Genetic Analysis-Guided Irinotecan Hydrochloride Dosing of mFOLFIRINOX in Treating Patients With Locally Advanced Gastroesophageal or Stomach Cancer

PRIMARY OBJECTIVES:

I. To determine the residual tumor (R) 0 resection rate. II. To determine the pathologic
complete response (pCR) rate of up to 36 patients treated with 4 cycles of neoadjuvant
mFOLFIRINOX (UGTA1A1 genotype-dosed irinotecan [irinotecan hydrochloride]) regimen.

SECONDARY OBJECTIVES:

I. Response rate (radiographic [computed tomography (CT)], and metabolic (positron emission
tomography [PET] maximum standardized uptake value [SUVmax]) to chemotherapy.

II. Chemotherapy-related toxicity. III. Surgical morbidity. IV. Overall survival (OS)
measured from the time of histologic diagnosis. V. Disease-free survival measured from the
time of histologic diagnosis. VI. Pattern of recurrence (distant, locoregional, both). VII.
Human epidermal growth factor receptor 2 positive (HER2+) vs HER2 negative (-) difference in
clinical outcomes.

OUTLINE:

PREOPERATIVE THERAPY: Patients receive oxaliplatin intravenously (IV) over 2 hours,
leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and
fluorouracil IV over 46 hours continuously on day 1. Courses repeat every 2 weeks for 4
courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo surgery.

POST-OPERATIVE THERAPY: Beginning 5-10 weeks after surgery, patients receive oxaliplatin IV
over 2 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90
minutes, and fluorouracil IV over 46 hours continuously on day 1. Courses repeat every 2
weeks for 4 more courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Histologically confirmed locally advanced gastric (primary endpoint includes proximal
and mid-body stomach) or esophagogastric adenocarcinoma; distal gastric (antral)
adenocarcinomas are eligible for enrolment but will not be included in the primary
analysis

- Locally advanced disease as determined by endoscopic ultrasound (EUS) stage > primary
tumor (T) 3 and/or any T, lymph nodes (N)+ disease without metastatic disease (Mx)

- All patients must have diagnostic laparoscopy with diagnostic washings for cytology;
both cytology positive and negative patients are eligible for enrolment, but only
cytology negative patients will be included in the primary analyses; gross peritoneal
disease is not eligible

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Eligible for surgery with curative intent

- Absolute neutrophil count (ANC) >= 1250/ul

- Hemoglobin >= 9 g/dL

- Platelets >= 100,000/ul

- Total bilirubin < 1.5 x upper limit of normal

- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate
transaminase (SGPT) < 2.5 x upper limit of normal for patients without liver
metastases OR SGOT and SGPT < 5 x upper limit of normal for patients with liver
metastases

- Creatinine =< 1.5 x upper limit of normal

- Measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumor
(RECIST) 1.1 will be allowed

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation, up until 30 days after final study treatment;
should a woman become pregnant or suspect that she is pregnant while participating in
this study, she should inform her treating physician immediately

- Patients taking substrates, inhibitors, or inducers of cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4) should be encouraged to switch to alternative
drugs whenever possible, given the potential for drug-drug interactions with
irinotecan

- Signed informed consent

Exclusion Criteria:

- 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%

- Inflammatory bowel disease that is uncontrolled or on active treatment (Crohn's
disease, ulcerative colitis)

- Diarrhea, grade 1 or greater by the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE, version [v] 4.0)

- Neuropathy, grade 2 or greater by NCI-CTCAE, v 4.0

- Serious underlying medical or psychiatric illnesses that would, in the opinion of the
treating physician, substantially increase the risk for complications related to
treatment

- Active uncontrolled bleeding

- Pregnancy or breastfeeding

- Major surgery within 4 weeks

- Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g, *6) will be
allowed and treated as in the *28/*28 dosing group