Intermittent G-CSF in Patients With Breast Cancer Receiving Adjuvant Docetaxel, Doxorubicin, and Cyclophosphamide (TAC)

Study Overview
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Brief Summary
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To compare the efficacy and safety of Day 2 (D2) once a cycle pegfilgrastim with Intermittent Every Other Days of 5 Shot (D3-11) filgrastim in early breast cancer patients treated with adjuvant Docetaxel, Doxorubicin, and Cyclophosphamide (TAC) regimen

Detailed Description
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According to manufacturers' recommendations (Amgen: Neupogenᵀᴹ), filgrastim are to start 24 hrs after the last dose of chemotherapy and continue until absolute neutrophil count (ANC) has recovered to within the normal range (or for 14 days). However, for economic and practical reasons and/or patient's convenience, it has been common practice to initiate filgrastim at a later days of cycle and/or administer a shorter course of treatment. Data from several clinical studies have shown that 10-11 days' filgrastim treatment is required for optimal prophylaxis for febrile neutropenia (FN), and data from other cancers shows that suboptimal use of G-CSFs could deteriorate clinical outcomes. However, in two recent randomized study with breast cancer patients undergoing TAC chemotherapy, acceptable incidence (7-18%) of FN was shown with the consecutive 6 or 7-daily filgrastim schemes. Also, although there is theoretical concern that there can be wide fluctuations in the patient's ANC over time in alternate or intermittent filgrastim administration, because there was no difference in clinical outcomes between daily- or intermittent-dose filgrastim schedules in previous literatures, the intermittent every other day of 5 shot-filgrastim scheme would have clinical outcomes comparable with previous consecutive 6 or 7-daily filgrastim schemes in coverage of ANC nadir. Therefore, it can be justified to investigate the non-inferiority of intermittent every other days of 5 shot-filgrastim scheme compared with control arm using of pegfilgrastim on D2.

Official Title
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Intermittent Every Other Days of 5 Shot-filgrastim Compared With Single Pegfilgrastim in Breast Cancer Patients Receiving Adjuvant Docetaxel, Doxorubicin, and Cyclophosphamide Chemotherapy (Intermittent G-CSF 105)

Conditions
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Breast Cancer, Neutropenia, Febrile Neutropenia

Intervention / Treatment
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* Drug: Filgrastim
* Drug: Peg-filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patients who underwent surgery for pathologically diagnosed early breast cancer (high risk stage II or stage III) or completely resected stage IV, and anticipated to undergo adjuvant chemotherapy with TAC regimen (docetaxel, doxorubicin, and cyclophosphamide) The patients satisfying laboratory findings below before the enrollment of clinical trials: A. Absolute Neutrophil Count(ANC) ≥ 1,500/mm³; B. Platelet Count ≥ 100,000/mm³; C. Adequate renal functions (Cr < 1.5 X ULN); and D. Adequate liver function (Bilirubin < 1.5 X ULN, AST/ALT < 2.5 X ULN) ECOG Performance status: 0-1 Cardiac ejection fraction ≥ 50% as measured by MUGA or 2D echocardiography without clinically significant abnormalities Voluntarily participated in this study, and written informed consent of the patient Exclusion Criteria: Past history of immunotherapy or chemotherapy Past history of autologous stem cell transplantation or bone marrow transplantation The patient undergone radiation therapy within 4 weeks after written informed consent Patient with any other concurrent malignancies or who are currently cured with past history within 5 years (excluding completely resected stage I early skin cancer) Pregnant or lactating women, women of childbearing potential not employing adequate contraception Other serious illness or medical conditions inadequate to chemotherapy: A. Unstable cardiac disease (i.e. congestive heart failure, arrhythmia, symptomatic coronary artery disease) despite treatment, myocardial infarction within 6 months prior to study entry; B. History of significant neurological or psychiatric disorders including dementia or seizures; Active uncontrolled infection (viral, bacterial or fungal infection); and D. Other serious medical illnesses Known hypersensitivity to any of the study drugs or its ingredients Concomitant administration of any other experimental drug under investigation, or concomitant chemotherapy, hormonal therapy, or immunotherapy. Past history of usage of granulocyte-colony stimulating factors Patients with a known history of HIV (+) or HCV (+). However, HBV(+) patients who undergo primary prophylaxis are eligible. Other serious illness or medical conditions determined by investigator

Ages Eligible for Study
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Minimum Age: 19 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A. Pegfilgrastim<br>D2 once a cycle pegfilgrastim arm | Drug: Peg-filgrastim<br>* Pegfilgrastim (Neulastaᵀᴹ) is administered at the D2 of each cycle. A dose of 6mg once a cycle is administered S.C., 24 (± 2) hours after completion of chemotherapy.<br>* Other names: Neulastaᵀᴹ pfs inj. 6mg/0.6ml;|
| Experimental: B. Filgrastim<br>Intermittent Every Other Days of 5 Shot (D3-11) filgrastim arm | Drug: Filgrastim<br>* Filgrastim (Gracinᵀᴹ) is administered at the D3, D5, D7, D9, and D11 of each cycle. A dose of 5 μg/kg/day filgrastim is administered S.C. either as a bolus injection or as a continuous injection. Administer into the outer upper arm, abdomen (except within 2 inches of navel), front middle thigh, or the upper outer buttocks area.<br>* Other names: Grasinᵀᴹ pfs inj.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of febrile neutropenia | Measured at the completion of cycle 3 | through the completion of cycle 1-3 (each cycle is 21 days), an average of 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of febrile neutropenia at each cycle | Measured at the completion of each cycle 1, 2, and 3 | At each cycle 1, 2, and 3 (each cycle is 21 days) | 
| Rates of anti-microbial use | Measured at the completion of cycle 3 | through the completion of cycle 1-3 (each cycle is 21 days), an average of 9 weeks | 
| Duration of anti-microbial use | Measured at the completion of cycle 3 | through the completion of cycle 1-3 (each cycle is 21 days), an average of 9 weeks | 
| Cumulative dose of chemotherapeutic agents | Measured at the completion of cycle 3 | through the completion of cycle 1-3 (each cycle is 21 days), an average of 9 weeks | 
| Delay rate of next chemotherapy cycle due to inadequate neutrophil recovery | Measured at the completion of each cycle 1, 2, and 3 | At each cycle 1, 2, and 3 (each cycle is 21 days) | 
| Duration of delay of next chemotherapy cycle due to inadequate neutrophil recovery | Measured at the completion of each cycle 1, 2, and 3 | At each cycle 1, 2, and 3 (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Adjuvant, Docetaxel, Adriamycin, Cyclophosphamide, Neutropenia, Filgrastim, Pegfilgrastim