PRIMARY OBJECTIVE:
I. To evaluate the clinical activity (as assessed by complete clinical response rate) of
pembrolizumab plus chemoradiation.
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of pembrolizumab plus chemoradiation.
II. To determine the overall survival efficacy of pembrolizumab plus chemoradiation.
III. Evaluate progression free survival (PFS) by local investigator review and by blinded
central radiologists' review.
EXPLORATORY OBJECTIVES:
I. To explore the association between PD-L1 expression by immunohistochemistry, somatic gene
expression profiling, and clinical efficacy of pembrolizumab.
II. To explore the relationship between genomic variation and response to study treatment.
III. To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may
correlate with clinical response/resistance, safety, pharmacodynamic activity, and/or the
mechanism of action of pembrolizumab in combination with chemoradiation.
IV. To determine the effect of pembrolizumab plus chemoradiation treatment on tumor T cell
infiltration.
OUTLINE:
INDUCTION CHEMOTHERAPY: Patients receive pembrolizumab intravenously (IV) over 30 minutes on
day 1. Treatment with pembrolizumab repeats every 3 weeks for up to 3 cycles in the absence
of disease progression or unacceptable toxicity. Patients also receive oxaliplatin IV over 2
hours on day 1 followed by fluorouracil IV over 48 hours once every 2 weeks (Q2W) for 8 weeks
(4 cycles) in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION CHEMORADIATION: After a 3 week treatment free period, patients receive
pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 3 weeks
for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients
also receive fluorouracil IV continuous over 5 days (Monday through Friday) for 5 weeks and
docetaxel IV over 1 hour once a week (QW) for 5 weeks in the absence of disease progression
or unacceptable toxicity. Starting no later than 3 days after the beginning of the
Consolidation Chemoradiation period, patients also undergo 28 fractions of radiation therapy
in the absence of disease progression or unacceptable toxicity.
After a 6-9 week treatment free period, patients continue pembrolizumab IV over 30 minutes on
day 1. Treatment with pembrolizumab repeats every 3 weeks for up to 30 cycles in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 9-12
weeks thereafter.
Inclusion Criteria:
- Participants with histologically confirmed diagnosis of unresectable gastroesophageal
adenocarcinoma will be enrolled in this study for systemic treatment first
- Have histologically documented locally advanced unresectable cancer or localized
cancer in a patient who declines surgery
- Participant is able to provide endoscopic research biopsies and research blood
- Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1, as assessed within 7 days prior to treatment initiation
- A male participant must agree to use a contraception during the treatment period and
for at least 120 days, corresponding to time needed to eliminate any study
treatment(s) after the last dose of study treatment and refrain from donating sperm
during this period
- 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 120 days/weeks after the last dose of study treatment
- Patients with stable brain metastasis and/or carcinomatous leptomeningeal disease as
defined in exclusion criteria
- The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial. The participant may also provide consent for future
biomedical research. However, the participant may participate in the main trial
without participating in future biomedical research
- Absolute neutrophil count >= 1500/uL (within 10 days prior to the start of study
treatment)
- Platelets >= 100 000/uL (within 10 days prior to the start of study treatment)
- Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 10 days prior to the start of study
treatment)
- Criteria may be met with blood transfusion as these tumors are losing blood
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated* creatinine
clearance (CrCl) >= 60 mL/min for participant with creatinine levels > 1.5 x
institutional ULN (within 10 days prior to the start of study treatment) (GFR can also
be used in place of creatinine or CrCl)
- 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 (within 10 days prior to the start of study treatment)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN (within 10 days prior to the start of study treatment)
- 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 (within 10 days prior to the start of study treatment)
Exclusion Criteria:
- Has cancer that is confined to the stomach and not involving gastroesophageal junction
- Has significant cardiovascular impairment within 6 months of the first dose of study
drug (New York Heart Association [NYHA] class III or IV)
- Has had major surgery, open biopsy, or significant traumatic injury within 28 days
prior to randomization, or anticipation of the need for major surgery during the
course of study treatment
- Note: If participant has had major surgery, they must have recovered adequately
from the toxicity and/or complications from the treatment prior to starting study
intervention
- Has pre-existing peripheral neuropathy > grade 1
- Participant has a history of (non-infectious) pneumonitis that required treatment with
steroids or currently has pneumonitis
- Participant has a known additional malignancy that is progressing or has required
active treatment in the last 2 years
- Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma
of the skin, ductal carcinoma in situ, or cervical carcinoma in situ that has
undergone potentially curative therapy are not excluded
- Participant has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis
- Note: Participants with previously treated brain metastases may participate
provided they are radiologically stable (i.e., without evidence of progression
for at least 4 weeks by repeat imaging [repeat imaging should be performed during
study screening]), clinically stable, and without requirement for steroid
treatment for at least 14 days prior to the first dose of study treatment
- Participant 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
treatment
- Participant has an 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)
- Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not
considered a form of systemic treatment
- Participant has an active infection requiring systemic therapy
- Participant has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
participant's involvement for the full duration of the trial, or is not in the best
interest of the participant to be involved, in the opinion of the treating
investigator
- Note: Participants who received colony-stimulating factors (e.g., granulocyte
colony stimulating factor [G-CSF], granulocyte macrophage colony-stimulating
factor [GM-CSF] or recombinant erythropoietin) within 2 weeks prior to the first
dose of study treatment are not eligible
- Participant has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial
- Participant has a known history of human immunodeficiency virus (HIV) infection. No
HIV testing is required unless mandated by local health authority
- Participant has a known history of hepatitis B (defined as hepatitis B surface antigen
[HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid
[RNA] [qualitative] is detected) infection. No testing for hepatitis B or hepatitis C
is required
- Participant 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 (e.g., CTLA-4, OX 40, CD137)
- Participant has received prior systemic anti-cancer therapy including investigational
agents
- Has received prior radiotherapy for the current disease
- Participant has received a live vaccine within 30 days prior to the first dose of
study treatment. 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 (e.g., FluMist) are live attenuated vaccines and are not
allowed
- Participant has severe hypersensitivity (>= grade 3) to pembrolizumab or any of its
excipients
- Participant is currently participating in or has participated in a study of an
investigational agent (anti-cancer agent only) or has used an investigational device
within 4 weeks prior to the first dose of study treatment
- Note: Participants who have entered the follow-up phase of an investigational
trial may participate as long as it has been 4 weeks after the last dose of the
previous investigational agent
- Participant is pregnant or breastfeeding or expecting to conceive children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of study treatment
- Participant has symptomatic ascites or pleural effusion. A participant who is
clinically stable following treatment for these conditions (including therapeutic
thoraco- or paracentesis) is eligible
- Has had an allogeneic tissue/solid organ transplant
