Pembrolizumab for the Treatment of Resectable Early Stage Gastroesophageal or Gastric Cancer
This phase II trial studies how well pembrolizumab works in treating patients with early stage gastroesophageal or gastric 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.
Inclusion Criteria
- Male/female participants who are at least 18 years of age on the day of signing informed consent
- Participants with histologically confirmed diagnosis of untreated esophageal adenocarcinoma (AC) (including Siewert type I and II esophagogastric junction AC) or gastric AC (including Siewert type III esophagogastric junction AC), with clinical stage T1b-T2, N0, and M0
- Patients must undergo endoscopic ultrasound (EUS), computed tomography (CT) chest/abdomen/pelvis with intravenous (IV)/oral (PO) contrast (magnetic resonance imaging [MRI] abdomen/pelvis plus noncontrast chest computed tomography [CT] is acceptable if patient has a contraindication to iodinated dye), and positron emission tomography (PET)/CT to complete staging and confirm absence of metastatic disease
- Patient must agree to a baseline EUS for centralized endoscopic staging to confirm the tumor is uT1b or uT2 and node negative, at which time a research biopsy endoscopically will also be obtained
- HER2+ and HER2- patients, and all other known molecular subsets are eligible
- Diagnostic laparoscopy is not mandated and can be performed as clinically indicated
- Eligible for willing to proceed with surgery with curative intent
- 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) as defined OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment
- The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
- Measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be allowed
- Is willing to provide tissue for correlative studies from the primary tumor lesion at baseline and at time of surgery. Is willing to provide blood and stool samples for all ordered studies
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation
- Absolute neutrophil count (ANC) >= 1500/uL
- Platelets >= 100 000/uL
- Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN * Creatinine clearance (CrCl) should be calculated per institutional standard
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
- International normalized ratio (INR) OR prothrombin time (PT) aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
- 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
Exclusion Criteria
- 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 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 (eg, CTLA-4, OX 40, CD137)
- Previous or concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer for which the patient has been previously treated and the lifetime recurrence risk is less than 30%
- Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist) are live attenuated vaccines and are not allowed
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- 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)
- Has a known history of active TB (Bacillus tuberculosis)
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, 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 study, starting with the screening visit through 120 days after the last dose of trial 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04089904.
PRIMARY OBJECTIVE:
I. To determine the pathologic complete response (pCR) rate in patients with cT1b-T2N0 gastroesophageal adenocarcinoma (GEA) treated with neoadjuvant pembrolizumab followed by surgical resection.
SECONDARY OBJECTIVES:
I. To determine the R0 resection rate in patients with cT1b-2N0 GEA treated with neoadjuvant pembrolizumab.
II. To determine rates of grade 1a (complete); 1b (minimal residual disease); 2 (partial response); and 3 (no response) pathologic response grades (PRG).
III. To evaluate the safety/ tolerability of pembrolizumab in patients with cT1b-2N0 GEA.
IV. To determine the disease free survival (DFS) measured from the time of first pembrolizumab dose.
V. To determinate overall survival (OS) measured from the time of first pembrolizumab dose.
EXPLORATORY OBJECTIVES:
I. To evaluate rates of PD-L1 positive expression (by Control Preference Scale [CPS] score >= 1 and >= 10), microsatellite instability (MSI) status, tumor mutation burden (TMB) and Epstein-Barr virus (EBV) status in pre-treatment biopsy specimens.
II. To evaluate whether PD-L1 expression, MSI status, TMB and/or EBV status in pre-treatment biopsy specimen is a predictive biomarker for pCR/PRG/R0 to pembrolizumab and other clinical outcomes.
III. To evaluate interval change in PD-L1 expression (by CPS score) pre/post pembrolizumab therapy in resected pathological specimens (if residual tumor is present).
IV. To determine the somatic genomic changes of actionable cancer related genes (mutation, amplification, indels, and translocation) using targeted deep next-generation sequencing (NGS) oncopanel in pre-treatment specimen and in resected specimen (if tumor is still present) and correlate with clinical outcomes (pCR/PRG, R0 rate, DFS, OS) and other molecular markers.
V. To evaluate circulating tumor deoxyribonucleic acid (ctDNA) next generation sequencing (NGS) pre-pembrolizumab, post-pembrolizumab, post-surgery, and if applicable at time of recurrence, and correlate with clinical outcomes (pCR/PRG, R0 rate, DFS, OS) and molecular markers.
VI. To determine baseline and interval changes in whole-exome ribonucleic acid sequencing (RNAseq) expression analysis pre-/post- therapy.
VII. To evaluate fecal flora via fecal 16S RNA seq pre-pembrolizumab, post-pembrolizumab, post-surgery, and if applicable at time of recurrence, and correlate with clinical outcomes.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for 3 cycles in the absence of disease progression or unacceptable toxicity. Between days 56-77, patients undergo standard of care surgery.
After completion of study treatment, patients are followed up on days 21, 42, 56, and 42-70, every 3 months for 3 years, every 6 months for 2 years, and then every 12 weeks thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorArdaman Shergill
- Primary IDIRB19-0310
- Secondary IDsNCI-2019-08727
- ClinicalTrials.gov IDNCT04089904