Phase 2 Study of SPI-2012 or Pegfilgrastim for the Management of Neutropenia in Participants With Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase 2, Open-Label, Dose-Ranging Study of SPI-2012 (HM10460A) or Pegfilgrastim Use for the Management of Neutropenia in Patients With Breast Cancer Who Are Candidates for Adjuvant and Neoadjuvant Chemotherapy With the Docetaxel + Cyclophosphamide (TC) Regimen

Conditions
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Neutropenia

Intervention / Treatment
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* Drug: SPI-2012
* Drug: Pegfilgrastim
* Drug: Docetaxel
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: SPI-2012 45 µg/kg and Docetaxel + Cyclophosphamide (TC)<br>Participants received SPI-2012 45 microgram/kilogram (µg/kg), subcutaneously (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 milligram/ square metre (mg/m^2) intravenous (IV) infusion over 60 minutes and Cyclophosphamide 600 mg/m^2 IV infusion over 30-60 minutes. | Drug: SPI-2012<br>* SPI-2012 SC injection.<br>* Other names: Eflapegrastim;Drug: Docetaxel<br>* Docetaxel given based on standard dose for chemotherapy.<br>* Other names: Taxotere;Drug: Cyclophosphamide<br>* Cyclophosphamide given based on standard dose for chemotherapy.<br>* Other names: Cytoxan;|
| Experimental: Arm 2: SPI-2012 135 µg/kg and Docetaxel + Cyclophosphamide (TC)<br>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 intravenous (IV) infusion over 60 minutes and Cyclophosphamide 600 mg/m^2 IV infusion over 30-60 minutes. | Drug: SPI-2012<br>* SPI-2012 SC injection.<br>* Other names: Eflapegrastim;Drug: Docetaxel<br>* Docetaxel given based on standard dose for chemotherapy.<br>* Other names: Taxotere;Drug: Cyclophosphamide<br>* Cyclophosphamide given based on standard dose for chemotherapy.<br>* Other names: Cytoxan;|
| Experimental: Arm 3: SPI-2012 270 µg/kg and Docetaxel + Cyclophosphamide (TC)<br>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 intravenous (IV) infusion over 60 minutes and Cyclophosphamide 600 mg/m^2 IV infusion over 30-60 minutes. | Drug: SPI-2012<br>* SPI-2012 SC injection.<br>* Other names: Eflapegrastim;Drug: Docetaxel<br>* Docetaxel given based on standard dose for chemotherapy.<br>* Other names: Taxotere;Drug: Cyclophosphamide<br>* Cyclophosphamide given based on standard dose for chemotherapy.<br>* Other names: Cytoxan;|
| Experimental: Arm 4: Pegfilgrastim and Docetaxel + Cyclophosphamide (TC)<br>Participants received Pegfilgrastim 6 milligram (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 intravenous (IV) infusion over 60 minutes and Cyclophosphamide 600 mg/m^2 IV infusion over 30-60 minutes. | Drug: Pegfilgrastim<br>* Pegfilgrastim SC injection, per manufacturer's Prescribing Information.<br>* Other names: Neulasta®;Drug: Docetaxel<br>* Docetaxel given based on standard dose for chemotherapy.<br>* Other names: Taxotere;Drug: Cyclophosphamide<br>* Cyclophosphamide given based on standard dose for chemotherapy.<br>* Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 (each cycle was 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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.. | 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. | 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 |  | 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. | 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. | 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. | 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. | 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. | 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) |