To determine the safety and tolerability of Oraxol as compared to IV paclitaxel in metastatic breast cancer

This is a Phase 3, open-label, randomized, multicenter study in approximately 360 adult female subjects with histologically- or cytologically-confirmed breast cancer that is metastatic for whom treatment with IV paclitaxel monotherapy has been recommended by their oncologist. Approximately 400 subjects will be enrolled to provide 360 evaluable subjects. The subjects must have measurable metastatic target lesion disease as per RECIST v1.1 criteria. Subjects will be randomized in a 2:1 ratio to either Oraxol or IV paclitaxel (as Taxol or generic).

Inclusion Criteria:

1. Signed written informed consent

2. Women ≥18 years of age

3. Histologically- or cytologically-confirmed breast cancer for whom IV paclitaxel (as Taxol or generic) monotherapy has been recommended by their oncologist

4. Measurable metastatic target lesion disease measurable by CT scan as per RECIST v1.1 criteria

5. Adequate hematological status as demonstrated by not requiring granulocyte-colony stimulating factor (G-CSF) or transfusion support to achieve the following at Screening:

   • Absolute neutrophil count (ANC) ≥1.5 x 109/L
   • Platelet count ≥100 x 109/L
   • Hemoglobin ≥10 g/dL

6. Adequate liver function as demonstrated by:

   • Total bilirubin within normal limits (WNL)
   • Alanine aminotransferase and aspartate aminotransferase ≤3 x upper limit of normal (ULN)
   • Alkaline phosphatase ≤3 x ULN or ≤5 x ULN if bone metastasis is present
   • Gamma glutamyl transferase (GGT) ≤5 x ULN

7. Adequate renal function as demonstrated by serum creatinine ≤1.5 x ULN

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

9. Life expectancy of at least 6 months, in the judgement of the investigator

10. Subjects must be postmenopausal (≥12 months without menses) or surgically sterile (ie, by hysterectomy and/or bilateral oophorectomy) or must be using effective contraception and agree to used of contraception for 30 days after their last dose of assigned study treatment.

11. Subjects who are of childbearing potential must have a negative screening serum pregnancy test.

Exclusion Criteria:

1. Have not recovered to ≤ Grade 1 toxicity from previous anticancer treatments or previous investigational products
2. If previously treated with a taxane (paclitaxel or docetaxel) as part of anthracycline-based adjuvant chemotherapy or for metastatic disease, the subject relapsed less than 1 year following treatment
3. Only evidence of metastatic disease is to bone or other nontarget or nonmeasurable lesions (including, for example, ascites or plural effusion) according to RECIST v1.1 criteria
4. Central nervous system metastasis, including leptomeningeal involvement
5. Received IPs within 14 days or 5 half-lives of the first study dosing day, whichever is longer
6. Are currently receiving other medications intended for the treatment of their malignancy
7. Received radiation therapy within 2 weeks prior to signing informed consent and those for whom radiation therapy is planned within 6 months from the time of signing informed consent
8. Women who are pregnant or breastfeeding
9. Taking a medication known to be a strong P-gp inhibitor or inducer within 14 days of starting treatment
10. Taking an oral medication with a narrow therapeutic index known to be a P-gp substrate within 24 hours prior to start of treatment
11. Taking a medication known to be a strong cytochrome P450 (CYP) 3A4 inhibitor (eg, ketoconazole) or inducer (eg, rifampin or St. John's Wort) within 14 days of starting treatment
12. Taking a medication known to be a strong inhibitor (eg, gemfibrozil) or inducer (eg, rifampin) of CYP2C8 within 14 days of starting treatment
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myocardial infarction within the last 6 months, unstable angina pectoris, cardiac arrhythmia, chronic pulmonary disease requiring oxygen, known bleeding disorders, or any concomitant illness or social situation that would limit compliance with study requirements
14. 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
15. History of significant hypersensitivity-type reactions to paclitaxel or Cremophor EL (polyoxyl 35 castor oil, NF) that would contraindicate the use of IV paclitaxel formulated with Cremophor EL
16. Known allergic reaction or intolerance to contrast media
17. Documented history of true systemic allergic reaction to 3 or more medications
18. For whom the Investigator believes that participation in this study would not be acceptable
19. Known chronic hepatitis or cirrhosis