Neutropenia
Conditions
Brief summary
The purpose of this study is to assess the effect of test doses of SPI-2012 on the duration of severe neutropenia (DSN) during Cycle 1 in participants with breast cancer who are candidates for adjuvant or neoadjuvant chemotherapy.
Detailed description
This is an open label, multicenter, dose ranging study, sequentially enrolled by study dose, with a non-inferiority design to compare the effectiveness of SPI-2012 relative to a fixed dose of pegfilgrastim as a concurrent active control to each dose of SPI-2012 in participants with breast cancer. This study included four arms comprising three dose levels of SPI-2012 (Arm 1: 45 µg/kg, Arm 2: 135 µg/kg, Arm 3: 270 µg/kg) versus pegfilgrastim (Arm 4: 6 mg). The start of study is defined as the initiation of treatment with SPI-2012 or pegfilgrastim. The duration of treatment consists of a maximum of 4 cycles (21 days per cycle) beginning on Day 1 with chemotherapy administration and continue through Day 21, plus a 30-day follow-up period, unless any of the discontinuation criteria applies. The target population are participants with breast cancer who are candidates for neoadjuvant or adjuvant treatment with Docetaxel + Cyclophosphamide (TC) chemotherapy. All participants who receive at least 1 dose of either SPI-2012 or pegfilgrastim were followed for safety through 30 days after their last dose of study treatment or until all treatment-related adverse events (AEs) have resolved or returned to baseline/Grade 1, whichever is longer, or until it is determined that the outcome will not change with further follow-up.
Interventions
DRUGSPI-2012
SPI-2012 SC injection.
DRUGPegfilgrastim
Pegfilgrastim SC injection, per manufacturer's Prescribing Information.
DRUGDocetaxel
Docetaxel given based on standard dose for chemotherapy.
DRUGCyclophosphamide
Cyclophosphamide given based on standard dose for chemotherapy.
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
* Histologically confirmed breast cancer and candidate for adjuvant or neoadjuvant chemotherapy * Candidate for docetaxel and cyclophosphamide chemotherapy * Female or male at least 18 years of age * Eastern Cooperative Oncology Group (ECOG) ≤ 2 * Absolute neutrophil count (ANC) ≥ 1.5×109/L * Platelet count ≥ 100 x 10\^9/L * Creatinine ≤ 1.5 x upper limit of normal (ULN) * Total bilirubin ≤1.5 mg/dL(≤ 25.65 μmol/L). * Aspartate aminotransferase per serum glutamic-oxaloacetic transaminase (AST/SGOT) and/or alanine aminotransferase per serum glutamic-pyruvic transaminase (ALT/SGPT) ≤ 2.5 x ULN * Hemoglobin \> 9 g/dL * Alkaline phosphatase ≤ 1.5 x ULN
Exclusion criteria
* Known sensitivity to E. coli-derived products or known sensitivity to any of the products to be administered * Known Human Immunodeficiency Virus (HIV) infection * Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) diagnosis with detectable viral load or immunological evidence of chronic active disease * Active infection or any serious underlying medical condition that would impair ability to receive protocol treatment * Prior bone marrow or stem cell transplant * Prolonged exposure to glucocorticosteroids and immunosuppressive agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Severe Neutropenia (DSN) in Cycle 1 | Cycle 1 (each cycle was 21 days) | DSN was defined as the interval from the day of first observation of severe neutropenia (ANC \<0.5\*10\^9/L, Grade 4 neutropenia per NCI CTCAE) to the first ANC recovery to =\> 2.0\*10\^9/L in Cycle 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of DSN in Cycle 2 | Cycle 2 (each cycle was 21 days) | DSN was defined as the interval from the day of first observation of severe neutropenia (ANC \<0.5\*10\^9/L, Grade 4 neutropenia per NCI CTCAE) to the first ANC recovery to =\> 2.0\*10\^9/L in Cycle 2. |
| Duration of DSN in Cycle 3 | Cycle 3 (each cycle was 21 days) | DSN was defined as the interval from the day of first observation of severe neutropenia (ANC \<0.5\*10\^9/L, Grade 4 neutropenia per NCI CTCAE) to the first ANC recovery to =\> 2.0\*10\^9/L in Cycle 3. |
| Duration of DSN in Cycle 4 | Cycle 4 (each cycle was 21 days) | DSN was defined as the interval from the day of first observation of severe neutropenia (ANC \<0.5\*10\^9/L, Grade 4 neutropenia per NCI CTCAE) to the first ANC recovery to =\> 2.0\*10\^9/L in Cycle 4. |
| Time to ANC Recovery in Cycle 1 | Cycle 1 (each cycle was 21 days) | Time to ANC recovery was defined as the time from chemotherapy administration until ANC increased to ≥ 2×10\^9/L after the expected nadir within Cycle 1. Time to ANC recovery was not calculated for participants whose ANC value didn't drop below 2 x10\^9/L within Cycle 1. |
| Time to ANC Recovery in Cycle 2 | Cycle 2 (each cycle was 21 days) | Time to ANC recovery was defined as the time from chemotherapy administration until ANC increased to ≥2×10\^9/L after the expected nadir within Cycle 2. Time to ANC recovery was not calculated for participants whose ANC value didn't drop below 2 x10\^9/L within Cycle 2. |
| Time to ANC Recovery in Cycle 3 | Cycle 3 (each cycle was 21 days) | Time to ANC recovery was defined as the time from chemotherapy administration until ANC increased to ≥2×10\^9/L after the expected nadir within Cycle 3. Time to ANC recovery was not calculated for participants whose ANC value didn't drop below 2 x10\^9/L within Cycle 3. |
| Time to ANC Recovery in Cycle 4 | Cycle 4 (each cycle was 21 days) | Time to ANC recovery was defined as the time from chemotherapy administration until ANC increased to ≥2×10\^9/L after the expected nadir within Cycle 4. Time to ANC recovery was not calculated for participants whose ANC value didn't drop below 2 x10\^9/L within Cycle 4. |
