This study will be a prospective, open-label, single arm, multi-center phase 2 clinical trial
of mFOLFOX6 + trastuzumab + avelumab in first-line, metastatic, HER2-amplified gastric and
esophageal adenocarcinomas. The primary objective of this study is to estimate the best
objective response rate (CR or PR, ORR) in these patients within 24 weeks by RECIST 1.1
criteria. Secondary objectives include; estimating PFS by both RECIST 1.1 and iRECIST
criteria, estimating OS, estimating the disease control rate (DCR) at 24 weeks by RECIST 1.1
and iRECIST, and characterizing the safety issues associated with this regimen.
1. Written informed consent and HIPAA authorization for release of personal health
information prior to registration.
2. Age ≥ 18 years at the time of consent.
3. ECOG Performance Status of 0 or 1.
4. Histologically confirmed esophageal, gastroesophageal junction, or gastric
adenocarcinoma, with unresectable or metastatic disease documented on diagnostic
5. HER2 amplification confirmed by standard of care testing of tumor specimen (3+ by
immunohistochemistry, or 2+ on IHC with ISH with HER2/CEP17 ratio ≥2).
6. Radiographically measurable disease according to RECIST 1.1 within 28 days prior to
7. Adequate organ function as defined in the table below. All screening labs to be
obtained within 28 days prior to registration.
- Absolute Neutrophil Count ≥ 1.5 x 109/L
- Hemoglobin (Hgb) ≥ 9 g/dL (may have been transfused)
- Platelets ≥ 100 x 109/L OR ≥ 75 x 109/L for patients who received Cycle 1 of
mFOLFOX6 +/- trastuzumab prior to registration
- Calculated creatinine clearance1 ≥ 30 mL/min OR creatinine ≤ 1.5 × upper limit of
- Bilirubin ≤ 1.5 × upper limit of normal (ULN) (Subjects with Gilbert's syndrome
may be enrolled despite a total bilirubin level >1.5 mg/dL, if their conjugated
bilirubin is < 1.5× ULN)
- Aspartate aminotransferase (AST) ≤ 2.5 × ULN OR ≤ 5x ULN in patients with known
- Alanine aminotransferase (ALT) ≤ 2.5 × ULN OR ≤ 5x ULN in patients with known
8. Left ventricular ejection fraction (LVEF) ≥ 50% or above the lower limit of the
institutional normal range, whichever is lower.
9. Females of childbearing potential must have a negative serum pregnancy test at
screening. NOTE: Females are considered of child bearing potential unless they are
surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or they are naturally postmenopausal for at least 12
10. Females of childbearing potential and males must be willing to abstain from
heterosexual activity or to use 2 forms of effective methods of contraception from the
time of informed consent until 210 days after treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method.
11. As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study.
1. Previous systemic therapy for stage IV disease - EXCEPT that patient may have received
one cycle of mFOLFOX6 +/- trastuzumab within the 4 weeks prior to registration.
2. Active infection requiring intravenous systemic therapy.
3. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).
4. Treatment with any investigational drug within 28 days prior to registration.
5. Prior immune checkpoint inhibitor therapy (i.e. anti-CTLA-4, anti-PD-L1, anti-PD-1),
or HER2-directed therapy (including trastuzumab)
6. Evidence of interstitial lung disease or active, non-infectious pneumonitis
7. Untreated brain metastasis or brain metastasis treated within 3 months prior to
8. Known additional malignancy that is active and/or progressive requiring treatment;
exceptions include basal cell or squamous cell skin cancer, in situ cervical or
bladder cancer, or other cancer for which the subject has been disease-free for at
least five years.
9. Serious cardiovascular event within 6 months prior to study entry, including
myocardial infarction, malignant hypertension, severe/unstable angina, symptomatic
congestive heart failure (≥ New York Heart Association Classification Class II),
cerebral vascular accident, transient ischemic attack, or serious cardiac arrhythmia
10. History of organ allograft or allogeneic stem cell transplantation
11. Active autoimmune disease requiring systemic treatment in the past 3 months (for
example with disease modifying agents, corticosteroids, or immunosuppressive drugs).
- Subjects with endocrine diseases stable on replacement therapy (e.g., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) or hormone suppression.
- Subjects that require intermittent use of bronchodilators, local steroid
injections, or inhaled or topical steroids
- Subjects with vitiligo, psoriasis, Sjogren's syndrome, or resolved childhood
12. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,
inhaled, topical steroids, or local steroid injection (e.g., intra-articular
injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone
or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT
13. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
14. Known history of Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.
15. Vaccination within 4 weeks of the first dose of avelumab and while on trials is
prohibited except for administration of inactivated vaccines.
16. Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v5 Grade ≥ 3).
17. Persisting toxicity related to prior therapy (NCI CTCAE v5 Grade > 1); however,
alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety
risk based on investigator's judgment are acceptable.
18. Other severe acute or chronic medical conditions including immune colitis,
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
conditions including recent (within the past year) or active suicidal ideation or
behavior; or laboratory abnormalities that may increase the risk associated with study
participation or study treatment administration or may interfere with informed
consent, the interpretation of study results and, in the judgment of the investigator,
would make the patient inappropriate for entry into this study.