Neutropenia
Conditions
Keywords
Neutropenia
Brief summary
The purpose of the study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of daily subcutaneous administration of 5 μg/kg tbo-filgrastim in infants, children and adolescents with solid tumors without bone marrow involvement.
Interventions
DRUGtbo-filgrastim
5 μg/kg
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to 16 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: 1. Male or female infants, children and adolescents aged 1 month to \<16 years. 2. Patients with solid tumors without bone marrow involvement, who are scheduled to receive myelosuppressive CTX. 3. Body weight ≥5 kg. 4. Patients must have an initial diagnosis and histologic proof of their malignancy. All enrolled subjects should have signed consent for a CTX regimen that is known to be myelotoxic, with counts expected to drop below the absolute neutrophil count (ANC) of 0.5 × 109/L for at least 3 days. These regimens would include at least one of the following: * Etoposide * doxorubicin * ifosfamide * cyclophosphamide 5. ANC and platelet count: Patients must have an ANC \>1 × 109/L and a platelet count \>100 × 109/L to be eligible for therapy at the start of CTX. 6. Normal cardiac, renal, and hepatic function. 7. All subjects must have a life expectancy of 12 weeks or more. 8. Performance Status: Lansky performance score \>60 (age 1 to \<16 years). * More criteria may apply, please contact the investigator for more information. Exclusion: 1. Bone marrow involvement. 2. Active myelogenous leukemia or history of myelogenous leukemia. 3. Previous treatment with colony-stimulating factors (granulocyte colony-stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor, interleukin 11 \[IL-11\]) less than 6 weeks prior to study entry. 4. History of congenital neutropenia or cyclic neutropenia. 5. Pregnant or nursing female patients. 6. Fertile patients who do not agree to use highly reliable contraceptive measures Prior bone marrow or stem cell transplant, or prior radiation to ≥25% of bone marrow within the 4 weeks prior to the first tbo-filgrastim dose. 7. Ongoing active infection or history of infectious disease within 2 weeks prior to the screening visit. 8. Treatment with lithium at screening or planned during the study * More criteria may apply, please contact the investigator for more information.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Adverse Events (AEs) | Non-TEAE: signing of informed consent to Day -1 (last day of CTX in week 1). And > 30 days after last dose of tbo-filgrastim (Day 46+). TEAE timeframe: Day 1 (start of tbo-filgrastim) to <= 30 days after the last dose (up to Day 45) | An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. A treatment-emergent AE (TEAE) is an AE occurring during the timeframe. A non-TEAE is any AE not considered a TEAE. Severity was rated by the investigator using the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale where 3=severe but not life-threatening, 4=life-threatening and 5=death. Relation of AE to treatment was determined by the investigator (related=reasonable possibility). Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. |
| Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | Day 1 (start of tbo-filgrastim administration) up to Day 21 | Serum chemistry tests included alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin, indirect bilirubin, total bilirubin, calcium, creatinine, gammaglutamyl transpeptidase (GGT), glucose, potassium, lactate dehydrogenase (LDH), phosphate, sodium and uric acid. Only tests with potentially clinically significant abnormal results are reported. ULN = upper limit of normal |
| Participants With Potentially Clinically Significant Abnormal Hematology Results | Day 1 (start of tbo-filgrastim administration) up to Day 21 | Hematology tests included Basophils ABS (x 10\^9/L), Basophils (%), Eosinophils ABS (x 10\^9/L), Eosinophils (%), Hematocrit (%), Hemoglobin (g/L), Lymphocytes Absolute Count (ABS) (x 10\^9/L), Lymphocytes (%), Monocytes ABS (x 10\^9/L), Monocytes (%), Neutrophils ABS (x 10\^9/L), Neutrophils (%), Platelets (x 10\^9/L), Red Blood Cell (RBC) (x 10\^12/L), White Blood Cell (WBC) (x 10\^9/L). Only tests with potentially clinically significant abnormal results are reported. ULN = upper limit of normal |
| Participants With Potentially Clinically Significant Abnormal Vital Signs | Day 1 (start of tbo-filgrastim administration) up to Day 21 | Vital sign tests included Pulse Rate (bpm), Systolic BP (mmHg), Diastolic BP (mmHg), Respiratory Rate (bpm), and Temperature (°C). Only tests with potentially clinically significant abnormal results are reported. |