| Absolute Neutrophil Count (ANC) Nadir Overtime in Cycle 1 | Cycle 1 (each cycle was 21 days) | Mean ANC nadir was defined as the mean of the lowest ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 1. |
| Time to ANC Nadir in Cycle 3 | Cycle 3 (each cycle was 21 days) | Time to ANC nadir was defined as the time from chemotherapy administration until the occurrence of the ANC nadir. |
| Absolute ANC Nadir Overtime in Cycle 2 | Cycle 2 (each cycle was 21 days) | Mean ANC nadir was defined as the mean of the lowest ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 2. |
| Absolute ANC Nadir Overtime in Cycle 3 | Cycle 3 (each cycle was 21 days) | Mean ANC nadir was defined as the mean of the lowest ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 3. |
| Absolute ANC Nadir Overtime in Cycle 4 | Cycle 4 (each cycle was 21 days) | Mean ANC nadir was defined as the mean of the lowest ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 4. |
| Depth of ANC Nadir in Cycle 1 | Cycle 1 (each cycle was 21 days) | Depth of ANC nadir was defined as the lowest Median ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 1. |
| Time to ANC Nadir in Cycle 2 | Cycle 2 (each cycle was 21 days) | Time to ANC nadir was defined as the time from chemotherapy administration until the occurrence of the ANC nadir. |
| Depth of ANC Nadir in Cycle 3 | Cycle 3 (each cycle was 21 days) | Depth of ANC nadir was defined as the lowest Median ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 3. |
| Depth of ANC Nadir in Cycle 4 | Cycle 4 (each cycle was 21 days) | Depth of ANC nadir was defined as the lowest Median ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 4. |
| Time to ANC Nadir in Cycle 1 | Cycle 1 (each cycle was 21 days) | Time to ANC nadir was defined as the time from chemotherapy administration until the occurrence of the ANC nadir. |
| Time to ANC Nadir in Cycle 4 | Cycle 4 (each cycle was 21 days) | Time to ANC nadir was defined as the time from chemotherapy administration until the occurrence of the ANC nadir. |
| Percentage of Participants With Febrile Neutropenia (FN) Across All Cycles From Cycle 1 to Cycle 4 | Cycle 1 to Cycle 4 (each cycle was 21 days) | FN was defined as a temperature of more than 38.2 degree Celsius (°C) concurrent with an ANC greater than 0.5×10\^9/L.. |
| Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | From the first dose up to 30 days post last dose of study drug (up to 4 months) | An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. Participants with SAE other than death were reported.AE and Laboratory Abnormalities (Hematology and Chemistry) were collected and graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03, where Grade 3 refers to severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated and Grade 4 refers to life-threatening consequences; urgent intervention indicated. |
| Percentage of Participants With Hospitalization Across All Cycles From Cycle 1 to Cycle 4 | All cycles from Cycle 1 to Cycle 4 (each cycle was 21 days) | — |
| Number of Participants With Positive Antibodies for SPI-2012 | Up to the end of the study (Approximately 3.5 months) | Serum samples were to be tested in a screening assay for antibodies binding to SPI-2012 using a validated enzyme-linked immunosorbent assay (ELISA). Any serum samples positive for the antibody were to be tested in a confirmatory competitive inhibition assay using two antigens, SPI-2012 or granulocyte colony-stimulating factor (G-CSF), to confirm the presence of antibodies binding to SPI-2012 and to identify samples that were positive for antibodies binding to G-CSF. |
| Time to Reach Maximum Concentration of SPI-2012 (Tmax) | Pre-dose and at 1, 3, 6, 8, 10, 24, 48, 72, 144, 192, and 312 hours post-dose in Cycle 1 (each cycle was 21 days) | Blood samples were collected at specific time points to determine the serum concentrations of SPI-2012 and to derive pharmacokinetic (PK) parameters. |
| Maximum Concentration of SPI-2012 (Cmax) | Pre-dose and at 1, 3, 6, 8, 10, 24, 48, 72, 144, 192, and 312 hours post-dose in Cycle 1 (each cycle was 21 days) | Blood samples were collected at specific time points to determine the serum concentrations of SPI-2012 and to derive PK parameters. |
| Area Under the Serum Concentration-Time Curve From Time Zero to 312 Hours Post-Dose (AUC0-312) | Pre-dose and at 1, 3, 6, 8, 10, 24, 48, 72, 144, 192, and 312 hours post-dose in Cycle 1 (each cycle was 21 days) | AUC(0-312) is the area under the serum concentration-time curve from time zero to 312 hour post dose calculated by the linear trapezoidal rule. Blood samples were collected at specific time points to determine the serum concentrations of SPI-2012 and to derive PK parameters. |
| Half-life of SPI-2012 (t1/2) | Pre-dose and at 1, 3, 6, 8, 10, 24, 48, 72, 144, 192, and 312 hours post-dose in Cycle 1 (each cycle was 21 days) | t1/2 data were calculated and reported as harmonic mean and pseudo standard deviation (SD). Blood samples were collected at specific time points to determine the serum concentrations of SPI-2012 and to derive PK parameters. |
| Depth of ANC Nadir in Cycle 2 | Cycle 2 (each cycle was 21 days) | Depth of ANC nadir was defined as the lowest Median ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 2. |
Countries
Australia, Georgia, Hungary, Israel, Poland, United States
Participant flow
Recruitment details
Participants were enrolled at 27 investigative sites in the United States (10 sites), Australia (5 sites), Georgia (2 sites), Hungary (5 sites), Israel (1 site), and Poland (4 sites) from 25 March 2013 to 12 August 2014.
