Breast Neoplasms, Chemotherapeutic Toxicity, Chemotherapy-induced Neutropenia, Neutropenic Complications
Conditions
Keywords
biosimilars, Pegfilgrastim,, G-CSF,, neutropenia,, breast cancer,, myelosuppressive chemotherapy,, supportive care, granulocyte-colony-stimulating factor
Brief summary
The study will assess the efficacy of LA-EP2006 compared to Neulasta® with respect to the mean duration of severe neutropenia during treatment with myelosuppressive chemotherapy in breast cancer patients.
Detailed description
This randomized, double-blind trial compared the proposed biosimilar LA-EP2006 with the reference Neulasta® in women (≥18 years) receiving chemotherapy for breast cancer. Therefore patients were randomized to receive LA-EP2006 (n = 159) or the reference product (n = 157) for ≤6 cycles of (neo)-adjuvant TAC (docetaxel 75mg/m\^2, doxorubicin 50 mg/m\^2, and cyclophosphamide 500mg/m\^2) chemotherapy. The primary end point was the duration of severe neutropenia (DSN) during Cycle 1 (defined as number of consecutive days with absolute neutrophil count \<0.5 × 10\^9/l). The equivalence was confirmed if 95% CIs were within a ±1 day margin. LA-EP2006 was equivalent to the reference product in DSN (difference: 0.07 days; 95% CI \[-0.12, 0.26\]). Further, LA-EP2006 and the reference Neulasta® showed no clinically meaningful differences regarding efficacy and safety.
Interventions
DRUGLA-EP2006
Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle pegfilgrastim is injected s.c. post chemotherapy application.
DRUGNeulasta®
Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle pegfilgrastim is injected s.c. post chemotherapy application.
Sponsors
Sandoz GmbH
Sandoz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* histologically proven breast cancer * eligible for six cycles of neoadjuvant or adjuvant chemotherapy
Exclusion criteria
* concurrent or prior chemotherapy for breast cancer * concurrent or prior anti-cancer treatment for breast cancer such as endocrine therapy, immunotherapy, monoclonal antibodies, and/or biological therapy * concurrent prophylactic antibiotics * previous therapy with any G-CSF (granulocyte-colony stimulating factor) product Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy | 21 days (Cycle 1 of chemotherapy treatment) | Mean duration of severe neutropenia, defined as number of consecutive days with ANC \<0.5 × 10\^9 cells/L (grade 4 neutropenia). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | across al cycles (18 weeks) | Fever was defined as an oral temperature ≥ 38.3°C. Fever episodes were characterized by maximum oral temperature and the number of patients who had fever at least once. |
| Depth of ANC Nadir in Cycle 1 | Cycle 1 (3 weeks) | The depth of ANC nadir was defined as the patient's lowest ANC (10\^9 cells/L) in Cycle 1. Only the evaluable patients with a depth of ANC in Cycle 1 are given. |
| Number of Patients With ANC Nadir Per Day in Cycle 1 | Cycle 1 (3 weeks) | Numbers of patients with ANC nadir based per day during Cycle 1 are given. |
| Incidence of Febrile Neutropenia (FN) | across all cycles (18 weeks) | FN was defined as an oral temperature ≥ 38.3°C while having an absolute neutrophil count (ANC) \< 0.5 × 10\^9 cells/L. Serious treatment-emergent adverse events (TEAEs) were reconciled with the fever and ANC results recorded in the patient diary and CRF and therefore only the serious TEAEs of FN (febrile neutropenia, neutropenic sepsis) were taken into account. |
| Frequency of Infections by Cycle and Across All Cycles | across all cycles (18 weeks) | The number of patients with infections was recorded for each cycle and across all cycles. Infections were identified by the AE documentation page selecting all events coded with System Organ Class Infections and Infestations. |
| Mortality Due to Infection | Study course (41 weeks) | Number of patients with death due to infections |
| Time to ANC Recovery in Days in Cycle 1 | across Cycle 1 (3 weeks) | Time to absolute neutrophil count (ANC) recovery in Cycle 1 was defined as the time in days from ANC nadir until the patient's ANC had increased to ≥ 2 × 10\^9 cells/L. Only the evaluable patients with a depth of ANC in Cycle 1 and a later increase of ANC ≥ 2 × 10\^9 cells/L are given. |
Countries
Brazil, India, Mexico, Romania, Russia, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LA-EP2006 During each chemotherapy cycle eligible patients receive LA-EP2006 s.c. post chemotherapy application.