| Participants With Potentially Clinically Significant Abnormal Electrocardiogram Results | Day 1 (start of tbo-filgrastim administration) pre-dose, 4 hours post dose and 6 hours post dose; Day 21 (end of study visit) | Triplicate 12-lead ECGs were conducted at screening, predose, 4 and 6 hours postdose on day 1 of tbo-filgrastim administration, and at the end-of-study visit. The ECGs were interpreted by both the investigator and a qualified physician at the central diagnostic center as normal, abnormal not clinically significant, or abnormal clinically significant. The following parameters were measured/derived for each ECG assessment: heart rate, PR interval, RR interval, QT interval, corrected QT interval according to Fridericia's formula (QTcF), corrected QT interval according to Bazett's formula (QTcB), QRS duration, and QRS axis. The count of participants with potentially clinically significant ECG findings is reported. |
| Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Baseline: Day -21, Day 21 (end of study visit) | Physical examination was performed at screening and at the end-of-study visit. The following body systems were marked as normal or abnormal and if abnormal, whether clinically significant: Head, ears, eyes, nose and throat (HEENT), chest and lungs, heart, abdomen, skin, lymph nodes and neurological. Any physical examination finding that is judged by the investigator as a clinically significant change (worsening) compared with a baseline value were considered as an adverse event. Counts of participants with a negative shift from baseline in any of the body systems (including shifts from normal to abnormal, not clinically significant) are presented. |
| Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Day 1 (start of tbo-filgrastim administration) up to Day 14 | Using Local Tolerability Assessment Scale ranging from Pain severity 0 (Absent) to 3 (Spontaneously painful) |
| Participants With Negative Shifts From Baseline to End of Study in Spleen Sonography Findings | Baseline: Day -21, Day 21 (end of study visit) | The investigator assessed spleen sonography findings as normal, abnormal not clinically significant, or abnormal clinically significant. Data representing counts of participants with a negative shift from baseline in spleen sonography findings (including shifts from normal to abnormal, not clinically significant) are presented. |
| Participants Who Were Alive at the 90 Day Follow-Up | 90 days post end of study visit (111 days from start of tbo-filgrastim administration) | Summary of participant survival at 90 day follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of the AUC0-∞ That Is Due To the Extrapolation (%AUCext) | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
| Terminal Elimination Rate (Lambda-z) | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
| Participants With Severe Neutropenia | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | Count of participants who had an incidence of severe neutropenia, defined as any value of absolute neutrophil count (ANC) \<0.5 \* 10\^9/L at any time. |
| Duration of Severe Neutropenia | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | The duration of severe neutropenia was derived by counting the number of days with absolute neutrophil count (ANC) values \<0.5 \* 10\^9/L. |
| Area Under The Serum Drug Concentration By Time Curve Of Absolute Neutrophil Count (AUC ANC) | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Absolute Neutrophil Count (ANC) Nadir | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | ANC nadir (measured in 10\^9/L) is the lowest ANC recorded. |
| Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Tbo-filgrastim Administration | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | Baseline (Day -21), Day 21 (end of study visit), Day 51 (30 Day follow-up) and Day 111 (90 Day follow-up) | Blood was drawn for the assessment of anti-drug antibody (ADA) at screening, at the end-of-study visit, and at 30 and 90 days after the last administration of tbo-filgrastim in chemotherapy (CTX) cycle 1. The main endpoint from the assessment was the presence of antibodies in the sample, reported as positive or negative. Participants with positive results are summarized. |
