Breast Cancer, Neutropenia
Conditions
Keywords
Neutropenia, Breast Cancer, Long-acting Myeloid Growth Factor, Early Stage Breast Cancer, Docetaxel + Cyclophosphamide (TC) chemotherapy
Brief summary
The purpose of this study was to compare the efficacy of a single dose of SPI-2012 versus pegfilgrastim in participants with early-stage breast cancer receiving docetaxel and cyclophosphamide (TC), as measured by the duration of severe neutropenia (DSN) in Cycle 1.
Detailed description
This was a Phase 3, randomized, open-label, active-controlled, multicenter study to compare the efficacy and safety of SPI-2012 vs pegfilgrastim in participants with breast cancer treated with TC chemotherapy. Each cycle was 21 days. Four cycles were evaluated in this study. On Day 1 of each cycle, participants received TC chemotherapy. On Day 2 of each cycle, participants received study drug (SPI-2012 or pegfilgrastim).
Interventions
DRUGSPI-2012
Single-use syringes for subcutaneous injection, administered on Day 2 of each cycle
DRUGPegfilgrastim
Single-dose subcutaneous injection administered on Day 2 of each cycle
DRUGDocetaxel
Standard therapy
DRUGCyclophosphamide
Standard therapy
Sponsors
Spectrum Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * New diagnosis of histologically confirmed early-stage breast cancer (ESBC), defined as operable Stage I to Stage IIIA breast cancer * Candidate for adjuvant or neoadjuvant TC chemotherapy * Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 * Absolute neutrophil count (ANC) ≥ 1.5×10\^9/L * Platelet count ≥ 100×10\^9/L * Hemoglobin \> 9 g/dL * Creatinine clearance \> 50 mL/min * Total bilirubin ≤ 1.5 mg/dL * Aspartate Aminotransferase per Serum Glutamic-Oxaloacetic Transaminase (AST/SGOT) and Alanine Aminotransferase per Serum Glutamic-Pyruvic Transaminase (ALT/SGPT) ≤ 2.5× Upper Limit of Normal (ULN). * Alkaline phosphatase ≤ 2.0×ULN Key
Exclusion criteria
* Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix) or life-threatening disease * Locally recurrent or metastatic breast cancer * Known sensitivity to E. coli -derived products or to any products to be administered during dosing * Concurrent adjuvant cancer therapy * Previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in clinical development within 12 months prior to the administration of study drug * Active infection, receiving anti-infectives, or any serious underlying medical condition that would impair ability to receive protocol treatment * Prior bone marrow or stem cell transplant * Use of any investigational drugs, biologics, or devices within 30 days prior to study treatment or plans to use any of these during the course of the study * Radiation therapy within 30 days prior to enrollment * Major surgery within 30 days prior to enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Severe Neutropenia (DSN) in Cycle 1 | Day 1 and Days 4-15 in Cycle 1 (each cycle was 21 days) | DSN was defined as the number of days of severe neutropenia (absolute neutrophil count \[ANC\] \<0.5×10\^9/L), after the administration of study drug in Cycle 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depth of Absolute Neutrophil Count (ANC) Nadir in Cycle 1 | Day 1 and Days 4, 15 in Cycle 1 (each cycle was 21 days) | Depth of ANC Nadir was defined as the lowest ANC value after administration of study drug (SPI-2012 or Pegfilgrastim) in Cycle 1. |
