Chemotherapy-induced Neutropenia
Conditions
Keywords
empegfilgrastim, pegylated filgrastim, neutropenia, febrile neutropenia, chemotherapy-associated neutropenia, breast cancer, docetaxel, doxorubicin
Brief summary
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
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.
Interventions
BIOLOGICALEmpegfilrastim 6 mg
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.
BIOLOGICALFilgrastim
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.
BIOLOGICALPlacebo №1
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.
BIOLOGICALPlacebo №2
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.
BIOLOGICALEmpegfilrastim 7.5 mg
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.
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Neutropenia CTCAE Grade 4 | 3 weeks | 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). |
Secondary
| Measure | 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) |
Countries
Russia
Participant flow
Pre-assignment details
7 patients were withdrawn for various reasons without receiving any dose of any of the studied products.
Participants by arm
| Arm | Count |
|---|---|
| Empegfilgrastim 6 mg 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
empegfilrastim 6 mg: 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.
Placebo №2: 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. | 42 |
| Empegfilgrastim 7.5 mg 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
Placebo №2: 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.
empegfilrastim 7.5 mg: 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. | 43 |
| Filgrastim 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 ubcutaneously, 24 h after the chemotherapy.
filgrastim: 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.
Placebo №1: 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. | 43 |
| Total | 128 |
Baseline characteristics
| Characteristic | Empegfilgrastim 7.5 mg | Total | Filgrastim | Empegfilgrastim 6 mg |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 43 Participants | 128 Participants | 43 Participants | 42 Participants |
| Age, Continuous | 50.42 years STANDARD_DEVIATION 9.19 | 50.23 years STANDARD_DEVIATION 10.03 | 51.86 years STANDARD_DEVIATION 9.68 | 48.38 years STANDARD_DEVIATION 11.07 |
| Disease stage IIA | 12 participants | 35 participants | 10 participants | 13 participants |
| Disease stage IIB | 7 participants | 21 participants | 9 participants | 5 participants |
| Disease stage IIIA | 7 participants | 22 participants | 10 participants | 5 participants |
| Disease stage IIIB | 10 participants | 30 participants | 8 participants | 12 participants |
| Disease stage IIIС | 1 participants | 3 participants | 0 participants | 2 participants |
| Disease stage IV | 6 participants | 17 participants | 6 participants | 5 participants |
| Duration of a disease | 11.62 months | 11.0 months | 5.37 months | 16.14 months |
| Histologic type Infiltrative ductal | 28 participants | 88 participants | 33 participants | 27 participants |
| Histologic type Infiltrative lobular | 3 participants | 11 participants | 2 participants | 6 participants |
| Histologic type Infiltrative not specified | 5 participants | 13 participants | 4 participants | 4 participants |
| Histologic type Low-grade differentiated carcinoma | 3 participants | 6 participants | 1 participants | 2 participants |
| Histologic type Medullar | 1 participants | 1 participants | 0 participants | 0 participants |
| Histologic type Squamous cell cancer | 1 participants | 1 participants | 0 participants | 0 participants |
| Histologic type Undifferentiated cancer | 2 participants | 8 participants | 3 participants | 3 participants |
| History previous therapy of breast cancer Adjuvant chemotherapy | 8 participants | 25 participants | 10 participants | 7 participants |
| History previous therapy of breast cancer Any treatment | 29 participants | 83 participants | 26 participants | 28 participants |
| History previous therapy of breast cancer Hormone therapy | 7 participants | 17 participants | 4 participants | 6 participants |
| History previous therapy of breast cancer Neoadjuvant chemotherapy | 1 participants | 2 participants | 0 participants | 1 participants |
| History previous therapy of breast cancer Radiotherapy | 4 participants | 15 participants | 3 participants | 8 participants |
| History previous therapy of breast cancer Surgery treatment | 27 participants | 77 participants | 22 participants | 28 participants |
| Region of Enrollment Russian Federation | 43 participants | 128 participants | 43 participants | 42 participants |
| Sex: Female, Male Female | 43 Participants | 128 Participants | 43 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 42 / 42 | 43 / 43 | 43 / 43 |
| serious Total, serious adverse events | 1 / 42 | 1 / 43 | 5 / 43 |
Outcome results
Primary
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).