| Time to ANC Recovery To ≥1.0 * 10^9/L From ANC Nadir | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Time to ANC Recovery To ≥2.0 * 10^9/L From ANC Nadir | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Tbo-filgrastim Administration | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Tbo-filgrastim Administration | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Chemotherapy | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Chemotherapy | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Participants With Febrile Neutropenia During the First Cycle of Chemotherapy | (relative to tbo-filgrastim therapy) Days -7 to Day 14 | Febrile neutropenia was defined as an axillary or external ear temperature \>38.3°C (100.94°F) or 2 consecutive readings \>37.8°C (100.04°F) at least 2 hours apart and an ANC \<0.5 \* 10\^9/L. The efficacy variable was evaluated for up to 21 days from the start of the first cycle of chemotherapy. |
| Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Chemotherapy | ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21) | — |
| Maximum Observed Serum Concentration (Cmax) of Tbo-Filgrastim | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
| Time to Maximum Observed Serum Concentration (Tmax) of Tbo-Filgrastim | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
| Area Under The Serum Concentration-Time Curve From Time 0 To Time Of Last Quantifiable Concentration (AUClast) | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
| Area Under The Serum Concentration-Time Curve From Time 0 To 12 Hours Postdose (AUC0-12) | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
| AUC From Time 0 to Infinity (AUC0-inf) | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
| Elimination Half-life (t1/2) | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
| Apparent Clearance (CL/F) | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose of Day 1 | — |
| Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1 | — |
Countries
Bulgaria, Croatia, Hungary, Poland, Romania, Russia, Ukraine, United States
Participant flow
Recruitment details
A total of 55 patients were screened for this study. Of the 55 patients screened, 50 patients at 33 investigational centers in Central and Eastern Europe met inclusion/exclusion criteria and were considered to be eligible for enrollment into the study.
Pre-assignment details
Of the 5 patients who were not enrolled, 2 patients were excluded due to inclusion criteria not met (baseline AST elevation, baseline ANC count was too low), 2 patients were excluded due to exclusion criteria not met (ongoing active infection or history of infectious disease within 2 weeks prior to screening), and 1 patient withdrew consent.
Participants by arm
| Arm | Count |
|---|---|
| Infants (1 Month to <2 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10\^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle. | 2 |
| Children (2 to <12 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10\^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle. | 30 |
| Adolescents (12 to <16 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10\^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle. | 18 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Patient was out of the city | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Children (2 to <12 Years) | Total | Infants (1 Month to <2 Years) | Adolescents (12 to <16 Years) |
|---|---|---|---|---|
| Age, Continuous | 6.80 Years | 9.05 Years | 1.65 Years | 13.80 Years |
| Body Mass Index | 15.2 kg/m^2 | 16.4 kg/m^2 | 16.0 kg/m^2 | 20.7 kg/m^2 |
| Chemotherapy Administration Mild | 6 Participants | 14 Participants | 0 Participants | 8 Participants |
| Chemotherapy Administration Moderate | 16 Participants | 25 Participants | 2 Participants | 7 Participants |
| Chemotherapy Administration Severe | 8 Participants | 11 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 50 Participants | 2 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 121.00 cm | 130.50 cm | 78.00 cm | 161.00 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 50 Participants | 2 Participants | 18 Participants |
| Sex: Female, Male Female | 13 Participants | 20 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 17 Participants | 30 Participants | 1 Participants | 12 Participants |
| Weight | 20.25 kg | 28.95 kg | 9.90 kg | 53.90 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 30 | 0 / 18 |
| other Total, other adverse events | 2 / 2 | 27 / 30 | 15 / 18 |
| serious Total, serious adverse events | 0 / 2 | 9 / 30 | 3 / 18 |
Outcome results
Primary
Participants Who Were Alive at the 90 Day Follow-Up
Summary of participant survival at 90 day follow-up.