LA-EP2006: Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle pegfilgrastim is injected s.c. post chemotherapy application. | 159 |
| Neulasta® During each chemotherapy cycle eligible patients receive Neulasta® s.c. post chemotherapy application.
Neulasta®: Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle pegfilgrastim is injected s.c. post chemotherapy application. | 157 |
| Total | 316 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 2 |
| Overall Study | Lost to Follow-up | 4 | 2 |
| Overall Study | Other (mostly EOS/EOT visit missing) | 13 | 7 |
| Overall Study | Withdrawal by Subject | 9 | 2 |
Baseline characteristics
| Characteristic | Total | LA-EP2006 | Neulasta® |
|---|---|---|---|
| Age, Continuous | 50.2 years STANDARD_DEVIATION 10.2 | 49.9 years STANDARD_DEVIATION 9.53 | 50.5 years STANDARD_DEVIATION 10.87 |
| BMI | 27.45 kg/m^2 STANDARD_DEVIATION 26.4 | 27.47 kg/m^2 STANDARD_DEVIATION 26.76 | 27.44 kg/m^2 STANDARD_DEVIATION 26.35 |
| Disease stage I | 7 Participants | 4 Participants | 3 Participants |
| Disease stage II | 147 Participants | 74 Participants | 73 Participants |
| Disease stage III | 159 Participants | 81 Participants | 78 Participants |
| Disease stage IV | 3 Participants | 0 Participants | 3 Participants |
| ECOG performance status 0 (fully active) | 251 Participants | 128 Participants | 123 Participants |
| ECOG performance status 1 (restricted in physically strenuous activity) | 65 Participants | 31 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants | 11 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 287 Participants | 148 Participants | 139 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Previous breast cancer surgery | 295 Participants | 149 Participants | 146 Participants |
| Previous radiotherapy | 16 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 54 Participants | 28 Participants | 26 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 256 Participants | 129 Participants | 127 Participants |
| Sex: Female, Male Female | 316 Participants | 159 Participants | 157 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Time since diagnosis | 1.38 months | 1.35 months | 1.38 months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 159 | 2 / 157 |
| other Total, other adverse events | 140 / 159 | 128 / 157 |
| serious Total, serious adverse events | 16 / 159 | 21 / 157 |
Outcome results
Primary
Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy
Mean duration of severe neutropenia, defined as number of consecutive days with ANC \<0.5 × 10\^9 cells/L (grade 4 neutropenia).
Time frame: 21 days (Cycle 1 of chemotherapy treatment)
Population: FAS set = full analysis set; PP set = per protocol set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LA-EP2006 | Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy | FAS | 0.75 days | Standard Deviation 0.878 |
| LA-EP2006 | Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy | PP | 0.75 days | Standard Deviation 0.875 |
| Neulasta® | Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy | PP | 0.79 days | Standard Deviation 0.872 |
| Neulasta® | Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy | FAS | 0.83 days | Standard Deviation 0.898 |
Comparison: The hierarchical test procedure aimed to show that~1. LA-EP2006 and Neulasta® are equivalent with respect to DSN duration in Cycle 1 (margin±1 day), and, if so~2. LA-EP2006 is non-inferior to Neulasta® with respect to DSN duration in Cycle 1 (margin of -0.6 days).p-value: 0.0595% CI: [-0.12, 0.26]ANCOVA
Comparison: The hierarchical test procedure aimed to show that~1. LA-EP2006 and Neulasta® are equivalent with respect to DSN duration in Cycle 1 (margin±1 day), and, if so~2. LA-EP2006 is non-inferior to Neulasta® with respect to DSN duration in Cycle 1 (margin of -0.6 days).p-value: 0.0595% CI: [-0.12, 0.26]ANCOVA
Secondary
Depth of ANC Nadir in Cycle 1
The depth of ANC nadir was defined as the patient's lowest ANC (10\^9 cells/L) in Cycle 1. Only the evaluable patients with a depth of ANC in Cycle 1 are given.
