Breast Cancer, Chemotherapy-induced Neutropenia
Conditions
Keywords
Pegfilgrastim, G-CSF, neutropenia, breast cancer, myelosuppressive chemotherapy
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
The Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare the proposed biosimilar LA-EP2006 with the reference pegfilgrastim in woman with early stage breast cancer receiving (neo)-adjuvant myelosuppressive chemotherapy. Patient received TAC (intravenous docetaxel 75mg/m\^2, doxorubicin 50 mg/m\^2, and cyclophosphamide 500mg/m\^2) on day1 of each cycle, for six or more cycles. A total of 308 patients were randomized to LA-EP2006 (n=155) or reference Neulasta® (n=153). Treatment was given subcutaneously on day 2 of each cycle. 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 cells/L). LA-EP2006 was equivalent to the reference product in DSN (difference: -0.16 days; 95% CI \[-0.40, 0.08\]). Further, LA-EP2006 and the reference pegfilgrastim 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 LA-EP2006 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 Neulasta® 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/l (grade 4 neutropenia). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Febrile Neutropenia (FN) | across all cycles (18 weeks) | FN was defined as 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. |
| 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 body temperature of ≥ 38.3°C. Fever episodes were described 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. |
| Time to ANC Recovery in Days in Cycle 1 | across Cycle 1 (3 weeks) | Time to absolute neutrophil count (ANC) recovery was defined as the time in days from ANC nadir until the patient's ANC had increased to ≥ 2 × 10\^9 cells/L after the nadir in Cycle 1. |
| 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 (19 weeks) | Number of patients with death due to infections |
| 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. |
Countries
Argentina, Chile, India, Malaysia, Puerto Rico, Russia, Spain, United States
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 LA-EP2006 is injected s.c. post chemotherapy application. | 155 |
| 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. | 153 |
| Total | 308 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 |
| Overall Study | Death | 3 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Other (not specified) | 0 | 1 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 4 |
Baseline characteristics
| Characteristic | LA-EP2006 | Total | Neulasta® |
|---|---|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 10.5 | 48.9 years STANDARD_DEVIATION 10.27 | 49.1 years STANDARD_DEVIATION 10.07 |
| BMI | 26.56 kg/m^2 STANDARD_DEVIATION 5.771 | 26.53 kg/m^2 STANDARD_DEVIATION 5.45 | 26.49 kg/m^2 STANDARD_DEVIATION 5.126 |
| Disease stage I | 7 Participants | 20 Participants | 13 Participants |
| Disease stage II | 70 Participants | 131 Participants | 61 Participants |
| Disease stage III | 78 Participants | 156 Participants | 78 Participants |
| Disease stage IV | 0 Participants | 1 Participants | 1 Participants |
| ECOG performance status 0 | 117 Participants | 227 Participants | 110 Participants |
| ECOG performance status 1 | 36 Participants | 79 Participants | 43 Participants |
| ECOG performance status 2 | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 16 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 145 Participants | 292 Participants | 147 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Previous breast cancer surgery | 154 Participants | 306 Participants | 152 Participants |
| Previous radiotherapy | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 62 Participants | 120 Participants | 58 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 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 | 90 Participants | 183 Participants | 93 Participants |
| Sex: Female, Male Female | 155 Participants | 308 Participants | 153 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Time since diagnosis | 1.28 months | 1.28 months | 1.28 months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 155 | 2 / 153 |
| other Total, other adverse events | 147 / 155 | 144 / 153 |
| serious Total, serious adverse events | 29 / 155 | 32 / 153 |
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/l (grade 4 neutropenia).