Time frame: 90 days post end of study visit (111 days from start of tbo-filgrastim administration)
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infants (1 Month to <2 Years) | Participants Who Were Alive at the 90 Day Follow-Up | 2 Participants |
| Children (2 to <12 Years) | Participants Who Were Alive at the 90 Day Follow-Up | 30 Participants |
| Adolescents (12 to <16 Years) | Participants Who Were Alive at the 90 Day Follow-Up | 18 Participants |
Primary
Participants With Adverse Events (AEs)
An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. A treatment-emergent AE (TEAE) is an AE occurring during the timeframe. A non-TEAE is any AE not considered a TEAE. Severity was rated by the investigator using the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale where 3=severe but not life-threatening, 4=life-threatening and 5=death. Relation of AE to treatment was determined by the investigator (related=reasonable possibility). Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time frame: Non-TEAE: signing of informed consent to Day -1 (last day of CTX in week 1). And > 30 days after last dose of tbo-filgrastim (Day 46+). TEAE timeframe: Day 1 (start of tbo-filgrastim) to <= 30 days after the last dose (up to Day 45)
Population: Safety analysis set. The safety analysis set included all enrolled patients who received at least 1 dose of tbofilgrastim.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any adverse event | 2 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any TEAE | 2 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any non-TEAE | 2 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any TEAE with NCI-CTCAE ToxicityGrade >=3 | 2 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any trt-related TEAE with Toxicity Grade >=3 | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any serious TEAE | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any serious treatment-related TEAE | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any TEAE leading to discontinuation | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE leading to discont | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any TEAE leading to death | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE leading to death | 0 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE leading to death | 0 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any adverse event | 28 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any serious TEAE | 9 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any TEAE leading to discontinuation | 0 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any TEAE | 28 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any trt-related TEAE with Toxicity Grade >=3 | 1 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any TEAE leading to death | 0 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any non-TEAE | 15 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any serious treatment-related TEAE | 1 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any TEAE with NCI-CTCAE ToxicityGrade >=3 | 18 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE | 4 Participants |
| Children (2 to <12 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE leading to discont | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE | 5 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any TEAE with NCI-CTCAE ToxicityGrade >=3 | 8 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE leading to discont | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any trt-related TEAE with Toxicity Grade >=3 | 2 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any serious TEAE | 3 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any serious treatment-related TEAE | 1 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any TEAE leading to death | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any adverse event | 16 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any TEAE | 15 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any TEAE leading to discontinuation | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any non-TEAE | 9 Participants |
| Adolescents (12 to <16 Years) | Participants With Adverse Events (AEs) | Any treatment-related TEAE leading to death | 0 Participants |
Primary
Participants With Injection Site Reactions to Tbo-Filgrastim Administration
Using Local Tolerability Assessment Scale ranging from Pain severity 0 (Absent) to 3 (Spontaneously painful)
Time frame: Day 1 (start of tbo-filgrastim administration) up to Day 14
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Surface ecchymosis | 2 Participants |
| Infants (1 Month to <2 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Surface erythema/redness | 2 Participants |
| Infants (1 Month to <2 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Induration | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Pain at the injection site | 0 Participants |
| Children (2 to <12 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Pain at the injection site | 0 Participants |
| Children (2 to <12 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Surface ecchymosis | 7 Participants |
| Children (2 to <12 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Induration | 1 Participants |
| Children (2 to <12 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Surface erythema/redness | 2 Participants |
| Adolescents (12 to <16 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Pain at the injection site | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Surface erythema/redness | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Induration | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Injection Site Reactions to Tbo-Filgrastim Administration | Surface ecchymosis | 2 Participants |
Primary
Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings
Physical examination was performed at screening and at the end-of-study visit. The following body systems were marked as normal or abnormal and if abnormal, whether clinically significant: Head, ears, eyes, nose and throat (HEENT), chest and lungs, heart, abdomen, skin, lymph nodes and neurological. Any physical examination finding that is judged by the investigator as a clinically significant change (worsening) compared with a baseline value were considered as an adverse event. Counts of participants with a negative shift from baseline in any of the body systems (including shifts from normal to abnormal, not clinically significant) are presented.
