The goal of this trial is to assess the safety, therapeutic dose, and leukostimulatory activity of the preparation Panagen in the therapeutic schemes for treating cancer diseases in the patients receiving a standard chemotherapy for breast cancer of stages II-IV (with distant metastases).

The limited liability company Panagen has designed the preparation named Panagen in a form of tablets, which is represented by a fragmented nucleoprotein complex isolated from the human placenta. The method allows for extraction of a full-fledged genomic DNA with retention of its fragments that are tightly associated with the nuclear matrix proteins. The length of fragmented DNA varies from 200 to 6000 base pairs.

This trial is a double-blind multisite placebo-controlled sequentially randomized phase II trial involving two groups of patients. Totally, 80 stage II breast cancer cases with an increased risk or stage III-IV breast cancer cases (with distant metastases) requiring chemotherapy will participate in this trial. All patients will be sequentially randomized, that is, any patient independently of the time she is included into this study may fall into one of the two groups. The patients will be divided into two groups at a ratio of 3 : 1; the first group receiving the preparation Panagen will contain 60 persons and the second one, receiving placebo, 20 persons. For the reasons of ethics, the size of the second group minimally possible for obtaining statistically significant data is chosen. The patients will be subject to a standard chemotherapy, including 500 mg/m2 cyclophosphan, 50 mg/m2 doxorubicin, and 500 mg/m2 fluorouracil; all preparations are administered intravenously once a day. In this trial, the patients will receive three chemotherapy courses with an interval of 3 weeks between the courses (unless an interruption is required).

On the background of this chemotherapy, the patients will receive the preparation Panagen at a dose of 30 mg/day or a placebo with a fractional uniform administration during the active day period, which will amount to one tablet six times a day (every 2 h). The patients start to receive the preparation immediately after the chemotherapy and take three tablets during 6 h, that is one tablet every 2 h. Then the patients stop taking the preparation and resume its administration after 42 h, that is, 48 h after the chemotherapy (day 3) and continue its administration for 17 days to and thorough day 20 after the chemotherapy. If the next chemotherapy course is delayed, the patients continue taking Panagen. The intake should be stopped 1 day before the next chemotherapy course. It is admissible to delay the next chemotherapy course by 1 week.

Inclusion Criteria:

• Signed and dated written informed consent
• Women at an age of ≥18 years
• Stage II-IV breast cancer (with distant metastases)
• The patients will be subject to chemotherapy with cyclophosphan/doxorubicin/ fluorouracil as a standard chemotherapy for treating breast cancer
• The patients have not been earlier subject to chemotherapy
• Functional status according to the Eastern Cooperative Oncology Group (ECOG) ≤2
• Leukocyte counts of ≥3 × 109/L before the treatment course
• Neutrophil counts of ≥1.5 × 109/L before the treatment course
• Platelet counts of ≥100 × 109/L before the treatment course
• Adequate heart function
• Adequate liver function, that is, alanine aminotransferase / aspartate aminotransferase (ALT / AST) activity < 2.5 × upper limit of normal (ULN); acid phosphatase activity < 5 × ULN; and bilirubin concentration < 5 × ULN; and
• Adequate renal function, that is, the creatinine concentration in the blood serum < 1.5 × ULN; urea concentration < ULN; and endogenous creatinine clearance

Exclusion Criteria:

• Participation in clinical trials less than 30 days before sequential randomization
• Previous exposure to Panagen or any other leukostimulatory drugs at a stage of clinical development
• Known hypersensitivity to cyclophosphan, doxorubicin, or fluorouracil
• Therapy with systemically active antibiotics less than 72 h before the beginning of chemotherapy
• Long-term oral intake of corticosteroids
• Previous X-ray therapy performed less than 4 weeks before randomization
• Previous transplantation of hematopoietic stem cells
• Other malignant neoplasms during the last 5 years except for basal cell or flat cell carcinoma or intraepithelial carcinoma of the uterine cervix
• Any disease or state that according to the opinion of researcher can influence patient's safety or the estimation of a final trial point; and
• Pregnant and nursing women; the fertile patients should use chemical or barrier contraceptives during the period of trials

Some Serious Adverse Events and Other (Not Including Serious) Adverse Events were estimated not for all patients, but only for 33 from Panagen group and 11 from Placebo group.