FDG-PET Directed Treatment in Improving Response in Patients With Locally Advanced Stomach or Gastroesophageal Junction Cancer

Pre-registered patients receive standard pre-operative chemotherapy comprising epirubicin
intravenously 50mg/m^2 (IV) on day 1; oxaliplatin 130 mg/m^2 IV or cisplatin 60 mg/m^2 IV on
day 1; and capecitabine 625 mg/m^2 orally (PO) twice daily (BID) or fluorouracil 200
mg/m^2/day IV continuously on days 1-21; and undergo FDG-PET following course 1 (days 15-19).
Patients defined as FDG-PET non-responders are registered and randomized to 1 of 2 treatment
arms.

Primary objective

To assess and compare the overall survival (OS) of patients with locally advanced gastric
cancer classified as FDG-PET non-responders after one cycle of pre-operative chemotherapy
randomly assigned to receive either salvage chemotherapy before and after surgery or
immediate surgery followed by fluorouracil sensitized radiotherapy.

Secondary objectives

1. To assess and compare progression-free survival (PFS) between the treatment arms (Arms A
and B).

2. To assess and compare R0 resection rate between the treatment arms (Arms A and B).

3. To assess and compare pathologic complete response (pCR) rate between the treatment arms
(Arms A and B).

4. To assess the adverse events (AE) profile and safety of each treatment arm (Arms A and
B), including post-operative mortality rate, 30-day post-operative targeted adverse
events (i.e., dehiscence, significant infection, and re-operation rate).

5. To examine the changes of FDG-PET SUV induced by pre-operative chemotherapy at different
time points (from baseline to completion of one cycle of treatment before randomization,
and 2 cycles of salvage treatment) in patients randomized to salvage treatment arm (Arm
B).

6. To collect measurement of fatigue and overall perception of QOL at registration of the
study (Alliance registration QOL assessment study).

Pre-Registration Eligibility Criteria

1. Documentation of Disease

1.1 Histologically confirmed adenocarcinoma of the stomach or gastroesophageal
junction (Siewert type II, III)

1.2 Pre-treatment clinical stage of T3-4N any M0 or T any N positive M0 as determined
by laparoscopy, CT scan (or PET/CT), or endoscopic ultrasound (histologic confirmation
of lymph involvement is not required). Therefore, patients can have measurable or
non-measurable disease.

1.3 Patients with T1-2N0M0 tumors or patients with metastatic disease are NOT
eligible.

2. Patients must be eligible for curative intent surgical resection.

3. FDG Avid malignancy - Patients must have an FDG avid tumor(s). FDG avid tumors are
defined as a primary tumor with an increased uptake in the region of the tumor that
has an SUV of > 5.0 or a tumor:liver SUV ratio of > 1.5.

4. No prior history of congestive heart failure - NYHA class I to IV or known DPD
deficiency

5. No current grade 2, 3, or 4 of neuropathy.

6. No known hypersensitivity to epirubicin, oxaliplatin and cisplatin, capecitabine and
5-flurouracil, docetaxel or irinotecan.

7. Not pregnant and not nursing, because this study involves an agent that has known
genotoxic, mutagenic and teratogenic effects.

7.1 Therefore, for women of childbearing potential only, a negative serum pregnancy
test pregnancy test done ≤ 7 days prior to pre-registration is required.

7.2 A female of childbearing potential is a sexually mature female who: 1) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in
the preceding 12 consecutive months).

8. Age ≥ 18 years

9. ECOG Performance Status 0 or 1

10. Required Initial Laboratory Values:

- Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3

- Platelet Count ≥ 100,000/mm^3

- Creatinine ≤ 1.5 x upper limit of normal (ULN)

- Total Bilirubin ≤ 1.5 x ULN, except in patients with Gilbert's disease

- AST and ALT ≤ 2.5 x ULN

- Alkaline Phosphatase ≤ 2.5 x ULN

Registration Eligibility Criteria to Treatment Arms A or B

1. Patient must continue to be eligible for curative intent surgical resection.

2. Disease Progression: FDG avid malignancy that is classified as an FDG PET non-
responder. PET non-responders are defined as having < 35% reduction in the FDG uptake
of the primary tumor when compared to baseline.

3. Concomitant Medications -

3.1 Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on
this trial. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days
prior to the start of study treatment.

3.2 Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients
must discontinue the drug 14 days prior to the start of study treatment.

4. Patient must have received only one cycle of the following regimens during the
pre-registration time period and no other therapy for gastric or gastroesophageal
junction cancer:

- Epirubicin, Oxaliplatin, and Capecitabine

- Epirubicin, Oxaliplatin, and Fluorouracil

- Epirubicin, Cisplatin, and Capecitabine

- Epirubicin, Cisplatin, and Fluorouracil

5. Toxicity recovery should include the following:

- Grade ≤ 2 neuropathy

- Grade ≤ 2 diarrhea

- Grade ≤ 2 mucositis

6. Pre-registration chemotherapy given within 42 days of treatment (treatment meaning
surgery if Arm A, chemotherapy if Arm B)