PRIMARY OBJECTIVES:
I. To estimate the overall response rate (ORR) of intravenous administration of pembrolizumab
by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in adult subjects with advanced
(unresectable and/or metastatic) and previously treated gastroesophageal adenocarcinoma.
SECONDARY OBJECTIVES:
I. To evaluate the duration of response (DOR), disease control rate (DCR), time to
progression (TTP), progression-free survival (PFS), and overall survival (OS) using RECIST
1.1 and immune-related (ir)RECIST criteria.
II. To perform exploratory biomarkers to study the correlation between immunological and
molecular changes in tumor tissues and peripheral blood with clinical outcomes (DOR, DCR,
TTP, PFS, and OS) using RECIST 1.1, and irRECIST rate of adverse events.
III. To determine the safety and tolerability of intravenous administration of pembrolizumab
or pembrolizumab plus ramucirumab in adult subjects with advanced (unresectable and/or
metastatic) and previously treated gastroesophageal adenocarcinoma.
EXPLORATORY OBJECTIVES:
I. To explore the association between PD-L1 expression by immunohistochemistry, shed PD-L1
levels, somatic gene expression profiling and antitumor efficacy of pembrolizumab based on
RECIST 1.1 imaging criteria as well as overall survival.
II. To explore the relationship between genomic variation and response to the treatment
administered.
III. Tissue and blood immune monitoring will be conducted through our immune platform group
as detailed per the biomarker section based on 3 biopsies done at the following time points:
1) pre-treatment, 2) 6 weeks after therapy, and 3) and an optional biopsy upon progression.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 21 days for up to 35 cycles in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 12
weeks thereafter.
Inclusion Criteria:
- The subject (or legally acceptable representative if applicable) provides written
informed consent for the trial. The subject may also provide consent for future
biomedical research. However the subject may participate in the main trial without
participating in future biomedical research.
- Be willing and able to provide written informed consent/assent for the trial.
- Histologically and cytologically documented diagnosis as gastroesophageal
adenocarcinoma.
- Have a documented advanced (metastatic and/or unresectable) gastroesophageal
adenocarcinoma that is incurable and for which prior first-line or later-line standard
of care (SOC) treatments have failed. There is no limit to the number of prior
treatment regimens. Prior neoadjuvant or adjuvant therapy included in initial
treatment may not be considered first- or later-line SOC treatment unless such
treatments were completed less than 12 months prior to the current tumor recurrence.
- Have submitted an evaluable tissue sample for biomarker analysis from a newly obtained
endoscopic, core, incisional, or excisional biopsy of a tumor lesion not previously
irradiated. The tumor tissue submitted for analysis must be from a single tumor tissue
specimen and of sufficient quantity and quality to allow biomarker study. A newly
obtained tumor specimen, defined as a specimen obtained up to 6 weeks (42 days) prior
to initiation of treatment on day 1, for biomarker characterization will be required
for enrollment of all subjects. Tissue from tumor progressing at a site of prior
radiation may be allowed for biomarker characterization upon agreement from Merck.
Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or
subject safety concern) may submit an archived specimen only upon agreement from the
Merck.
- Have measurable disease based on RECIST 1.1 as assessed by the investigator. Lesions
situated in a previously irradiated area are considered measurable if progression has
been demonstrated in such lesions.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale.
- Life expectancy of greater than 3 months per the judgment of the investigators.
- Absolute neutrophil count (ANC) >= 1,500 /mcL (within 5 days prior to the start of
study treatment).
- Platelets >= 100,000/mcL (within 5 days prior to the start of study treatment).
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 7 days of assessment) (within 5 days prior to the start of study
treatment).
- Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration
rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =<
1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels >
1.5 X institutional upper limit of normal (ULN) (within 5 days prior to the start of
study treatment). Creatinine clearance should be calculated per institutional
standard.
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN (within 5 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 OR =< 5 X ULN for subjects with liver metastases (within 5 days prior to the start
of study treatment).
- Albumin: >= 2.5 mg/dL (within 5 days prior to the start of study treatment).
- International normalized ratio (INR) or 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 5
days prior to the start of study treatment).
- 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 5 days prior to the start of study treatment).
- 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.
- Male and female subjects of childbearing potential must be willing to use an adequate
method of contraception, for the course of the study through 120 days after the last
dose of study medication. Note: Abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the subject.
Exclusion Criteria:
- Is currently participating in or has participated in a study of an investigational
agent or used an investigational device within 4 weeks prior to the first dose of
study treatment. Note: Subjects 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.
- Has a diagnosis of immunodeficiency or is receiving 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 trial treatment.
- Has severe hypersensitivity (>= grade 3) to pembrolizumab or any of its excipients.
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.
- 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: Subjects with =< grade 2 neuropathy or alopecia are an exception to this
criterion.
- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention as determined by the
investigators prior to starting therapy.
- Has a known additional malignancy that is progressing or requires active treatment.
Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have
undergone potentially curative therapy are not excluded.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are radiological stable (i.e., without evidence of progression for at least 4
weeks by repeat imaging (note that the repeat imaging should be performed during study
screening), clinically stable and without requirement of steroid treatment for at
least 14 days prior to the first dose of trial treatment. This exception does not
include carcinomatous meningitis which is excluded regardless of clinical stability.
- 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). Replacement therapy (e.g. thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment and is allowed.
- Has a history of (non-infectious) pneumonitis that required treatment with steroids or
has current 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 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 or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR) (e.g.,
CTLA-4, OX 40, CD137).
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). No HIV
testing is required unless mandated by local health authority.
- Had a solid organ or hematologic transplant.
- Has a known history of hepatitis B virus (HBV; hepatitis B surface antigen [HBsAg]
reactive) or known active hepatitis C virus (HCV; HCV ribonucleic acid [RNA]
[qualitative] is detected) infection. No testing for hepatitis B and hepatitis C is
required unless mandated by local health authority.
- Has received a live vaccine within 30 days prior to the first dose of the trial 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.