Pre-assignment details
A total of 148 participants were randomized in the study, out of which 138 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC Participants received SPI-2012 45 µg/kg, SC once per cycle on Day 2 of each cycle up to cycle 4 (each cycle was 21 days), approximately 24 hours after the administration of TC chemotherapy. TC chemotherapy was administered on Day 1 of each cycle as follows:
Docetaxel 75 mg/m\^2 IV infusion over 60 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes. | 39 |
| Arm 2: SPI-2012 135 µg/kg and TC Participants received SPI-2012 135 µg/kg, SC once per cycle on Day 2 of each cycle up to cycle 4 (each cycle was 21 days), approximately 24 hours after the administration of TC chemotherapy. TC chemotherapy was administered on Day 1 of each cycle as follows:
Docetaxel 75 mg/m\^2 IV infusion over 60 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes. | 36 |
| Arm 3: SPI-2012 270 µg/kg and TC Participants received SPI-2012 270 µg/kg, SC once per cycle on Day 2 of each cycle up to cycle 4 (each cycle was 21 days), approximately 24 hours after the administration of TC chemotherapy. TC chemotherapy was administered on Day 1 of each cycle as follows:
Docetaxel 75 mg/m\^2 IV infusion over 60 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes. | 36 |
| Arm 4: Pegfilgrastim and TC Participants received Pegfilgrastim 6 mg, SC once per cycle on Day 2 of each cycle up to cycle 4 (each cycle was 21 days), approximately 24 hours after the administration of TC chemotherapy. TC chemotherapy was administered on Day 1 of each cycle as follows:
Docetaxel 75 mg/m\^2 IV infusion over 60 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes. | 36 |
| Total | 147 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 |
| Overall Study | Initiation of Non-Protocol Therapy Either for Progressive Disease or Intolerance of TC Regimen | 0 | 2 | 0 | 0 |
| Overall Study | Investigator's Discretion | 0 | 1 | 1 | 0 |
| Overall Study | Need for Chemotherapy or Chemotherapy Regimen was Changed due to Amended HER2 Status | 1 | 0 | 0 | 0 |
| Overall Study | Participant Refused Further Treatment or Withdrew Consent | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Arm 1: SPI-2012 45 µg/kg and TC | Arm 2: SPI-2012 135 µg/kg and TC | Arm 3: SPI-2012 270 µg/kg and TC | Arm 4: Pegfilgrastim and TC | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.8 years STANDARD_DEVIATION 11.31 | 56.8 years STANDARD_DEVIATION 10.63 | 55.7 years STANDARD_DEVIATION 9.79 | 60.4 years STANDARD_DEVIATION 10.43 | 58.2 years STANDARD_DEVIATION 10.64 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 2 Participants | 2 Participants | 4 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 34 Participants | 34 Participants | 32 Participants | 133 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Others | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 36 Participants | 36 Participants | 35 Participants | 32 Participants | 139 Participants |
| Sex: Female, Male Female | 39 Participants | 35 Participants | 34 Participants | 36 Participants | 144 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 3 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 / 39 | 0 / 37 | 0 / 36 | 0 / 36 |
| other Total, other adverse events | 36 / 39 | 33 / 37 | 33 / 36 | 35 / 36 |
| serious Total, serious adverse events | 5 / 39 | 4 / 37 | 2 / 36 | 8 / 36 |
Outcome results
Primary
Duration of Severe Neutropenia (DSN) in Cycle 1
DSN was defined as the interval from the day of first observation of severe neutropenia (ANC \<0.5\*10\^9/L, Grade 4 neutropenia per NCI CTCAE) to the first ANC recovery to =\> 2.0\*10\^9/L in Cycle 1.
Time frame: Cycle 1 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Duration of Severe Neutropenia (DSN) in Cycle 1 | 1.03 days | Standard Deviation 1.547 |
| Arm 2: SPI-2012 135 µg/kg and TC | Duration of Severe Neutropenia (DSN) in Cycle 1 | 0.44 days | Standard Deviation 1.275 |
| Arm 3: SPI-2012 270 µg/kg and TC | Duration of Severe Neutropenia (DSN) in Cycle 1 | 0.03 days | Standard Deviation 0.167 |
| Arm 4: Pegfilgrastim and TC | Duration of Severe Neutropenia (DSN) in Cycle 1 | 0.31 days | Standard Deviation 0.822 |
Comparison: A 2-sided 95% confidence interval (CI) for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: 0.29695% CI: [0.19, 1.27]Bootstrap method
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: 0.00295% CI: [-0.28, 0.64]Bootstrap method
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-values was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: <0.00195% CI: [-0.56, -0.06]Bootstrap method
Secondary
Absolute ANC Nadir Overtime in Cycle 2
Mean ANC nadir was defined as the mean of the lowest ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 2.
