Study of the Efficacy and Safety of Empegfilgrastim for Neutropenia Prophylaxis in Breast Cancer Patients

Study Overview
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Brief Summary
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The purpose of the study is to compare safety and efficacy of a single dose of empegfilgrastim and daily dosing of filgrastim for prevention of neutropenia in patients receiving AT (docetaxel 75 mg/m2 + doxorubicin 50 mg/m2).

Detailed Description
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BCD-017-3 is an double-blind randomized phase III clinical study to compare the incidence of CTCAE grade 3/4 neutropenia after a single administration of recombinant human pegylated filgrastim empegfilgrastim (Extimia®) at a dose of 6 or 7.5 mg versus daily administration of filgrastim at a dose of 5 μg/kg/day for neutropenia prophylaxis in breast cancer patients receiving myelosuppressive chemotherapy. The study also includes the following determination of pharmacokinetic parameters after repeated administration of the study drug.

Official Title
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Multicenter Randomized Double-blind Phase III Clinical Study Comparing the Efficacy and Safety of a Single Dose Extimia® Versus Daily Filgrastim for Neutropenia Prophylaxis in Breast Cancer Patients Receiving Myelosuppressive Chemotherapy

Conditions
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Chemotherapy-induced Neutropenia

Intervention / Treatment
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* Biological: Empegfilrastim 6 mg
* Biological: Filgrastim
* Biological: Placebo №1
* Biological: Placebo №2
* Biological: Empegfilrastim 7.5 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form; Histologically verified diagnosis of stage IIb/III/IV breast cancer; Age of 18-70 years inclusive; Life expectancy of at least 6 months after inclusion in the study; If the patient had received the chemotherapy for breast cancer, it should be finished 30 days before the beginning of the study; ECOG Performance Status of 0- 2, not increasing within during 2 weeks before randomization; ANC level of 1500/μL and more at the beginning of the study Platelet count of 100 000/μL and more at the beginning of the study Hemoglobin level of 90 g/l and more Creatinine level <1.5 mg/dl Total bilirubin level <1.5 × the upper limit of normal (ULN) ALT and/or AST levels <2.5×ULN (5×ULN for patients with liver metastases); Alkaline phosphatase <5×ULN; Left ventricular ejection fraction >50% and more; If the patient had received adjuvant and/or neoadjuvant therapy, the cumulative dose of anthracyclines should not exceed 250 mg/m2 for doxorubicin or 540 mg/m2 for epirubicin,if in this study planned 6 cycles of chemotherapy ; If the patient had received adjuvant and/or neoadjuvant therapy, the cumulative dose of anthracyclines should not exceed 350 mg/m2 for doxorubicin or 660 mg/m2 for epirubicin,if in this study planned 4 cycles of chemotherapy ; Ability of the participant to follow the protocol requirements, according to the Investigator's opinion; Patients of childbearing potential must implement reliable contraceptive measures during the study treatment, starting 4 weeks prior randomization and for 6 months after the last administration of the study drug; Patients should be able to follow the Protocol procedures (according to Investigator's assessment. Exclusion Criteria: Patient has received two or more chemotherapy regimens for the metastatic breast cancer; Documented hypersensitivity to filgrastim, pegfilgrastim, docetaxel, doxorubicin, dexamethasone and/or its excipients, PEGylated drugs, recombinant proteins. Pregnancy or breastfeeding; Systemic antibiotic therapy within 72 h prior empegfilgrastim/filgrastim administration; Concomitant radiotherapy (except selective radiotherapy of bone metastases); Surgery, radiotherapy (except selective radiotherapy of bone metastases), administration of any experimental drugs within 30 days prior randomization; History of bone marrow/stem cell transplantation; Conditions limiting the patient's ability to follow the protocol; CTCAE grade 3-4 neuropathy; HIV, HCV, HBV, T.Pallidum infection(s); Acute or active chronic infections; Severe concurrent diseases (for example, severe arterial hypertension, severe heart failure, and other); Severe depression, schizophrenia, any other mental disorders; Obstacles in intravenous administration of study drugs; Simultaneous participation in other clinical trials, previous participation in other clinical trials within 30 days before entering into the trial, previous participation in the same trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empegfilgrastim 6 mg<br>Patients will receive a single administration of empegfilgrastim at a dose of 6 mg subcutaneously, 24 h after the chemotherapy and placebo #2 in a dose of 0.0083 ml/kg in 24-27 hour after chemotherapy, then patient received placebo #2 in dose 0.0083 ml/kg until ANC ≥ 10x109/L or during 14 days | Biological: Empegfilrastim 6 mg<br>* Empegfilgrastim is supplied as solution for injection 3 mg/ml. Empegfilgrastim is to be administered 24 h after the chemotherapy at dose of 6 mg.<br>* Other names: peg-GCSF;Biological: Placebo №2<br>* Placebo №2 should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. Placebo №2 is supplied as solution for injection 0.0083 ml/kg.<br>|
| Experimental: Empegfilgrastim 7.5 mg<br>Patients will receive a single administration of empegfilgrastim at a dose of 7.5 mg subcutaneously, 24 h after the chemotherapy and placebo #2 in a dose of 0.0083 ml/kg in 24-27 hour after chemotherapy, then patient received placebo #2 in dose 0.0083 ml/kg until ANC ≥ 10x109/L or during 14 days | Biological: Placebo №2<br>* Placebo №2 should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. Placebo №2 is supplied as solution for injection 0.0083 ml/kg.<br>Biological: Empegfilrastim 7.5 mg<br>* Empegfilgrastim is supplied as solution for injection 3 mg/ml. Empegfilgrastim is to be administered 24 h after the chemotherapy at dose of 6 mg.<br>* Other names: peg-GCSF;|
| Active Comparator: Filgrastim<br>Patients will receive filgrastim at a dose of 5 μg/kg subcutaneously daily (until ANC 10 000/μL or for 14 days, whichever occurred first), starting 24 h after the chemotherapy and placebo #1 in dose 1.0 ml subcutaneously, 24 h after the chemotherapy. | Biological: Filgrastim<br>* Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. Filgrastim should be administered daily for up to 2 weeks until the ANC has reached 10 000/mm3 following the expected chemotherapy-induced neutrophil nadir.<br>* Other names: GCSF;Biological: Placebo №1<br>* Placebo №1 is supplied as solution for injection 1.0 ml. Placebo №1 is to be administered 24 h after the chemotherapy at dose of 1.0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Neutropenia CTCAE Grade 4 | The primary endpoint, which will allow to compare the efficacy of the single dose of Extimia® versus nonpegylated daily filgrastim is the number of breast cancer patients developing CTCAE grade 3/4 neutropenia after the first AT chemotherapy cycle (doxorubicin+docetaxel). | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); |  | 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12) | 
| The Incidence of Severe Neutropenia (Grade 3-4) |  | 16 weeks | 
| Low Level (Nadir) ANC x 10^9/L |  | 1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12) | 
| Neutropenia Duration, Any Grade |  | 1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12) | 
| Duration From ANC Nadir to ANC < 2.0 x 10^9/L |  | 1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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empegfilgrastim, pegylated filgrastim, neutropenia, febrile neutropenia, chemotherapy-associated neutropenia, breast cancer, docetaxel, doxorubicin