Prospective Phase I Study of GAX for Metastatic Pancreatic Cancer

It is the investigators expectation that this combination will induce apoptotic pathways
downstream of biochemical mechanisms of resistance and synergistically induce pathways for
apoptosis that are non-p53 dependent, which have not been previously explored in
chemotherapy trials for this cancer. ABRAXANE® is novel in that it induces apoptosis to the
same degree in mutant and wt p53 cancers. Mutant p53 tumors occur in 80-90% of PC and mutant
p53 is thought of as one of the major mechanisms of drug resistance.

Furthermore, the investigators will be starting Xeloda and gemcitabine at slightly lower
doses than the initial GTX studies. This is because the investigators have found that the
efficacy is maintained at these slightly lower doses while side effects are minimized. The
reason that GTX works at lower doses, as well as higher doses, is the synergy between drugs.
Drug regimens that are synergistic can maintain their antitumor effect at doses lower than
in non-synergistic regimens, but must maintain their dose intensity to achieve their
anti-tumor effect. RECIST 1.1 criteria will be utilized for judging response, progression
and stable disease. Overall assessment of the data will be by intention to treat analysis
(ITT).

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of pancreas metastatic to any distant site.
(Stage IV).

2. Must have a lesion reproducibly measurable by CT or MRI scans per Recist 1.1 criteria

3. Prior radiation and surgery allowed (except Target lesions) but GAX treatment should
be: >3 weeks since major surgery

1. Bilirubin < 1.5 mg/dL

2. Patients must have adequate liver function: AST and ALT < 2.5 X upper limit of
normal, alkaline phosphatase < 2.5 X upper limit of normal, unless bone
metastasis is present (<5 X upper limit of normal) in the absence of liver
metastasis.

3. Patients must have adequate bone marrow function: Platelets >100,000, Hemoglobin
> 9.0g/dL and ANC > 1,500

4. Patients must have adequate renal function: creatinine <1.5 mg/dL is recommended

4. Women of childbearing potential and sexually active males must use an effective
contraception method during treatment and for three months after completing
treatment.

5. Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE)

6. Clinical Parameters Life expectancy > three months Age ≥ 18 years and ≤ 75 years
Performance status 0-1 (ECOG) Pre-existing Peripheral Neuropathy (sensory) must be ˂
grade 2 Able to tolerate oral medications

7. Informed Consent: Each patient must be completely aware of the nature of his/her
disease process and must willingly give consent after being informed of the
experimental nature of the therapy, alternatives, potential benefits, side-effects,
risks, and discomforts.

8. PT/PTT within normal or therapeutic limits as determined by the investigator. All
subjects will be on Xeloda, use of warfarin is exclusionary.

Exclusion Criteria:

1. Neuroendocrine cancer should be ruled out by histology or immunohistochemical
staining of the specimen. Mixed histology, pancreatic neuroendocrine and
adenocarcinoma tumors, will also be excluded.

2. Prior chemotherapy is allowed, as long as less than or equal to two of the components
of GAX were used previously for their treatment: this includes gemcitabine,
capecitabine, 5-FU, or ABRAXANE® .

3. Hypersensitivity: Patients with a history of severe hypersensitivity reaction to
taxanes or other drugs formulated with polysorbate 80, or any of the other drugs in
the GAX regimen are excluded.

4. Serious medical or psychiatric illness preventing informed consent or intensive
treatment (e.g. serious infection) that would in the opinion of the investigator,
increase the risk of serious neutropenic complications.

5. Serious medical risk factors involving any of the major organ systems, or serious
psychiatric disorders, which could compromise the subject's safety or the study data
integrity.

6. Patients with compromised immune systems who are at increased risk of toxicity and
lethal infections when treated with marrow-suppressive therapy.

7. Serious cardiovascular thromboembolic disease, including: congestive heart failure
NYHA class III or greater; unstable angina or new onset angina (starting within three
months of screening for this protocol), or myocardial infarction within the past 3
months (prior to screening); serious cardiac arrhythmias requiring therapy;
cerebrovascular accident including transient ischemic attacks within the past 3
months (prior to screening).

8. Serious non-healing wound, ulcer, or bone fracture.

9. Evidence or history of bleeding diathesis.

10. Major surgery, open biopsy or significant traumatic injury within 3 weeks of
receiving first study drug.

11. Use of cytochrome P450 enzyme inducing drugs such as: antiepileptic drugs (phenytoin,
carbamazepine, or phenobarbital, but not Keppra), or St. John's Wort or rifampin
(rifampicin).

12. Prior malignancy in last 2 years other than curatively treated carcinoma in-situ of
any site, non-melanoma skin cancer, or Stage I breast and/or bladder cancers (in
situ), or early stage prostate cancer Stage I or II, curatively treated by surgery
and/or radiation.