Time frame: Cycle 2 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 2 | 2.0 10^9 ANC/L | Standard Deviation 1.89 |
| Arm 2: SPI-2012 135 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 2 | 3.9 10^9 ANC/L | Standard Deviation 2.55 |
| Arm 3: SPI-2012 270 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 2 | 6.8 10^9 ANC/L | Standard Deviation 6.3 |
| Arm 4: Pegfilgrastim and TC | Absolute ANC Nadir Overtime in Cycle 2 | 3.3 10^9 ANC/L | Standard Deviation 2.16 |
p-value: 0.005Asymptotic Normality Assumption
p-value: 0.633Asymptotic Normality Assumption
p-value: 0.027Asymptotic Normality Assumption
Secondary
Absolute ANC Nadir Overtime in Cycle 3
Mean ANC nadir was defined as the mean of the lowest ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 3.
Time frame: Cycle 3 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 3 | 2.3 10^9 ANC/L | Standard Deviation 1.87 |
| Arm 2: SPI-2012 135 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 3 | 4.4 10^9 ANC/L | Standard Deviation 3.26 |
| Arm 3: SPI-2012 270 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 3 | 6.1 10^9 ANC/L | Standard Deviation 4.81 |
| Arm 4: Pegfilgrastim and TC | Absolute ANC Nadir Overtime in Cycle 3 | 3.5 10^9 ANC/L | Standard Deviation 1.92 |
p-value: 0.015Asymptotic Normality Assumption
p-value: 0.571Asymptotic Normality Assumption
p-value: 0.066Asymptotic Normality Assumption
Secondary
Absolute ANC Nadir Overtime in Cycle 4
Mean ANC nadir was defined as the mean of the lowest ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 4.
Time frame: Cycle 4 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 4 | 2.1 10^9 ANC/L | Standard Deviation 2.12 |
| Arm 2: SPI-2012 135 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 4 | 4.1 10^9 ANC/L | Standard Deviation 2.86 |
| Arm 3: SPI-2012 270 µg/kg and TC | Absolute ANC Nadir Overtime in Cycle 4 | 4.8 10^9 ANC/L | Standard Deviation 3 |
| Arm 4: Pegfilgrastim and TC | Absolute ANC Nadir Overtime in Cycle 4 | 2.7 10^9 ANC/L | Standard Deviation 1.64 |
p-value: 0.106Asymptotic Normality Assumption
p-value: 0.156Asymptotic Normality Assumption
p-value: 0.005Asymptotic Normality Assumption
Secondary
Absolute Neutrophil Count (ANC) Nadir Overtime in Cycle 1
Mean ANC nadir was defined as the mean of the lowest ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 1.
Time frame: Cycle 1 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Absolute Neutrophil Count (ANC) Nadir Overtime in Cycle 1 | 1.5 10^9 ANC per liter | Standard Deviation 1.77 |
| Arm 2: SPI-2012 135 µg/kg and TC | Absolute Neutrophil Count (ANC) Nadir Overtime in Cycle 1 | 4.0 10^9 ANC per liter | Standard Deviation 3.86 |
| Arm 3: SPI-2012 270 µg/kg and TC | Absolute Neutrophil Count (ANC) Nadir Overtime in Cycle 1 | 7.2 10^9 ANC per liter | Standard Deviation 5.47 |
| Arm 4: Pegfilgrastim and TC | Absolute Neutrophil Count (ANC) Nadir Overtime in Cycle 1 | 3.2 10^9 ANC per liter | Standard Deviation 2.43 |
p-value: 0.008Asymptotic Normality Assumption
p-value: 0.911Asymptotic Normality Assumption
p-value: 0.002Asymptotic Normality Assumption
Secondary
Area Under the Serum Concentration-Time Curve From Time Zero to 312 Hours Post-Dose (AUC0-312)
AUC(0-312) is the area under the serum concentration-time curve from time zero to 312 hour post dose calculated by the linear trapezoidal rule. Blood samples were collected at specific time points to determine the serum concentrations of SPI-2012 and to derive PK parameters.
Time frame: Pre-dose and at 1, 3, 6, 8, 10, 24, 48, 72, 144, 192, and 312 hours post-dose in Cycle 1 (each cycle was 21 days)
Population: The PK Population included subset of participants who had received at least one dose of SPI-2012 in Arms 1 to 3 and have sufficient number of blood samples to estimate AUC. The AUC0-312 was not calculated for the 45 µg/kg dose due to insufficient data in the serum concentration profiles. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 2: SPI-2012 135 µg/kg and TC | Area Under the Serum Concentration-Time Curve From Time Zero to 312 Hours Post-Dose (AUC0-312) | 16000 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 5850 |
| Arm 3: SPI-2012 270 µg/kg and TC | Area Under the Serum Concentration-Time Curve From Time Zero to 312 Hours Post-Dose (AUC0-312) | 22900 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 25100 |
Secondary
Depth of ANC Nadir in Cycle 1
Depth of ANC nadir was defined as the lowest Median ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 1.