Time frame: Baseline: Day -21, Day 21 (end of study visit)
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Chest and lungs | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Skin | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Abdomen | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | HEENT | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Neurological | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Lymph nodes | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Heart | 0 Participants |
| Children (2 to <12 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Abdomen | 0 Participants |
| Children (2 to <12 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | HEENT | 0 Participants |
| Children (2 to <12 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Chest and lungs | 0 Participants |
| Children (2 to <12 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Heart | 0 Participants |
| Children (2 to <12 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Skin | 1 Participants |
| Children (2 to <12 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Lymph nodes | 0 Participants |
| Children (2 to <12 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Neurological | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Skin | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Chest and lungs | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Neurological | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Lymph nodes | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Abdomen | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | Heart | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings | HEENT | 0 Participants |
Primary
Participants With Negative Shifts From Baseline to End of Study in Spleen Sonography Findings
The investigator assessed spleen sonography findings as normal, abnormal not clinically significant, or abnormal clinically significant. Data representing counts of participants with a negative shift from baseline in spleen sonography findings (including shifts from normal to abnormal, not clinically significant) are presented.
Time frame: Baseline: Day -21, Day 21 (end of study visit)
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Negative Shifts From Baseline to End of Study in Spleen Sonography Findings | 0 Participants |
| Children (2 to <12 Years) | Participants With Negative Shifts From Baseline to End of Study in Spleen Sonography Findings | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Negative Shifts From Baseline to End of Study in Spleen Sonography Findings | 0 Participants |
Primary
Participants With Potentially Clinically Significant Abnormal Electrocardiogram Results
Triplicate 12-lead ECGs were conducted at screening, predose, 4 and 6 hours postdose on day 1 of tbo-filgrastim administration, and at the end-of-study visit. The ECGs were interpreted by both the investigator and a qualified physician at the central diagnostic center as normal, abnormal not clinically significant, or abnormal clinically significant. The following parameters were measured/derived for each ECG assessment: heart rate, PR interval, RR interval, QT interval, corrected QT interval according to Fridericia's formula (QTcF), corrected QT interval according to Bazett's formula (QTcB), QRS duration, and QRS axis. The count of participants with potentially clinically significant ECG findings is reported.
Time frame: Day 1 (start of tbo-filgrastim administration) pre-dose, 4 hours post dose and 6 hours post dose; Day 21 (end of study visit)
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Electrocardiogram Results | 0 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Electrocardiogram Results | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Electrocardiogram Results | 0 Participants |
Primary
Participants With Potentially Clinically Significant Abnormal Hematology Results
Hematology tests included Basophils ABS (x 10\^9/L), Basophils (%), Eosinophils ABS (x 10\^9/L), Eosinophils (%), Hematocrit (%), Hemoglobin (g/L), Lymphocytes Absolute Count (ABS) (x 10\^9/L), Lymphocytes (%), Monocytes ABS (x 10\^9/L), Monocytes (%), Neutrophils ABS (x 10\^9/L), Neutrophils (%), Platelets (x 10\^9/L), Red Blood Cell (RBC) (x 10\^12/L), White Blood Cell (WBC) (x 10\^9/L). Only tests with potentially clinically significant abnormal results are reported. ULN = upper limit of normal
Time frame: Day 1 (start of tbo-filgrastim administration) up to Day 21
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Lymphocytes ABS (x 10^9/L): >=0.2 and <0.5 | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | White Blood Cell (WBC) (x 10^9/L):>=1 and <2 | 1 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Neutrophils ABS (x 10^9/L): >=0.5 and <1.0 | 1 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Neutrophils ABS (x 10^9/L): <0.5 | 1 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Participants with >=1 abnormality | 2 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | White Blood Cell (WBC) (x 10^9/L):<1.0 | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Hemoglobin (g/L): increase of >40 *ULN or baseline | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Hemoglobin (g/L): <80 | 1 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Platelets (x 10^9/L): >=25 and <50 | 0 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Neutrophils ABS (x 10^9/L): <0.5 | 1 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Participants with >=1 abnormality | 6 