Time frame: 3 weeks
Population: The efficacy analysis included only those patients who received at least one dose of study drug, and who were participated in the study for 2 weeks or more.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empegfilgrastim 6 mg | Duration of Neutropenia CTCAE Grade 4 | 0.905 days | Standard Deviation 1.206 |
| Empegfilgrastim 7.5 mg | Duration of Neutropenia CTCAE Grade 4 | 0.791 days | Standard Deviation 1.013 |
| Filgrastim | Duration of Neutropenia CTCAE Grade 4 | 1.725 days | Standard Deviation 1.519 |
Secondary
Duration From ANC Nadir to ANC < 2.0 x 10^9/L
Time frame: 1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12)
Population: The efficacy analysis included only those patients who received at least one dose of study drug, and who were participated in the study for 2 weeks or more.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empegfilgrastim 6 mg | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 3rd cycle (week 9) | 1.20 days | Standard Deviation 1.21 |
| Empegfilgrastim 6 mg | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 1st cycle (week 3) | 1.74 days | Standard Deviation 0.98 |
| Empegfilgrastim 6 mg | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 4th cycle (week 12) | 1.12 days | Standard Deviation 1.05 |
| Empegfilgrastim 6 mg | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 2nd cycle (week 6) | 1.43 days | Standard Deviation 1.29 |
| Empegfilgrastim 7.5 mg | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 3rd cycle (week 9) | 0.98 days | Standard Deviation 0.9 |
| Empegfilgrastim 7.5 mg | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 2nd cycle (week 6) | 1.05 days | Standard Deviation 1.31 |
| Empegfilgrastim 7.5 mg | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 4th cycle (week 12) | 1.03 days | Standard Deviation 1.2 |
| Empegfilgrastim 7.5 mg | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 1st cycle (week 3) | 1.51 days | Standard Deviation 0.86 |
| Filgrastim | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 4th cycle (week 12) | 2.14 days | Standard Deviation 1.7 |
| Filgrastim | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 1st cycle (week 3) | 2.98 days | Standard Deviation 2.4 |
| Filgrastim | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 2nd cycle (week 6) | 2.05 days | Standard Deviation 1.08 |
| Filgrastim | Duration From ANC Nadir to ANC < 2.0 x 10^9/L | 3rd cycle (week 9) | 1.90 days | Standard Deviation 1.87 |
Secondary
Low Level (Nadir) ANC x 10^9/L
Time frame: 1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12)
Population: The efficacy analysis included only those patients who received at least one dose of study drug, and who were participated in the study for 2 weeks or more.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empegfilgrastim 6 mg | Low Level (Nadir) ANC x 10^9/L | 2nd cycle (week 6) | 1.44 cells x 10^9/L | Standard Deviation 1.3 |
| Empegfilgrastim 6 mg | Low Level (Nadir) ANC x 10^9/L | 3rd cycle (week 9) | 1.77 cells x 10^9/L | Standard Deviation 1.39 |
| Empegfilgrastim 6 mg | Low Level (Nadir) ANC x 10^9/L | 1st cycle (week 3) | 0.68 cells x 10^9/L | Standard Deviation 0.68 |
| Empegfilgrastim 6 mg | Low Level (Nadir) ANC x 10^9/L | 4th cycle (week 12) | 1.67 cells x 10^9/L | Standard Deviation 1.12 |
| Empegfilgrastim 7.5 mg | Low Level (Nadir) ANC x 10^9/L | 2nd cycle (week 6) | 2.10 cells x 10^9/L | Standard Deviation 1.78 |
| Empegfilgrastim 7.5 mg | Low Level (Nadir) ANC x 10^9/L | 1st cycle (week 3) | 0.91 cells x 10^9/L | Standard Deviation 1.11 |
| Empegfilgrastim 7.5 mg | Low Level (Nadir) ANC x 10^9/L | 3rd cycle (week 9) | 1.88 cells x 10^9/L | Standard Deviation 1.71 |
| Empegfilgrastim 7.5 mg | Low Level (Nadir) ANC x 10^9/L | 4th cycle (week 12) | 2.07 cells x 10^9/L | Standard Deviation 1.75 |
| Filgrastim | Low Level (Nadir) ANC x 10^9/L | 3rd cycle (week 9) | 0.94 cells x 10^9/L | Standard Deviation 1.04 |
| Filgrastim | Low Level (Nadir) ANC x 10^9/L | 1st cycle (week 3) | 0.47 cells x 10^9/L | Standard Deviation 0.74 |
