C-Met Inhibitor AMG 337, Oxaliplatin, Leucovorin Calcium, and Fluorouracil in Treating Patients With Advanced Stomach or Esophageal Cancer

PRIMARY OBJECTIVES:

I. To evaluate the toxicity of combination therapy with AMG 337 (c-Met inhibitor AMG 337) and
mFOLFOX6 (oxaliplatin, leucovorin calcium, and fluorouracil) chemotherapy in patients with
advanced or metastatic gastrointestinal (GI) cancers. (Phase I) II. To determine the dose of
AMG 337 to be used in combination with mFOLFOX6 chemotherapy in the phase II portion of the
trial. (Phase I) III. To determine the pharmacokinetics of AMG 337 in combination with
mFOLFOX6. (Phase I) IV. To determine if the addition of AMG 337 to mFOLFOX6 chemotherapy
improves median progression-free survival (PFS) in the first line treatment of patients with
human epidermal growth factor receptor 2 (Her2Neu) negative and high c-met proto-oncogene
(MET) expressing advanced esophagogastric and gastroesophageal junction (GEJ) adenocarcinoma.
(Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the
placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with
Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma,
with regards to overall survival (OS). (Phase II) II. To evaluate the addition of AMG 337 to
mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in
the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced
esophagogastric and GEJ adenocarcinoma, with regards to response rate and disease control
rate. (Phase II) III. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also
to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of
patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ
adenocarcinoma, with regards to toxicity rates. (Phase II) IV. To evaluate the addition of
AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy
combination in the first line treatment of patients with Her2Neu negative and high c-MET
expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to time to
development of new metastasis. (Phase II) V. To evaluate the addition of AMG 337 to mFOLFOX6
chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first
line treatment of patients with Her2Neu negative and high c-MET expressing advanced
esophagogastric and GEJ adenocarcinoma, with regards to evaluation of MET amplification.
(Phase II) VI. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to
evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of
patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ
adenocarcinoma, with regards to evaluation of MET amplification and MET expression as
determined by DAKO immunohistochemistry (IHC) for comparison to Ventana IHC. (Phase II) VII.
To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the
placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with
Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma,
with regards to a retrospective re-evaluation of the cutpoint used by the computer algorithm
for c-MET IHC to assess its ability to distinguish responding versus non-responding patients
will be undertaken in this population, so that a potentially more optimal cutpoint to define
high c-MET tumors in patients can be identified. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of c-Met inhibitor AMG 337 followed by a
phase II study.

PHASE I: Patients receive c-Met inhibitor AMG 337 orally (PO) once daily (QD) on days 1-28;
and oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and
fluorouracil IV over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive c-Met inhibitor AMG 337 PO QD on days 1-28; and oxaliplatin IV over 2
hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and
15.

ARM B: Patients receive placebo PO QD on days 1-28; and oxaliplatin IV over 2 hours,
leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and 15.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

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

Inclusion Criteria:

- Patients must have a life expectancy >= 12 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood test or urine study within 48 hours prior to randomization to rule
out pregnancy; a female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) for the duration of study
therapy and for 3 months after the last dose of AMG 337 plus mFOLFOX6 chemotherapy;
should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately; should a man impregnate
or suspect that he has impregnated a woman while participating in this study, he
should inform his treating physician immediately

- Patients must NOT have a known immediate or delayed hypersensitivity reaction to drugs
chemically related to fluorouracil, platins or their excipients nor have a known
history of dihydropyrimidine dehydrogenase (DPD) deficiency

- Patients must be able to swallow tablets whole

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 9 g/dL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 X institutional upper limit of normal (ULN) or =< 5 X ULN if the patient has
liver metastases

- Creatinine =< 1.5 X institutional ULN or creatinine clearance >= 50 mL/min for
patients with creatinine levels above institutional normal

- Patients must NOT be taking current medications or substances that are inhibitors or
inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)

- Patients with known human immunodeficiency virus (HIV) are not eligible if cluster of
differentiation (CD)4 count is =< 200 cell/mm^3 or if receiving antiretroviral therapy

- Patients must not have a pre-existing > grade 1 (Common Terminology Criteria for
Adverse Events version 4 [CTCAEv4]) motor or sensory neuropathy

- Patients must not have an uncontrolled infection, active hepatic, biliary disease or
other uncontrolled intercurrent illnesses including, but not limited to: uncontrolled
ascites, uncontrolled hypertension, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia or psychiatric illness/addictive disorders that
would limit compliance with study requirements

- PHASE I:

- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 criteria within 4 weeks prior to registration; patients must not have
clinical or radiographic evidence of brain metastasis

- Patients must have histologically or cytologically confirmed adenocarcinoma
originating from anywhere in the gastrointestinal tract

- Patients must have progression on standard therapies, for which effective therapy is
not available (or patients are not a candidate for or are intolerant of such
therapies)

- Patients must NOT have previous or concurrent malignancy; exceptions are made for
patients who meet any of the following conditions:

- Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or
superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)

- Prior malignancy completely excised or removed and patient has been continuously
disease free for > 5 years from registration

- Patients may have received prior surgery or radiotherapy if > 4 weeks prior to
registration and patient does not have any unresolved or unstable serious toxicity

- Patients must not be receiving an investigational agent concurrently and must not have
received any other investigational agents within 4 weeks prior to randomization

- PHASE II:

- Patients must have measurable disease by RECIST 1.1 criteria within 4 weeks prior to
registration to Step 0; patients must not have clinical or radiographic evidence of
brain metastasis because of their poor prognosis

- Patient disease status must be as follows:

- Adenocarcinoma or poorly differentiated carcinoma of the stomach, esophagus or
gastroesophageal (GE) junction

- Histologically or cytologically confirmed Her2/neu negative cancer prior to
pre-registration; Her2/neu status must be determined by a Clinical Laboratory
Improvement Amendments (CLIA) certified laboratory

- Locally advanced or metastatic disease that is inoperable and not amenable to
curative therapy; linitis plastica is permitted

- Patient must NOT have gastric carcinoid, sarcomas or squamous cell carcinoma

- Patients may have received prior surgery or radiotherapy if > 4 weeks prior to
registration to Step 0 and patient does not have any unresolved or unstable serious
toxicity

- Patients must NOT have previous or concurrent malignancy; exceptions are made for
patients who meet any of the following conditions:

- Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or
superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)

- Prior malignancy completely excised or removed and patient has been continuously
disease free for > 5 years from registration to Step 0

- Patients must not be receiving an investigational agent concurrently and must not have
received any other investigational agents within 4 weeks prior to registration to Step
0

- Patient may not have received prior chemotherapy for advanced disease or prior
oxaliplatin or anti-MET therapy

- Previous neo-adjuvant or adjuvant treatment is allowed provided that it was
discontinued >= 6 months prior to registration to Step 0

- Patients must have paraffin-embedded tumor specimen available for submission for
central determination of MET expression status

- NOTE: it is recommended that patients not be pre-registered until the required
tumor specimens are on hand and ready for submission; if submission of tissue
will be submitted more than 5 working days after pre-registration, immediately
notify the receiving laboratory

- Patients must have had MET expression status determined by the Immunohistochemistry
Laboratory and Image Analysis Laboratory in the Department of Pathology of The
University of Texas MD Anderson Cancer Center in Houston: the report from the central
laboratory indicates tumor tissue has MET

- NOTE: for this protocol, 'MET High' will be defined as: >= 50% tumor cells with a
staining intensity of 2+ or 3+ in IHC utilizing the CONFIRM anti-total MET, SP44,
rabbit monoclonal primary antibody