| Number of Participants With Febrile Neutropenia (FN) in Cycle 1 | Day 1 and Days 4, 15 in Cycle 1 (each cycle was 21 days) | FN was defined as an oral temperature \> 38.3 degrees Celsius (C) (101.0 degrees Fahrenheit \[F\]) or two consecutive readings of \>=38.0 degrees C (100.4 degrees F) for 2 hours and ANC \<1.0×10\^9/L. |
| Duration of Severe Neutropenia in Cycle 2, 3 and 4 | Days 1, 4, 7, 10, and 15 in cycles 2, 3, and 4 (each cycle was 21 days) | DSN was defined as the number of days of severe neutropenia (ANC \<0.5×10\^9 /L) from the first occurrence of an ANC below the threshold in Cycles 2, 3, and 4. |
| Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1 | Day 1 and Days 4, 15 in Cycle 1 (each cycle was 21 days) | Time to ANC Recovery was defined as the time from chemotherapy administration until ANC increased to ≥1.5×10\^9/L after the expected nadir within Cycle 1. Time to ANC recovery was assigned as 0 for participants whose ANC value never dropped below 1.5 x10\^9/L. |
| Number of Participants With Febrile Neutropenia in Cycles 2, 3, and 4 | Days 1, 4, 7, 10, and 15 of Cycles 2, 3, and 4 (each cycle was 21 days) | FN was defined as an oral temperature \> 38.3 degrees C (101.0 degrees Fahrenheit \[F\]) or two consecutive readings of \>=38.0 degrees C (100.4 degrees F) for 2 hours and ANC \<1.0×10\^9/L. |
| Relative Dose Intensity (RDI) of TC (Docetaxel + Cyclophosphamide) in Cycles 1 to 4 | Cycles 1 to 4 (each cycle was 21 days) | RDI was defined as the percentage of the planned dose that each participant actually received during the study, expressed as the total dose received, divided by the total dose planned and multiplied by 100. The planned dose was defined as the dose that would be given if no doses were missed and/or no dose reductions were made for the number of cycles started. The total planned dose was the sum of planned doses over all cycles. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the first dose of TC (Docetaxel + Cyclophosphamide) until 12 months after the last dose of study treatment (up to approximately 34 months) | An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product or study procedure, whether or not considered related to the medicinal product. A TEAE for Treatment Period is defined as adverse event with an onset date on or after the date of study drug administration through the end of treatment. TEAE for follow up is defined as any new onset or ongoing AE at the end of Treatment. SAE is defined as any AE which meets any of the following criteria: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in a persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, includes important medical events. |
| Number of Participants With Neutropenic Complications in Cycle 1 | Day 1 and Days 4, 15 in Cycle 1 (each cycle was 21 days) | Neutropenic complications refer to hospitalizations due to neutropenic events and/or the use of anti-infectives due to neutropenia. |
Countries
Canada, South Korea, United States
Participant flow
Recruitment details
Participants were enrolled from 19 Jan 2016 to 31 Oct 2018. A total of 406 participants were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: SPI-2012 and TC Participants received SPI-2012 13.2 mg/0.6mL (3.6 mg G-CSF) fixed-dose SC injection once per cycle on Day 2 of each cycle up to Cycle 4 (each cycle was 21 days), approximately 24-26 hours after TC chemotherapy administration. TC chemotherapy was administered on Day 1 of each cycle and included Docetaxel 75 mg/m\^2 IV infusion and Cyclophosphamide 600 mg/m\^2 IV infusion per institute's standard of care. | 196 |