Time frame: Cycle 1 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Depth of ANC Nadir in Cycle 1 | 0.8 10^9 ANC/L |
| Arm 2: SPI-2012 135 µg/kg and TC | Depth of ANC Nadir in Cycle 1 | 3.0 10^9 ANC/L |
| Arm 3: SPI-2012 270 µg/kg and TC | Depth of ANC Nadir in Cycle 1 | 6.2 10^9 ANC/L |
| Arm 4: Pegfilgrastim and TC | Depth of ANC Nadir in Cycle 1 | 3.0 10^9 ANC/L |
95% CI: [0.25, 0.8]
95% CI: [0.53, 2.04]
95% CI: [1.4, 4.54]
Secondary
Depth of ANC Nadir in Cycle 2
Depth of ANC nadir was defined as the lowest Median ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 2.
Time frame: Cycle 2 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Depth of ANC Nadir in Cycle 2 | 1.3 10^9 ANC/L |
| Arm 2: SPI-2012 135 µg/kg and TC | Depth of ANC Nadir in Cycle 2 | 3.3 10^9 ANC/L |
| Arm 3: SPI-2012 270 µg/kg and TC | Depth of ANC Nadir in Cycle 2 | 4.8 10^9 ANC/L |
| Arm 4: Pegfilgrastim and TC | Depth of ANC Nadir in Cycle 2 | 2.9 10^9 ANC/L |
95% CI: [0.3, 0.8]
95% CI: [0.7, 1.79]
95% CI: [1.07, 2.79]
Secondary
Depth of ANC Nadir in Cycle 3
Depth of ANC nadir was defined as the lowest Median ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 3.
Time frame: Cycle 3 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Depth of ANC Nadir in Cycle 3 | 1.9 10^9 ANC/L |
| Arm 2: SPI-2012 135 µg/kg and TC | Depth of ANC Nadir in Cycle 3 | 3.4 10^9 ANC/L |
| Arm 3: SPI-2012 270 µg/kg and TC | Depth of ANC Nadir in Cycle 3 | 4.1 10^9 ANC/L |
| Arm 4: Pegfilgrastim and TC | Depth of ANC Nadir in Cycle 3 | 3.5 10^9 ANC/L |
95% CI: [0.34, 0.89]
95% CI: [0.71, 1.85]
95% CI: [0.97, 2.49]
Secondary
Depth of ANC Nadir in Cycle 4
Depth of ANC nadir was defined as the lowest Median ANC value (\*10\^9/L) after administration of the study drug (SPI-2012 or pegfilgrastim) on any day in Days 1-3 of Cycle 4.
Time frame: Cycle 4 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Depth of ANC Nadir in Cycle 4 | 8.0 10^9 ANC/L |
| Arm 2: SPI-2012 135 µg/kg and TC | Depth of ANC Nadir in Cycle 4 | 4.2 10^9 ANC/L |
| Arm 3: SPI-2012 270 µg/kg and TC | Depth of ANC Nadir in Cycle 4 | 4.2 10^9 ANC/L |
| Arm 4: Pegfilgrastim and TC | Depth of ANC Nadir in Cycle 4 | 2.4 10^9 ANC/L |
95% CI: [0.4, 1.1]
95% CI: [0.87, 2.38]
95% CI: [1.23, 2.96]
Secondary
Duration of DSN in Cycle 2
DSN was defined as the interval from the day of first observation of severe neutropenia (ANC \<0.5\*10\^9/L, Grade 4 neutropenia per NCI CTCAE) to the first ANC recovery to =\> 2.0\*10\^9/L in Cycle 2.
Time frame: Cycle 2 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Duration of DSN in Cycle 2 | 0.46 days | Standard Deviation 1.022 |
| Arm 2: SPI-2012 135 µg/kg and TC | Duration of DSN in Cycle 2 | 0.12 days | Standard Deviation 0.478 |
| Arm 3: SPI-2012 270 µg/kg and TC | Duration of DSN in Cycle 2 | 0.03 days | Standard Deviation 0.171 |
| Arm 4: Pegfilgrastim and TC | Duration of DSN in Cycle 2 | 0.08 days | Standard Deviation 0.368 |
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: 0.00195% CI: [0.06, 0.74]Bootstrap method
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: <0.00195% CI: [-0.16, 0.24]Bootstrap method
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: <0.00195% CI: [-0.19, 0.06]Bootstrap method
Secondary
Duration of DSN in Cycle 3
DSN was defined as the interval from the day of first observation of severe neutropenia (ANC \<0.5\*10\^9/L, Grade 4 neutropenia per NCI CTCAE) to the first ANC recovery to =\> 2.0\*10\^9/L in Cycle 3.
Time frame: Cycle 3 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Duration of DSN in Cycle 3 | 0.45 days | Standard Deviation 1.132 |
| Arm 2: SPI-2012 135 µg/kg and TC | Duration of DSN in Cycle 3 | 0.16 days | Standard Deviation 0.628 |
| Arm 3: SPI-2012 270 µg/kg and TC | Duration of DSN in Cycle 3 | 0.15 days | Standard Deviation 0.61 |
| Arm 4: Pegfilgrastim and TC | Duration of DSN in Cycle 3 | 0.14 days | Standard Deviation 0.593 |
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: 0.00295% CI: [-0.07, 0.72]Bootstrap method
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: <0.00195% CI: [-0.27, 0.3]Bootstrap method
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: <0.00195% CI: [-0.27, 0.28]Bootstrap method
Secondary
Duration of DSN in Cycle 4
DSN was defined as the interval from the day of first observation of severe neutropenia (ANC \<0.5\*10\^9/L, Grade 4 neutropenia per NCI CTCAE) to the first ANC recovery to =\> 2.0\*10\^9/L in Cycle 4.
