Pembrolizumab with Trastuzumab and Chemotherapy for the Treatment Resectable HER2-Positive Gastric, Esophageal, and Gastroesophageal Junction Cancer
This phase II trial tests the safety, side effects and effectiveness of pembrolizumab with trastuzumab and chemotherapy in treating patients with HER2-positive gastric, esophageal and gastroesophageal junction cancer that can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Trastuzumab is a form of targeted therapy because it works by attaching itself to specific molecules (receptors) on the surface of tumor cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by body's immune system. Chemotherapy drugs, such as oxaliplatin, capecitabine, fluorouracil (5-FU), docetaxel, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding trastuzumab and pembrolizumab to standard chemotherapy and surgery may be an effective and safe treatment for HER2-positive gastric, esophageal and gastroesophageal junction cancers.
Inclusion Criteria
- Age 18 years or older at time of signing informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- HER2+ esophageal, gastroesophageal junction (GEJ), or gastric adenocarcinoma biopsy or resection specimen as defined by local HER2 immunohistochemistry (IHC)3+ or IHC 2+/fluorescence in situ hybridization (FISH) > 2.0 expression
- Complete surgical resection of the primary tumor must be achievable
- Absolute neutrophil count (ANC) ≥ 1,500 /mcL
- Platelets ≥ 100,000 / mcL
- Hemoglobin ≥ 8 g/dL
- Creatinine clearance ≥ 50 mL/minute
- Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN. Except patients with Gilbert's disease (≤ 3 x ULN)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 X ULN
- Albumin ≥ 3 mg/dL
- International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) < 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
- Male participants: A male participant must agree to use contraception during the treatment period and for at least 230 days (5 terminal half-lives of trastuzumab plus an additional 90 days [spermatogenesis cycle]) after the last dose of study treatment and refrain from donating sperm during this period
- Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 230 days (200 days plus an additional 30 days [menstruation cycle]) after the last dose of study treatment
Exclusion Criteria
- Presence of metastatic or recurrent disease
- Has received prior treatment for esophagogastric cancer
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 agent
- Has received prior therapy with an anti-HER2 agent
- Left ventricular ejection fraction < 50% within 1 month of screening by MUGA or echocardiogram. Patients with an ejection fraction 45-49% may be permissible in the absence of any cardiac symptoms, if cleared by a cardiologist, and per the investigator’s discretion
- 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
- Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., dexamethasone containing antiemetic regimen or steroids as CT scan contrast premedication) may be enrolled
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- Has been diagnosed or treated for another malignancy in the past 3 years (not including non-melanoma skin cancer)
- 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 230 days after the last dose of trial treatment
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Has had an allogeneic tissue or solid organ transplant
- 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 antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [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, unwilling to participate, or unable to comply with the protocol for the duration of the study
Additional locations may be listed on ClinicalTrials.gov for NCT06123338.
Locations matching your search criteria
United States
Massachusetts
Boston
New Jersey
Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
West Harrison
Pennsylvania
Philadelphia
Texas
Houston
PRIMARY OBJECTIVE:
I. To determine the rate of 2-year event-free survival (EFS) after treatment with peri-operative pembrolizumab +
trastuzumab + chemotherapy in patients with resectable HER2+ esophagogastric tumors.
SECONDARY OBJECTIVES:
I. To observe the safety and tolerability of this regimen.
II. To observe other measures of efficacy including complete response rate (cCR and pathological CR), major pathological response (MPR), metabolic response rate as measured by Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST), median EFS, 3- and 5-year EFS, and overall survival (OS (median, 2-year and 5-year).
III. To observe effect on circulating tumor deoxyribonucleic acid (ctDNA) including 1) rates of decrease in ctDNA by ≥ 50% following neoadjuvant therapy and prior to surgery, 2) rate of ctDNA clearance following neoadjuvant therapy and prior to surgery, and 3) rate of ctDNA clearance after completing all therapy.
EXPLORATORY OBJECTIVES:
I. To collect archival tumor samples, including pre-treatment, on-treatment, and post-recurrence tumor biopsies for correlative analysis, including T-cell receptor (TCR) rearrangements, transcriptomic analysis, and immunohistochemistry.
II. To utilize blood and tissue specimens collected during the course of study to explore the evolution of immune response as well as the mechanisms of primary and acquired resistance to trastuzumab and pembrolizumab and their relationship to response, event-free survival and overall survival.
III. To bank tumor and blood material for future correlative analysis, including but not limited to whole exome analysis to determine mutation load and specific neoantigen landscape.
IV. To describe the ability of plasma-based whole genome sequencing (WGS) using the MRD-EDGE platform to detect minimal residual disease (MRD) in gastroesophageal adenocarcinoma and determine its ability to predict outcomes.
OUTLINE:
NEOADJUVANT THERAPY (PRIOR TO AMENDMENT 6): Patients receive pembrolizumab intravenously (IV) over 30 minutes, trastuzumab IV over 30-90 minutes, and oxaliplatin IV on day 1 of each cycle, as well as capecitabine orally (PO) twice daily (BID) on days 1-14 of each cycle or fluorouracil (5-FU) IV continuously on days 1-5 of each cycle. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery. Patients who achieve a cCR following neoadjuvant therapy are reviewed and considered for the option of non-operative management.
NEOADJUVANT THERAPY (AS OF AMENDMENT 6): Patients receive trastuzumab IV over 30-90 minutes, 5-FU IV continuously, and oxaliplatin IV, docetaxel IV, and leucovorin IV on day 1 of each cycle, as well as pembrolizumab IV on day 1 of cycle 1 and day 1 of cycle 4. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery. Patients who achieve a cCR following neoadjuvant therapy are reviewed and considered for the option of non-operative management.
ADJUVANT THERAPY (PRIOR TO AMENDMENT 6): Patients receive pembrolizumab and trastuzumab as in Neoadjuvant Therapy. Treatment repeats every 21 days up to 9 cycles in the absence of disease progression or unacceptable toxicity.
ADJUVANT THERAPY (AS OF AMENDMENT 6): Patients receive 5-FU IV continuously, and oxaliplatin IV, docetaxel IV, and leucovorin IV on day 8 of cycle 1 and on day 1 of cycle 2. Treatment repeats every 14 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive trastuzumab IV over 30-90 minutes and pembrolizumab IV on day 1 of each cycle. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Patients also undergo urine sample collection during screening, and esophagogastroduodenoscopy (EGD), endoscopy with biopsy, positron emission tomography (PET)/computed tomography (CT) scans during screening and on study, and additional CT scans on study and during follow up. Additionally, patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and collection of blood throughout the trial, and may undergo an optional biopsy at time of recurrence.
After completion of the study treatment, patients are followed up every 3 months for years 1 and 2, then every 6 months for years 3 and 4 then once for year 5.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorYelena Y. Janjigian
- Primary ID23-124
- Secondary IDsNCI-2024-01388
- ClinicalTrials.gov IDNCT06123338