| Arm 2: Pegfilgrastim and TC Participants received pegfilgrastim 6 mg SC injection once per cycle on Day 2 of each cycle up to Cycle 4 (each cycle was 21 days), approximately 24-26 hours after TC chemotherapy administration. TC chemotherapy on Day 1 of each cycle included Docetaxel 75 mg/m\^2 IV infusion and Cyclophosphamide 600 mg/m\^2 IV infusion per institute's standard of care. | 210 |
| Total | 406 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Initiation of Non-Protocol Therapy for Breast Cancer | 6 | 12 |
| Overall Study | Investigator Decision | 2 | 4 |
| Overall Study | Lost to Follow-up | 6 | 10 |
| Overall Study | Reason not Specified | 8 | 7 |
| Overall Study | Sponsor decision | 1 | 1 |
| Overall Study | Treatment with Additional Myeloid Growth Factors During Follow-up | 6 | 10 |
| Overall Study | Withdrawal by Subject | 25 | 19 |
Baseline characteristics
| Characteristic | Total | Arm 1: SPI-2012 and TC | Arm 2: Pegfilgrastim and TC |
|---|---|---|---|
| Age, Continuous | 59.5 years STANDARD_DEVIATION 11.47 | 59.9 years STANDARD_DEVIATION 11.12 | 59.0 years STANDARD_DEVIATION 11.79 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 74 Participants | 34 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 332 Participants | 162 Participants | 170 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 18 Participants | 9 Participants | 9 Participants |
| Race/Ethnicity, Customized Black or African American | 58 Participants | 26 Participants | 32 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized White or Caucasian | 315 Participants | 156 Participants | 159 Participants |
| Sex: Female, Male Female | 404 Participants | 195 Participants | 209 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 197 | 1 / 208 | 0 / 197 | 1 / 208 |
| other Total, other adverse events | 192 / 197 | 203 / 208 | 92 / 197 | 82 / 208 |
| serious Total, serious adverse events | 36 / 197 | 29 / 208 | 8 / 197 | 2 / 208 |
Outcome results
Primary
Duration of Severe Neutropenia (DSN) in Cycle 1
DSN was defined as the number of days of severe neutropenia (absolute neutrophil count \[ANC\] \<0.5×10\^9/L), after the administration of study drug in Cycle 1.
Time frame: Day 1 and Days 4-15 in Cycle 1 (each cycle was 21 days)
Population: The ITT population included all participants who were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 and TC | Duration of Severe Neutropenia (DSN) in Cycle 1 | 0.20 days | Standard Deviation 0.503 |
| Arm 2: Pegfilgrastim and TC | Duration of Severe Neutropenia (DSN) in Cycle 1 | 0.35 days | Standard Deviation 0.683 |
p-value: <0.000195% CI: [-0.266, -0.031]t-statistics
Secondary
Depth of Absolute Neutrophil Count (ANC) Nadir in Cycle 1
Depth of ANC Nadir was defined as the lowest ANC value after administration of study drug (SPI-2012 or Pegfilgrastim) in Cycle 1.
Time frame: Day 1 and Days 4, 15 in Cycle 1 (each cycle was 21 days)
Population: The ITT population included all participants who were randomized. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 and TC | Depth of Absolute Neutrophil Count (ANC) Nadir in Cycle 1 | 2.56 10^9 ANC/L | Standard Deviation 3.086 |
| Arm 2: Pegfilgrastim and TC | Depth of Absolute Neutrophil Count (ANC) Nadir in Cycle 1 | 2.53 10^9 ANC/L | Standard Deviation 3.317 |
p-value: 0.15595% CI: [0.93, 1.56]Asymptotic normality assumption
Secondary
Duration of Severe Neutropenia in Cycle 2, 3 and 4
DSN was defined as the number of days of severe neutropenia (ANC \<0.5×10\^9 /L) from the first occurrence of an ANC below the threshold in Cycles 2, 3, and 4.