Time frame: Cycle 4 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Duration of DSN in Cycle 4 | 1.05 days | Standard Deviation 4.579 |
| Arm 2: SPI-2012 135 µg/kg and TC | Duration of DSN in Cycle 4 | 0.19 days | Standard Deviation 0.738 |
| Arm 3: SPI-2012 270 µg/kg and TC | Duration of DSN in Cycle 4 | 0.09 days | Standard Deviation 0.522 |
| Arm 4: Pegfilgrastim and TC | Duration of DSN in Cycle 4 | 0.11 days | Standard Deviation 0.404 |
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: 0.78195% CI: [-0.01, 2.47]Bootstrap method
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: <0.00195% CI: [-0.17, 0.38]Bootstrap method
Comparison: A 2-sided 95% CI for the difference in mean DSN between any 2 arms was calculated. Non-inferiority p-value was calculated as two times the proportion of treatment difference greater than 1 in the resampling.p-value: <0.00195% CI: [-0.23, 0.22]Bootstrap method
Secondary
Half-life of SPI-2012 (t1/2)
t1/2 data were calculated and reported as harmonic mean and pseudo standard deviation (SD). Blood samples were collected at specific time points to determine the serum concentrations of SPI-2012 and to derive PK parameters.
Time frame: Pre-dose and at 1, 3, 6, 8, 10, 24, 48, 72, 144, 192, and 312 hours post-dose in Cycle 1 (each cycle was 21 days)
Population: The PK Population included subset of participants who had received at least one dose of SPI-2012 in Arms 1 to 3 and had sufficient number of blood samples to estimate AUC. The t1/2 was not calculated for the 45 µg/kg arm because there were insufficient data in terminal phase of serum concentration profiles. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 2: SPI-2012 135 µg/kg and TC | Half-life of SPI-2012 (t1/2) | 81.0 hrs | Standard Deviation 88.4 |
| Arm 3: SPI-2012 270 µg/kg and TC | Half-life of SPI-2012 (t1/2) | 31.5 hrs | — |
Secondary
Maximum Concentration of SPI-2012 (Cmax)
Blood samples were collected at specific time points to determine the serum concentrations of SPI-2012 and to derive PK parameters.
Time frame: Pre-dose and at 1, 3, 6, 8, 10, 24, 48, 72, 144, 192, and 312 hours post-dose in Cycle 1 (each cycle was 21 days)
Population: The PK Population included subset of participants who had received at least one dose of SPI-2012 in Arms 1 to 3 and had sufficient number of blood samples. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Maximum Concentration of SPI-2012 (Cmax) | 7.00 nanograms per milliliter (ng/mL) | Standard Deviation 6.08 |
| Arm 2: SPI-2012 135 µg/kg and TC | Maximum Concentration of SPI-2012 (Cmax) | 247 nanograms per milliliter (ng/mL) | Standard Deviation 276 |
| Arm 3: SPI-2012 270 µg/kg and TC | Maximum Concentration of SPI-2012 (Cmax) | 299 nanograms per milliliter (ng/mL) | Standard Deviation 329 |
Secondary
Number of Participants With Positive Antibodies for SPI-2012
Serum samples were to be tested in a screening assay for antibodies binding to SPI-2012 using a validated enzyme-linked immunosorbent assay (ELISA). Any serum samples positive for the antibody were to be tested in a confirmatory competitive inhibition assay using two antigens, SPI-2012 or granulocyte colony-stimulating factor (G-CSF), to confirm the presence of antibodies binding to SPI-2012 and to identify samples that were positive for antibodies binding to G-CSF.
Time frame: Up to the end of the study (Approximately 3.5 months)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed included participants who were treated with SPI-2012 and had post-treatment samples collected, and excluded participants who tested positive before being treated with SPI-2012. Data was collected and analyzed only for the SPI-2012 reporting arms as per the planned analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Number of Participants With Positive Antibodies for SPI-2012 | 0 Participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Number of Participants With Positive Antibodies for SPI-2012 | 0 Participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Number of Participants With Positive Antibodies for SPI-2012 | 2 Participants |
Secondary
Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities
An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. Participants with SAE other than death were reported.AE and Laboratory Abnormalities (Hematology and Chemistry) were collected and graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03, where Grade 3 refers to severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated and Grade 4 refers to life-threatening consequences; urgent intervention indicated.
