Neulasta-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy

This is a randomized, multi-center, single dose, open-label and Neulasta controlled phase 3 study to evaluate the efficacy and safety of F-627 in women with Stage I - III invasive breast cancer receiving chemotherapy treatment.

This is a Phase III, global, two arm, open label clinical study will randomize approximately 400 female subjects (approximately 200 per arm) with Stage I - III invasive breast cancer who are to receive neoadjuvant or adjuvant myelotoxic TC chemotherapy treatment (docetaxel + cyclophosphamide, 75 and 600 mg/m2, respectively). Subjects in this study will be those who are scheduled to undergo at least four 21-day cycles of chemotherapy treatment. Subjects may be scheduled for more than 4 cycles of chemotherapy; however, study participation will be limited to a subject's first 4 cycles.

The primary objective of this study will be to evaluate the efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe as compared to Neulasta® standard dosing (6 mg) in the first chemotherapy cycle. The primary endpoint will be the duration of grade 4 (severe) neutropenia - the number of days in which the patient has had an absolute neutrophil count (ANC \<0.5 x 10\^9/L) observed in chemotherapy cycle 1.

Approximately 24 hours after chemotherapy completion in each cycle (Day 2 of the cycle), subjects will receive one of the following treatments:

Arm 1: F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles.

Arm 2: 6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Randomization will occur in an equal ratio (1:1) using a central randomization system (IWRS) on Day 1 of the study, the day of chemotherapy administration for the first chemotherapy cycle.

This study is open-label, however, study drug injections are to be administered separately by qualified study personnel to allow study investigators to remain blinded and perform study assessments without knowledge of treatment assignment.

Eligibility Criteria:
Inclusion Criteria:

1. Show evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.
2. Females ≥18 years of age.
3. Diagnosed with Stage I-III breast cancer.
4. Subject is scheduled to undergo 4 cycles of neoadjuvant or adjuvant TC chemotherapy (docetaxel, cyclophosphamide, 75, 600 mg/m2, respectively).
5. ECOG Performance status of ≤2.
6. WBC count ≥4.0 × 109/L, hemoglobin ≥11.5 g/dL and a platelet count ≥150 × 109/L.
7. Demonstrate adequate renal, hepatic, and cardiac function (liver function tests \[alanine aminotransferase {ALT}, aspartate aminotransferase {AST}, alkaline phosphatase, and total bilirubin\]) should be less than 2.5x the upper limits of normal (ULN). Serum creatinine should be less than 1.7x ULN.
8. All subjects must agree to use at least one of the following types of contraception: intrauterine device, implantable progesterone device, progesterone intramuscular injection, or oral contraceptive, which has been started at least one month prior to visit one and will continue for the duration of the trial. The contraceptive patch or condom use with spermicide is also acceptable forms of contraception as long as they will be used continually throughout the duration of the trial.

Exclusion Criteria:

1. Subject is \<18 years of age.
2. Disease progression has occurred while receiving a taxane regimen.
3. Subject has undergone radiation therapy within 4 weeks of enrollment.
4. Subject has undergone bone marrow or stem-cell transplantation.
5. Subject has a history of prior malignancy other than breast cancer that is NOT in remission.
6. Subjects that have used G-CSF or any other drug that may potentiate the release of neutrophils (i.e., lithium) within 6 weeks of the screening period are excluded.
7. Subject has had chemotherapy within 180 days of screening.
8. Subject has documented congestive heart failure, cardiomyopathy or myocardial infarction by clinical diagnosis, electrocardiogram (ECG) test, or any other relevant test.
9. History of alcohol or drug abuse that would interfere with the ability to be compliant with the study procedure.
10. Unwillingness to participate in the study.
11. Any underlying medical condition that, in the Investigator's opinion, would make the administration of study drug hazardous to the patient or that would obscure the interpretation of adverse events.
12. Receiving other investigational drugs or biologics within 1 month or five half lives of enrollment (if known), which ever is less.
13. Any condition, which can cause splenomegaly.
14. Chronic constipation or diarrhea, irritable bowel syndrome, inflammatory bowel disease.
15. ALT, AST, alkaline phosphatase, total bilirubin ≥2.5x ULN.
16. Subject with active infection, or known to be infected with chronic active Hepatitis B within the last 1 year (unless shown at the time of study entry to be Hepatitis B antigen negative), or having any history of Hepatitis C.
17. Women who are pregnant or breast-feeding.
18. Subject known to be seropositive for HIV, or who have had an AIDS defining illness or a known immunodeficiency disorder.
19. Subject with a history of tuberculosis or exposure to tuberculosis. Patients that have received a prior chest X-ray for suspicion of tuberculosis are also excluded unless they have been confirmed to be PPD negative or they had latent tuberculosis that has been previously treated.
20. Subjects with Sickle Cell disease
21. Subjects with known hypersensitivity to E.coli derived proteins' pegfilgrastim' filgrastim, or any other component of the study drug.