Time frame: Days 1, 4, 7, 10, and 15 in cycles 2, 3, and 4 (each cycle was 21 days)
Population: The ITT population included all participants who were randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: SPI-2012 and TC | Duration of Severe Neutropenia in Cycle 2, 3 and 4 | Cycle 2 | 0.13 days | Standard Deviation 0.383 |
| Arm 1: SPI-2012 and TC | Duration of Severe Neutropenia in Cycle 2, 3 and 4 | Cycle 3 | 0.11 days | Standard Deviation 0.326 |
| Arm 1: SPI-2012 and TC | Duration of Severe Neutropenia in Cycle 2, 3 and 4 | Cycle 4 | 0.11 days | Standard Deviation 0.362 |
| Arm 2: Pegfilgrastim and TC | Duration of Severe Neutropenia in Cycle 2, 3 and 4 | Cycle 2 | 0.09 days | Standard Deviation 0.374 |
| Arm 2: Pegfilgrastim and TC | Duration of Severe Neutropenia in Cycle 2, 3 and 4 | Cycle 3 | 0.08 days | Standard Deviation 0.273 |
| Arm 2: Pegfilgrastim and TC | Duration of Severe Neutropenia in Cycle 2, 3 and 4 | Cycle 4 | 0.09 days | Standard Deviation 0.281 |
Comparison: DSN in Cycle 2p-value: <0.000195% CI: [-0.032, 0.116]t-statistics
Comparison: DSN in Cycle 3p-value: <0.000195% CI: [-0.032, 0.085]t-statistics
Comparison: DSN in Cycle 4p-value: <0.000195% CI: [-0.036, 0.089]t-statistics
Secondary
Number of Participants With Febrile Neutropenia (FN) in Cycle 1
FN was defined as an oral temperature \> 38.3 degrees Celsius (C) (101.0 degrees Fahrenheit \[F\]) or two consecutive readings of \>=38.0 degrees C (100.4 degrees F) for 2 hours and ANC \<1.0×10\^9/L.
Time frame: Day 1 and Days 4, 15 in Cycle 1 (each cycle was 21 days)
Population: The ITT population included all participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: SPI-2012 and TC | Number of Participants With Febrile Neutropenia (FN) in Cycle 1 | 4 Participants |
| Arm 2: Pegfilgrastim and TC | Number of Participants With Febrile Neutropenia (FN) in Cycle 1 | 2 Participants |
p-value: 0.43595% CI: [-8.6, 10.8]Fisher Exact
Secondary
Number of Participants With Febrile Neutropenia in Cycles 2, 3, and 4
FN was defined as an oral temperature \> 38.3 degrees C (101.0 degrees Fahrenheit \[F\]) or two consecutive readings of \>=38.0 degrees C (100.4 degrees F) for 2 hours and ANC \<1.0×10\^9/L.
Time frame: Days 1, 4, 7, 10, and 15 of Cycles 2, 3, and 4 (each cycle was 21 days)
Population: The ITT population included all participants who were randomized
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: SPI-2012 and TC | Number of Participants With Febrile Neutropenia in Cycles 2, 3, and 4 | Cycle 2 | 1 Participants |
| Arm 1: SPI-2012 and TC | Number of Participants With Febrile Neutropenia in Cycles 2, 3, and 4 | Cycle 3 | 4 Participants |
| Arm 1: SPI-2012 and TC | Number of Participants With Febrile Neutropenia in Cycles 2, 3, and 4 | Cycle 4 | 2 Participants |
| Arm 2: Pegfilgrastim and TC | Number of Participants With Febrile Neutropenia in Cycles 2, 3, and 4 | Cycle 2 | 1 Participants |
| Arm 2: Pegfilgrastim and TC | Number of Participants With Febrile Neutropenia in Cycles 2, 3, and 4 | Cycle 3 | 1 Participants |
| Arm 2: Pegfilgrastim and TC | Number of Participants With Febrile Neutropenia in Cycles 2, 3, and 4 | Cycle 4 | 0 Participants |
Comparison: FN in Cycle 2p-value: 195% CI: [-9.7, 9.8]Fisher Exact
Comparison: FN in Cycle 3p-value: 0.20195% CI: [-8.2, 11.3]Fisher Exact
Comparison: FN in Cycle 4p-value: 0.23295% CI: [-8.7, 10.8]Fisher Exact
Secondary
Number of Participants With Neutropenic Complications in Cycle 1
Neutropenic complications refer to hospitalizations due to neutropenic events and/or the use of anti-infectives due to neutropenia.
