adenocarcinoma as measured by 6 month progression free survival (PFS).
I. To establish the safety of pembrolizumab in combination with capecitabine/5-FU, oxaliplatin/cisplatin, and trastuzumab in patients with metastatic HER2-positive metastatic EG adenocarcinoma.
II. To observe other measures of efficacy of pembrolizumab in combination with capecitabine/5-FU, oxaliplatin/cisplatin, and trastuzumab, including response rate, overall and 1-year survival in patients with stage IV EG adenocarcinoma.
III. Determine overall clinical benefit defined as stable disease (SD), complete response rate (CR), or partial response (PR) safety and tolerability.
IV. Median PFS, overall and 1-year survival in patients with HER2+ stage IV esophageal, gastric, or gastroesophageal junction (GEJ) adenocarcinoma will be estimated using the Kaplan-Meier method.
I. To utilize peripheral blood mononuclear cell (PMBC) and cell-free tumor deoxyribonucleic acid (cfDNA) from blood specimens collected during the course of treatment to explore mechanism of primary and acquired resistance to pembrolizumab and trastuzumab therapy.
II. To explore tumor PD-L1 as predictive biomarker.
III. To bank tumor material for future correlative analysis, including but not limited to whole exome analysis to determine mutation load and specific neoantigen landscape with strong association with regimen efficacy and survival.
IV. To explore changes in 89 zirconium (Zr)-trastuzumab positron emission tomography (PET) with trastuzumab and pembrolizumab treatment.
V. To explore response rate of pembrolizumab with trastuzumab in patients with HER-2 positive metastatic esophagogastric cancer.
Patients receive pembrolizumab intravenously (IV) and trastuzumab IV over 30 minutes on day 1 cycle 1, fluorouracil IV on days 1-5, and cisplatin IV over 60-120 minutes starting on cycle 2 day 1. Patients also receive oxaliplatin IV over 2 hours starting on cycle 2 day 1 and capecitabine orally (PO) twice daily (BID) starting on cycle 2 days 1-14. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Treatment with cisplatin repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Treatment with oxaliplatin repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months.
Trial Phase Phase II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
Yelena Y. Janjigian
- Primary ID 16-937
- Secondary IDs NCI-2016-01716
- Clinicaltrials.gov ID NCT02954536