Time frame: 21 days (Cycle 1 of chemotherapy treatment)
Population: Missing patients in FAS set due to blind data review meeting decision (no ANC profiles available). 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 | 1.36 days | Standard Deviation 1.133 |
| LA-EP2006 | Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy | PP | 1.34 days | Standard Deviation 1.141 |
| Neulasta® | Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy | FAS | 1.19 days | Standard Deviation 0.984 |
| Neulasta® | Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy | PP | 1.19 days | Standard Deviation 0.991 |
Comparison: The primary objective of the study was to compare LA-EP2006 and Neulasta in terms of the DSN in Cycle 1. It was to be shown in a hierarchical way:~1. that LA-EP2006 is equivalent (margin: ±1 day) to Neulasta® with respect to DSN duration in Cycle 1 and, if this was successfully established,~2. that LA-EP2006 is non-inferior (margin: -0.6 days) to Neulasta® with respect to DSN duration in Cycle 1.p-value: 0.0595% CI: [-0.4, 0.08]ANCOVA
Comparison: The primary objective of the study was to compare LA-EP2006 and Neulasta in terms of the DSN in Cycle 1. It was to be shown in a hierarchical way:~1. that LA-EP2006 is equivalent (margin: ±1 day) to Neulasta® with respect to DSN duration in Cycle 1 and, if this was successfully established,~2. that LA-EP2006 is non-inferior (margin: -0.6 days) to Neulasta® with respect to DSN duration in Cycle 1.p-value: 0.0595% CI: [-0.4, 0.08]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.
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 | 0.490 10^9 cells/L | Standard Deviation 0.7205 |
| Neulasta® | Depth of ANC Nadir in Cycle 1 | 0.444 10^9 cells/L | Standard Deviation 0.5684 |
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 3 | 2 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 5 | 2 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 2 | 5 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 | Cycle 4 | 4 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Overall | 26 Participants |
| LA-EP2006 | Frequency of Infections by Cycle and Across All Cycles | Cycle 1 | 10 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Overall | 32 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 1 | 14 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 2 | 3 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 3 | 5 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 4 | 5 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 5 | 6 Participants |
| Neulasta® | Frequency of Infections by Cycle and Across All Cycles | Cycle 6 | 5 Participants |
Secondary
Incidence of Febrile Neutropenia (FN)
FN was defined as 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: FAS set = full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 3 | 3 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 5 | 0 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 2 | 0 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 6 | 2 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 4 | 2 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | All cycles (at least on incidence) | 16 Participants |
| LA-EP2006 | Incidence of Febrile Neutropenia (FN) | Cycle 1 | 12 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | All cycles (at least on incidence) | 20 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 1 | 15 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 2 | 3 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 3 | 1 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 4 | 1 Participants |
| Neulasta® | Incidence of Febrile Neutropenia (FN) | Cycle 5 | 1 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 (19 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 | 155 Participants |
| Neulasta® | Mortality Due to Infection | Yes | 0 Participants |
| Neulasta® | Mortality Due to Infection | No | 153 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 8 | 20 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 9 | 3 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 6 | 9 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Days 10-15 | 2 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Days 1-5 | 1 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | not definable | 3 Participants |
| LA-EP2006 | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 7 | 117 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | not definable | 4 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Days 1-5 | 0 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 6 | 8 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 7 | 109 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 9 | 2 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Days 10-15 | 0 Participants |
| Neulasta® | Number of Patients With ANC Nadir Per Day in Cycle 1 | Day 8 | 30 Participants |
Secondary
Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles
Fever was defined as an oral body temperature of ≥ 38.3°C. Fever episodes were described 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 | 4 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 5 | 3 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 2 | 8 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 | 32 Participants |
| LA-EP2006 | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 1 | 13 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Overall | 35 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 1 | 17 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 2 | 6 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 3 | 7 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 4 | 10 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 5 | 3 Participants |
| Neulasta® | Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles | Cycle 6 | 4 Participants |
Secondary
Time to ANC Recovery in Days in Cycle 1
Time to absolute neutrophil count (ANC) recovery was defined as the time in days from ANC nadir until the patient's ANC had increased to ≥ 2 × 10\^9 cells/L after the nadir in Cycle 1.
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 | 2.11 days | Standard Deviation 0.889 |
| Neulasta® | Time to ANC Recovery in Days in Cycle 1 | 2.04 days | Standard Deviation 0.951 |