Time frame: Day 1 and Days 4, 15 in Cycle 1 (each cycle was 21 days)
Population: The ITT population included all participants who was randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: SPI-2012 and TC | Number of Participants With Neutropenic Complications in Cycle 1 | 8 Participants |
| Arm 2: Pegfilgrastim and TC | Number of Participants With Neutropenic Complications in Cycle 1 | 8 Participants |
p-value: 195% CI: [-9.5, 10]Fisher Exact
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product or study procedure, whether or not considered related to the medicinal product. A TEAE for Treatment Period is defined as adverse event with an onset date on or after the date of study drug administration through the end of treatment. TEAE for follow up is defined as any new onset or ongoing AE at the end of Treatment. SAE is defined as any AE which meets any of the following criteria: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in a persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, includes important medical events.
Time frame: From the first dose of TC (Docetaxel + Cyclophosphamide) until 12 months after the last dose of study treatment (up to approximately 34 months)
Population: Safety Population included all participants who received at least one dose of any protocol-specified drug (TC, SPI-2012 or pegfilgrastim). One participant was randomized to pegfilgrastim but was given SPI-2012 in Safety Population. Data was summarized and reported separately for Treatment Period and Follow-up Period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: SPI-2012 and TC | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 192 Participants |
| Arm 1: SPI-2012 and TC | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 36 Participants |
| Arm 2: Pegfilgrastim and TC | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 29 Participants |
| Arm 2: Pegfilgrastim and TC | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 204 Participants |
| Arm 1: SPI-2012 and TC - Follow up Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 95 Participants |
| Arm 1: SPI-2012 and TC - Follow up Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 8 Participants |
| Arm 2: Pegfilgrastim and TC - Follow up Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 83 Participants |
| Arm 2: Pegfilgrastim and TC - Follow up Period | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 2 Participants |
Secondary
Relative Dose Intensity (RDI) of TC (Docetaxel + Cyclophosphamide) in Cycles 1 to 4
RDI was defined as the percentage of the planned dose that each participant actually received during the study, expressed as the total dose received, divided by the total dose planned and multiplied by 100. The planned dose was defined as the dose that would be given if no doses were missed and/or no dose reductions were made for the number of cycles started. The total planned dose was the sum of planned doses over all cycles.
Time frame: Cycles 1 to 4 (each cycle was 21 days)
Population: Safety Population included all participants who received at least one dose of any protocol-specified drug (TC, SPI-2012 or pegfilgrastim). One participant was randomized to pegfilgrastim but was given SPI-2012 in Safety Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: SPI-2012 and TC | Relative Dose Intensity (RDI) of TC (Docetaxel + Cyclophosphamide) in Cycles 1 to 4 | Docetaxel | 99.1 percentage of planned dose | Standard Deviation 5.47 |
| Arm 1: SPI-2012 and TC | Relative Dose Intensity (RDI) of TC (Docetaxel + Cyclophosphamide) in Cycles 1 to 4 | Cyclophosphamide | 99.3 percentage of planned dose | Standard Deviation 3.86 |
| Arm 2: Pegfilgrastim and TC | Relative Dose Intensity (RDI) of TC (Docetaxel + Cyclophosphamide) in Cycles 1 to 4 | Docetaxel | 98.1 percentage of planned dose | Standard Deviation 8.45 |
| Arm 2: Pegfilgrastim and TC | Relative Dose Intensity (RDI) of TC (Docetaxel + Cyclophosphamide) in Cycles 1 to 4 | Cyclophosphamide | 99.0 percentage of planned dose | Standard Deviation 4.33 |
Secondary
Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1
Time to ANC Recovery was defined as the time from chemotherapy administration until ANC increased to ≥1.5×10\^9/L after the expected nadir within Cycle 1. Time to ANC recovery was assigned as 0 for participants whose ANC value never dropped below 1.5 x10\^9/L.
Time frame: Day 1 and Days 4, 15 in Cycle 1 (each cycle was 21 days)
Population: The ITT population included all participants who were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 and TC | Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1 | 3.24 days | Standard Deviation 3.565 |
| Arm 2: Pegfilgrastim and TC | Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1 | 3.49 days | Standard Deviation 3.589 |
p-value: 0.68595% CI: [-1.43, 0.94]Negative binomial regression