Time frame: From the first dose up to 30 days post last dose of study drug (up to 4 months)
Population: The Safety Population included all randomized participants who had received at least one dose of any protocol specified drug (i.e., docetaxel, cyclophosphamide, SPI-2012 or pegfilgrastim).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 TEAEs | 24 Participants |
| Arm 1: SPI-2012 45 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Death | 0 Participants |
| Arm 1: SPI-2012 45 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | SAEs Other Than Death | 5 Participants |
| Arm 1: SPI-2012 45 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | TEAEs Leading to Discontinuation From Study Therapy | 0 Participants |
| Arm 1: SPI-2012 45 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 Lab Abnormalities: Hematology | 33 Participants |
| Arm 1: SPI-2012 45 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 Lab Abnormalities: Chemistry | 8 Participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 Lab Abnormalities: Chemistry | 4 Participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | TEAEs Leading to Discontinuation From Study Therapy | 2 Participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 TEAEs | 12 Participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | SAEs Other Than Death | 4 Participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Death | 0 Participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 Lab Abnormalities: Hematology | 19 Participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Death | 0 Participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | SAEs Other Than Death | 2 Participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | TEAEs Leading to Discontinuation From Study Therapy | 1 Participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 Lab Abnormalities: Chemistry | 6 Participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 Lab Abnormalities: Hematology | 18 Participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 TEAEs | 13 Participants |
| Arm 4: Pegfilgrastim and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 Lab Abnormalities: Hematology | 28 Participants |
| Arm 4: Pegfilgrastim and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 Lab Abnormalities: Chemistry | 8 Participants |
| Arm 4: Pegfilgrastim and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Death | 0 Participants |
| Arm 4: Pegfilgrastim and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | TEAEs Leading to Discontinuation From Study Therapy | 1 Participants |
| Arm 4: Pegfilgrastim and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | Grade 3-4 TEAEs | 12 Participants |
| Arm 4: Pegfilgrastim and TC | Number of Participants With Worst Grade Adverse Events (AEs), Deaths, Other Serious Adverse Events (SAEs), and Other AEs Leading to Discontinuation From Study Therapy, and Worst Grade Laboratory Abnormalities | SAEs Other Than Death | 8 Participants |
Secondary
Percentage of Participants With Febrile Neutropenia (FN) Across All Cycles From Cycle 1 to Cycle 4
FN was defined as a temperature of more than 38.2 degree Celsius (°C) concurrent with an ANC greater than 0.5×10\^9/L..
Time frame: Cycle 1 to Cycle 4 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Percentage of Participants With Febrile Neutropenia (FN) Across All Cycles From Cycle 1 to Cycle 4 | 7.7 percentage of participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Percentage of Participants With Febrile Neutropenia (FN) Across All Cycles From Cycle 1 to Cycle 4 | 2.8 percentage of participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Percentage of Participants With Febrile Neutropenia (FN) Across All Cycles From Cycle 1 to Cycle 4 | 2.8 percentage of participants |
| Arm 4: Pegfilgrastim and TC | Percentage of Participants With Febrile Neutropenia (FN) Across All Cycles From Cycle 1 to Cycle 4 | 5.6 percentage of participants |
p-value: 195% CI: [-20.2, 24.9]Fisher Exact
p-value: 195% CI: [-26.7, 21.4]Fisher Exact
p-value: 195% CI: [-26.7, 21.4]Fisher Exact
Secondary
Percentage of Participants With Hospitalization Across All Cycles From Cycle 1 to Cycle 4
Time frame: All cycles from Cycle 1 to Cycle 4 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Percentage of Participants With Hospitalization Across All Cycles From Cycle 1 to Cycle 4 | 7.7 percentage of participants |
| Arm 2: SPI-2012 135 µg/kg and TC | Percentage of Participants With Hospitalization Across All Cycles From Cycle 1 to Cycle 4 | 8.3 percentage of participants |
| Arm 3: SPI-2012 270 µg/kg and TC | Percentage of Participants With Hospitalization Across All Cycles From Cycle 1 to Cycle 4 | 2.8 percentage of participants |
| Arm 4: Pegfilgrastim and TC | Percentage of Participants With Hospitalization Across All Cycles From Cycle 1 to Cycle 4 | 13.9 percentage of participants |
p-value: 0.46995% CI: [-28.5, 16.9]Fisher Exact
p-value: 0.7195% CI: [-29.3, 18.7]Fisher Exact
p-value: 0.19995% CI: [-34.6, 13.3]Fisher Exact
Secondary
Time to ANC Nadir in Cycle 1
Time to ANC nadir was defined as the time from chemotherapy administration until the occurrence of the ANC nadir.
Time frame: Cycle 1 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to ANC Nadir in Cycle 1 | 8.0 Days |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to ANC Nadir in Cycle 1 | 7.0 Days |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to ANC Nadir in Cycle 1 | 7.0 Days |
| Arm 4: Pegfilgrastim and TC | Time to ANC Nadir in Cycle 1 | 7.5 Days |
Secondary
Time to ANC Nadir in Cycle 2
Time to ANC nadir was defined as the time from chemotherapy administration until the occurrence of the ANC nadir.
Time frame: Cycle 2 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to ANC Nadir in Cycle 2 | 8.0 days |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to ANC Nadir in Cycle 2 | 7.0 days |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to ANC Nadir in Cycle 2 | 8.0 days |
| Arm 4: Pegfilgrastim and TC | Time to ANC Nadir in Cycle 2 | 8.0 days |
Secondary
Time to ANC Nadir in Cycle 3
Time to ANC nadir was defined as the time from chemotherapy administration until the occurrence of the ANC nadir.
Time frame: Cycle 3 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to ANC Nadir in Cycle 3 | 8.0 days |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to ANC Nadir in Cycle 3 | 7.0 days |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to ANC Nadir in Cycle 3 | 8.0 days |
| Arm 4: Pegfilgrastim and TC | Time to ANC Nadir in Cycle 3 | 8.0 days |
Secondary
Time to ANC Nadir in Cycle 4
Time to ANC nadir was defined as the time from chemotherapy administration until the occurrence of the ANC nadir.
