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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
148
SPI-2012 SC injection.
Pegfilgrastim SC injection, per manufacturer's Prescribing Information.
Docetaxel given based on standard dose for chemotherapy.
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)
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)
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)
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)
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)
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.
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Cyclophosphamide given based on standard dose for chemotherapy.
Arizona Center for Cancer Care
Glendale, Arizona, United States
Desert Springs Cancer Care
Scottsdale, Arizona, United States
California Cancer Associates for Research and Excellence
Fresno, California, United States
Beaver Medical Group
Highland, California, United States
California Cancer Associates for Research and Excellence
Los Angeles, California, United States
Innovative Clinical Research Institute
Whittier, California, United States
Kentucky Cancer Clinic
Hazard, Kentucky, United States
New York Oncology Hematology, PC
Albany, New York, United States
North Shore Hematology/Oncology Associates
Setauket, New York, United States
Good Samaritan Hospital, Corvallis
Corvallis, Oregon, United States
...and 17 more locations
Time frame: Cycle 2 (each cycle was 21 days)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)