| Filgrastim | Low Level (Nadir) ANC x 10^9/L | 2nd cycle (week 6) | 0.87 cells x 10^9/L | Standard Deviation 1.12 |
| Filgrastim | Low Level (Nadir) ANC x 10^9/L | 4th cycle (week 12) | 0.75 cells x 10^9/L | Standard Deviation 0.87 |
Secondary
Neutropenia Duration, Any Grade
Time frame: 1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12)
Population: The efficacy analysis included only those patients who received at least one dose of study drug, and who were participated in the study for 2 weeks or more.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empegfilgrastim 6 mg | Neutropenia Duration, Any Grade | 1st cycle (week 3) | 2.214 days | Standard Deviation 1.152 |
| Empegfilgrastim 6 mg | Neutropenia Duration, Any Grade | 2nd cycle (week 6) | 1.881 days | Standard Deviation 2.276 |
| Empegfilgrastim 6 mg | Neutropenia Duration, Any Grade | 3rd cycle (week 9) | 1.585 days | Standard Deviation 1.897 |
| Empegfilgrastim 6 mg | Neutropenia Duration, Any Grade | 4th cycle (week 12) | 1.146 days | Standard Deviation 1.195 |
| Empegfilgrastim 7.5 mg | Neutropenia Duration, Any Grade | 4th cycle (week 12) | 1.525 days | Standard Deviation 2.364 |
| Empegfilgrastim 7.5 mg | Neutropenia Duration, Any Grade | 1st cycle (week 3) | 1.953 days | Standard Deviation 1.194 |
| Empegfilgrastim 7.5 mg | Neutropenia Duration, Any Grade | 3rd cycle (week 9) | 1.024 days | Standard Deviation 1.199 |
| Empegfilgrastim 7.5 mg | Neutropenia Duration, Any Grade | 2nd cycle (week 6) | 1.233 days | Standard Deviation 1.702 |
| Filgrastim | Neutropenia Duration, Any Grade | 4th cycle (week 12) | 2.919 days | Standard Deviation 2.488 |
| Filgrastim | Neutropenia Duration, Any Grade | 2nd cycle (week 6) | 2.775 days | Standard Deviation 2.434 |
| Filgrastim | Neutropenia Duration, Any Grade | 3rd cycle (week 9) | 2.487 days | Standard Deviation 2.48 |
| Filgrastim | Neutropenia Duration, Any Grade | 1st cycle (week 3) | 4.0 days | Standard Deviation 3.121 |
Secondary
The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12);
Time frame: 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12)
Population: The efficacy analysis included only those patients who received at least one dose of study drug, and who were participated in the study for 2 weeks or more.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empegfilgrastim 6 mg | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 3rd cycle (week 9) | 0.244 days | Standard Deviation 0.734 |
| Empegfilgrastim 6 mg | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 2nd cycle (week 6) | 0.452 days | Standard Deviation 1.194 |
| Empegfilgrastim 6 mg | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 4th cycle (week 12) | 0.195 days | Standard Deviation 0.601 |
| Empegfilgrastim 7.5 mg | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 3rd cycle (week 9) | 0.310 days | Standard Deviation 0.68 |
| Empegfilgrastim 7.5 mg | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 2nd cycle (week 6) | 0.326 days | Standard Deviation 0.919 |
| Empegfilgrastim 7.5 mg | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 4th cycle (week 12) | 0.475 days | Standard Deviation 1.32 |
| Filgrastim | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 2nd cycle (week 6) | 0.925 days | Standard Deviation 1.385 |
| Filgrastim | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 4th cycle (week 12) | 0.892 days | Standard Deviation 1.197 |
| Filgrastim | The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12); | 3rd cycle (week 9) | 0.641 days | Standard Deviation 0.932 |
Secondary
The Incidence of Severe Neutropenia (Grade 3-4)
Time frame: 16 weeks
Population: The efficacy analysis included only those patients who received at least one dose of study drug, and who were participated in the study for 2 weeks or more.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Empegfilgrastim 6 mg | The Incidence of Severe Neutropenia (Grade 3-4) | 40 participants |
| Empegfilgrastim 7.5 mg | The Incidence of Severe Neutropenia (Grade 3-4) | 34 participants |
| Filgrastim | The Incidence of Severe Neutropenia (Grade 3-4) | 40 participants |