Time frame: Cycle 4 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to ANC Nadir in Cycle 4 | 8.0 days |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to ANC Nadir in Cycle 4 | 8.0 days |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to ANC Nadir in Cycle 4 | 8.0 days |
| Arm 4: Pegfilgrastim and TC | Time to ANC Nadir in Cycle 4 | 8.0 days |
Secondary
Time to ANC Recovery in Cycle 1
Time to ANC recovery was defined as the time from chemotherapy administration until ANC increased to ≥ 2×10\^9/L after the expected nadir within Cycle 1. Time to ANC recovery was not calculated for participants whose ANC value didn't drop below 2 x10\^9/L within Cycle 1.
Time frame: Cycle 1 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants with recovery in Cycle 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to ANC Recovery in Cycle 1 | 10.0 days |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to ANC Recovery in Cycle 1 | 8.5 days |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to ANC Recovery in Cycle 1 | 8.0 days |
| Arm 4: Pegfilgrastim and TC | Time to ANC Recovery in Cycle 1 | 9.0 days |
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.00295% CI: [1.1, 1.8]Log Rank
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.71195% CI: [0.6, 1.4]Log Rank
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.02895% CI: [0.1, 0.9]Log Rank
Secondary
Time to ANC Recovery in Cycle 2
Time to ANC recovery was defined as the time from chemotherapy administration until ANC increased to ≥2×10\^9/L after the expected nadir within Cycle 2. Time to ANC recovery was not calculated for participants whose ANC value didn't drop below 2 x10\^9/L within Cycle 2.
Time frame: Cycle 2 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants with recovery in Cycle 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to ANC Recovery in Cycle 2 | 11.0 days |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to ANC Recovery in Cycle 2 | 9.5 days |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to ANC Recovery in Cycle 2 | 10.0 days |
| Arm 4: Pegfilgrastim and TC | Time to ANC Recovery in Cycle 2 | 10.0 days |
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.67295% CI: [0.8, 1.4]Log Rank
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.34895% CI: [0.5, 1.3]Log Rank
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.97395% CI: [0.4, 2.9]Log Rank
Secondary
Time to ANC Recovery in Cycle 3
Time to ANC recovery was defined as the time from chemotherapy administration until ANC increased to ≥2×10\^9/L after the expected nadir within Cycle 3. Time to ANC recovery was not calculated for participants whose ANC value didn't drop below 2 x10\^9/L within Cycle 3.
Time frame: Cycle 3 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants with recovery in Cycle 3.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to ANC Recovery in Cycle 3 | 10.0 days |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to ANC Recovery in Cycle 3 | 9.5 days |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to ANC Recovery in Cycle 3 | 9.0 days |
| Arm 4: Pegfilgrastim and TC | Time to ANC Recovery in Cycle 3 | 10.0 days |
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.61895% CI: [0.8, 1.4]Log Rank
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.66195% CI: [0.5, 1.6]Log Rank
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.75495% CI: [0.3, 2.8]Log Rank
Secondary
Time to ANC Recovery in Cycle 4
Time to ANC recovery was defined as the time from chemotherapy administration until ANC increased to ≥2×10\^9/L after the expected nadir within Cycle 4. Time to ANC recovery was not calculated for participants whose ANC value didn't drop below 2 x10\^9/L within Cycle 4.
Time frame: Cycle 4 (each cycle was 21 days)
Population: The Evaluable Population included all randomized participants who had received either SPI-2012 or pegfilgrastim and had completed Cycle 1. Overall number of participants analyzed signifies the number of participants with recovery in Cycle 4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to ANC Recovery in Cycle 4 | 11.0 days |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to ANC Recovery in Cycle 4 | 10.0 days |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to ANC Recovery in Cycle 4 | 10.0 days |
| Arm 4: Pegfilgrastim and TC | Time to ANC Recovery in Cycle 4 | 10.0 days |
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.00995% CI: [1.1, 1.7]Log Rank
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.52795% CI: [0.7, 1.8]Log Rank
Comparison: A Cox proportional hazards model was used to estimate the hazard ratio and its two-sided 95% CI.p-value: 0.81595% CI: [0.4, 3.9]Log Rank
Secondary
Time to Reach Maximum Concentration of SPI-2012 (Tmax)
Blood samples were collected at specific time points to determine the serum concentrations of SPI-2012 and to derive pharmacokinetic (PK) parameters.
Time frame: Pre-dose and at 1, 3, 6, 8, 10, 24, 48, 72, 144, 192, and 312 hours post-dose in Cycle 1 (each cycle was 21 days)
Population: The PK Population included subset of participants who had received at least one dose of SPI-2012 in Arms 1 to 3 and have sufficient number of blood samples. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: SPI-2012 45 µg/kg and TC | Time to Reach Maximum Concentration of SPI-2012 (Tmax) | 58.7 hours (hrs) |
| Arm 2: SPI-2012 135 µg/kg and TC | Time to Reach Maximum Concentration of SPI-2012 (Tmax) | 9.00 hours (hrs) |
| Arm 3: SPI-2012 270 µg/kg and TC | Time to Reach Maximum Concentration of SPI-2012 (Tmax) | 24.0 hours (hrs) |