Time frame: Cycle 1 (3 weeks)
Population: FAS set = full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LA-EP2006 | Depth of ANC Nadir in Cycle 1 | 1.102 10^9 cells/L | Standard Deviation 1.5398 |
| Neulasta® | Depth of ANC Nadir in Cycle 1 | 0.921 10^9 cells/L | Standard Deviation 1.1771 |
Secondary
Frequency of Infections by Cycle and Across All Cycles
The number of patients with infections was recorded for each cycle and across all cycles. Infections were identified by the AE documentation page selecting all events coded with System Organ Class Infections and Infestations.
Time frame: across all cycles (18 weeks)
Population: Patients with more than 1 event during the study (overall) are counted only once. FAS set = full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 4 | 2 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 1 | 7 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 5 | 11 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 3 | 3 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 6 | 5 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Overall | 22 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 2 | 6 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Overall | 24 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 1 | 4 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 2 | 5 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 3 | 8 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 4 | 3 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 5 | 4 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 6 | 3 Participants |
Secondary
Incidence of Febrile Neutropenia (FN)
FN was defined as an oral temperature ≥ 38.3°C while having an absolute neutrophil count (ANC) \< 0.5 × 10\^9 cells/L. Serious treatment-emergent adverse events (TEAEs) were reconciled with the fever and ANC results recorded in the patient diary and CRF and therefore only the serious TEAEs of FN (febrile neutropenia, neutropenic sepsis) were taken into account.
Time frame: across all cycles (18 weeks)
Population: Number of patients with at least one episode of febrile neutropenia by cycle and across all cycles (FAS set)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 3 | 2 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 5 | 2 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 2 | 2 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 6 | 1 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 4 | 1 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | All cycles (at least on incidence) | 9 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 1 | 6 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | All cycles (at least on incidence) | 12 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 1 | 11 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 2 | 1 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 3 | 1 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 4 | 0 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 5 | 0 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 6 | 1 Participants |
Secondary
Mortality Due to Infection
Number of patients with death due to infections
Time frame: Study course (41 weeks)
Population: FAS set = full analysis set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LA-EP2006 | Mortality Due to Infection | Yes | 0 Participants |
| LA-EP2006 | Mortality Due to Infection | No | 159 Participants |
| Neulasta® | Mortality Due to Infection | Yes | 2 Participants |
| Neulasta® | Mortality Due to Infection | No | 155 Participants |
Secondary
Number of Patients With ANC Nadir Per Day in Cycle 1
Numbers of patients with ANC nadir based per day during Cycle 1 are given.
Time frame: Cycle 1 (3 weeks)
Population: FAS set = full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 6 | 7 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Days 1-5 | 5 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 7 | 101 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 8 | 34 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 9 | 1 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Days 10-15 | 8 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 9 | 7 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 8 | 25 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Days 1-5 | 5 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 6 | 4 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Days 10-15 | 10 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 7 | 104 Participants |
Secondary
Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles
Fever was defined as an oral temperature ≥ 38.3°C. Fever episodes were characterized by maximum oral temperature and the number of patients who had fever at least once.
Time frame: across al cycles (18 weeks)
Population: Patients with more than 1 event during the study (overall) are counted only once. FAS set = full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 3 | 7 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 5 | 7 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 2 | 6 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 6 | 5 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 4 | 5 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Overall | 26 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 1 | 9 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Overall | 26 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 1 | 14 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 2 | 2 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 3 | 6 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 4 | 2 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 5 | 4 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 6 | 3 Participants |
Secondary
Time to ANC Recovery in Days in Cycle 1
Time to absolute neutrophil count (ANC) recovery in Cycle 1 was defined as the time in days from ANC nadir until the patient's ANC had increased to ≥ 2 × 10\^9 cells/L. Only the evaluable patients with a depth of ANC in Cycle 1 and a later increase of ANC ≥ 2 × 10\^9 cells/L are given.
Time frame: across Cycle 1 (3 weeks)
Population: FAS set = full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LA-EP2006 | Time to ANC Recovery in Days in Cycle 1 | 1.58 days | Standard Deviation 1.053 |
| Neulasta® | Time to ANC Recovery in Days in Cycle 1 | 1.72 days | Standard Deviation 1.1 |