Ph1b Study of Oraxol in Comb. w. Ramucirumab in Patients w. Gastric, Gastro-esophageal, or Esophageal Cancers

This is a sequential-group, dose escalation trial to determine the maximum tolerated dose of
oral Oraxol in combination with intravenous ramucirumab. After a screening period of up to 28
days subjects will be enrolled into the treatment phase of the study. Each cycle of therapy
will last 4 weeks. Subjects may continue in the study until they experience disease
progression or unacceptable toxicity. Three to six subjects will be enrolled at each dose
level. Once the tolerability of a dose level has been determined, an additional 3-6 subjects
may be enrolled at a higher dose level, to determine the maximum tolerated dose. Safety will
be monitored through recording of adverse events, serious adverse events, monitoring of
laboratory tests including hematology, blood chemistry, urinalyses, physical examinations and
electrocardiograms. Subjects will undergo radiographic assessments for tumor response at
specified time points. Blood samples will also be obtained in the first cycle of therapy at
multiple time points for determination of the amount of paclitaxel and metabolites and
HM30181 in the circulation. After the treatment period, there will be a follow-up period
during which the subject or family may be contacted every three months for follow-up.

Inclusion Criteria:

- Subjects must meet all of the following criteria to be included in this study:

1. Signed written informed consent

2. ≥18 years of age

3. Histologically or cytologically confirmed diagnosis of advanced stage gastric,
gastro-esophageal, or esophageal cancers in whom ramucirumab and paclitaxel are
reasonable treatments

4. Have documented testing for human epidermal growth factor receptor 2 (HER2-neu)
overexpressing, and for those with tumors overexpressing HER2-neu, have
documented progression on Trastuzumab-containing therapy

5. Measurable disease on computed tomography (CT) scan of thorax, abdomen, and
pelvis per RECIST v1.1 criteria

6. Able to swallow oral medication as an intact dosage form

7. Adequate hematologic status as demonstrated by not requiring transfusion support
or granulocyte-colony stimulating factor (G-CSF) to maintain: Absolute neutrophil
count (ANC) ≥1500 cells/mm3, Platelet count ≥100 x 109/L, Hemoglobin ≥10 g/dL;
subjects with thalassemia having a hemoglobin <10 g/dL may be enrolled, per
Investigator discretion

8. Adequate liver function as demonstrated by: Total bilirubin of ≤1.5 mg/dL or ≤2.0
mg/dL for subjects with liver metastasis, Alanine aminotransferase (ALT) ≤3 x
upper limit of normal (ULN) or ≤5 x ULN if liver metastasis is present, Alkaline
phosphatase ≤3 x ULN or ≤5 x ULN if bone or liver metastasis is present,
Gamma-glutamyl transferase (GGT) <10 x ULN

9. Adequate renal function as demonstrated by serum creatinine ≤1.5 x ULN or
creatinine clearance calculation ≥60 mL/min as calculated by the Cockcroft and
Gault formula

10. Normal prothrombin time (PT) or international normalized ratio (INR) and normal
activated partial thromboplastin time (aPTT)

11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

12. Life expectancy of at least 3 months

13. Women must be postmenopausal (>12 months without menses) or surgically sterile
(ie, by hysterectomy and/or bilateral oophorectomy) or must be using effective
contraception (ie, oral contraceptives, intrauterine device, double barrier
method of condom and spermicide) and agree to continue use of contraception for
30 days after their last dose of study drug

14. Sexually active male subjects must use a barrier method of contraception during
the study and agree to continue the use of male contraception for at least 30
days after the last dose of study drug.

Exclusion Criteria:

- Subjects who meet any of the following criteria will be excluded from this study:

1. Unresolved toxicity from previous anticancer treatments, including
investigational products (subjects must have recovered all unacceptable toxicity
to ≤ Grade 1 Common Terminology Criteria for Adverse Events [CTCAE] toxicity).
This does not extend to symptoms or findings that are attributable to the
underlying disease

2. Received investigational products within 14 days or 5 half-lives of the first
study dosing day, whichever is longer

3. Are currently receiving other medications or radiation intended for the treatment
of their malignancy

4. Central nervous system metastases, including leptomeningeal involvement

5. Women of childbearing potential who are pregnant or breastfeeding

6. Currently taking a concomitant medication, other than a premedication, that is:

- A known P-glycoprotein (P-gp) inhibitor or inducer. Subjects who are taking
such medications but who are otherwise eligible may be enrolled if they
discontinue the medication ≥1 week before dosing

- An oral medication with a narrow therapeutic index known to be a P-gp
substrate within 24 hours prior to start of dosing in the study

- Medications known to be clinically significant inhibitors (eg. gemfibrozil)
or inducers (eg. rifampin) of CYP2C8 or medications known to be strong
cytochrome P450 (CYP) 3A4 inhibitors (eg. ketoconazole) or inducers (eg.
rifampin or St. John's Wort). Subjects who are currently taking such
medications but who are otherwise eligible may be enrolled if they
discontinue the medication 1 week before dosing and remain off that
medication during treatment with Oraxol.

7. Require therapeutic use of anticoagulants other than daily aspirin or low
molecular weight heparin

8. Require therapeutic use of nonsteroidal anti-inflammatory drugs (NSAIDs)

9. Unable to receive iv contrast for required CT scans

10. Systolic blood pressure >140mm Hg or diastolic blood pressure > 90 mm Hg

11. Grade 3 gastrointestinal (GI) bleeding within 3 months prior to screening

12. Arterial thromboembolic event including, but not limited to, myocardial
infarction, transient ischemic attack, or cerebrovascular accident within 6
months of enrollment

13. Deep vein thrombosis (DVT) or pulmonary embolus which require use of oral
anticoagulants or, if on low molecular weight heparin, have not been on a stable
dose for at least 2 weeks

14. Uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, poorly controlled diabetes or diabetes with established
vascular complications, chronic pulmonary disease requiring oxygen, known
bleeding disorders, or any concomitant illness or social situation that would
limit compliance with study requirements

15. Major surgery to the upper GI tract, or have a history of GI disease or other
medical condition that, in the opinion of the investigator may interfere with
oral drug absorption

16. History of hypersensitivity to paclitaxel, not attributed to a hypersensitivity
type reaction to Cremophor®, or history of hypersensitivity type reaction to
polysorbate 80 or other components of the formulation of Oraxol

17. History of developing any condition during prior treatment with ramucirumab for
which ramucirumab must be permanently discontinued according to the ramucirumab
label.