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Hemoglobin (g/L): <80 | 2 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Hemoglobin (g/L): increase of >40 *ULN or baseline | 0 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Lymphocytes ABS (x 10^9/L): >=0.2 and <0.5 | 3 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Neutrophils ABS (x 10^9/L): >=0.5 and <1.0 | 1 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Platelets (x 10^9/L): >=25 and <50 | 1 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | White Blood Cell (WBC) (x 10^9/L):<1.0 | 1 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | White Blood Cell (WBC) (x 10^9/L):>=1 and <2 | 3 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Hemoglobin (g/L): increase of >40 *ULN or baseline | 1 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Participants with >=1 abnormality | 3 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Platelets (x 10^9/L): >=25 and <50 | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Hemoglobin (g/L): <80 | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | White Blood Cell (WBC) (x 10^9/L):>=1 and <2 | 1 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Neutrophils ABS (x 10^9/L): <0.5 | 1 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Lymphocytes ABS (x 10^9/L): >=0.2 and <0.5 | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | White Blood Cell (WBC) (x 10^9/L):<1.0 | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Hematology Results | Neutrophils ABS (x 10^9/L): >=0.5 and <1.0 | 1 Participants |
Primary
Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results
Serum chemistry tests included alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin, indirect bilirubin, total bilirubin, calcium, creatinine, gammaglutamyl transpeptidase (GGT), glucose, potassium, lactate dehydrogenase (LDH), phosphate, sodium and uric acid. Only tests with potentially clinically significant abnormal results are reported. ULN = upper limit of normal
Time frame: Day 1 (start of tbo-filgrastim administration) up to Day 21
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | AST: >5 * ULN and <= 20 * ULN | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | AST: >20 * ULN | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | Participants with >=1 abnormality | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | ALT: >20 * ULN | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | GGT: >5 * ULN and <= 20 * ULN | 0 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | AST: >20 * ULN | 1 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | Participants with >=1 abnormality | 3 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | ALT: >20 * ULN | 1 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | AST: >5 * ULN and <= 20 * ULN | 0 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | GGT: >5 * ULN and <= 20 * ULN | 3 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | GGT: >5 * ULN and <= 20 * ULN | 1 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | AST: >5 * ULN and <= 20 * ULN | 1 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | Participants with >=1 abnormality | 1 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | AST: >20 * ULN | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | ALT: >20 * ULN | 1 Participants |
Primary
Participants With Potentially Clinically Significant Abnormal Vital Signs
Vital sign tests included Pulse Rate (bpm), Systolic BP (mmHg), Diastolic BP (mmHg), Respiratory Rate (bpm), and Temperature (°C). Only tests with potentially clinically significant abnormal results are reported.
Time frame: Day 1 (start of tbo-filgrastim administration) up to Day 21
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Systolic BP (mmHg): change of >=20mmHg | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Temperature (°C): >=38.0 °C | 1 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Diastolic BP (mmHg): change of >=15 mmHg | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Pulse Rate (bpm): change of >=15 bpm | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Participants with >=1 abnormality | 1 Participants |
| Infants (1 Month to <2 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Respiratory Rate (bpm): change of >=8 breaths/min | 0 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Participants with >=1 abnormality | 23 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Pulse Rate (bpm): change of >=15 bpm | 14 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Systolic BP (mmHg): change of >=20mmHg | 5 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Diastolic BP (mmHg): change of >=15 mmHg | 5 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Respiratory Rate (bpm): change of >=8 breaths/min | 5 Participants |
| Children (2 to <12 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Temperature (°C): >=38.0 °C | 14 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Pulse Rate (bpm): change of >=15 bpm | 9 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Temperature (°C): >=38.0 °C | 4 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Respiratory Rate (bpm): change of >=8 breaths/min | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Systolic BP (mmHg): change of >=20mmHg | 3 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Participants with >=1 abnormality | 11 Participants |
| Adolescents (12 to <16 Years) | Participants With Potentially Clinically Significant Abnormal Vital Signs | Diastolic BP (mmHg): change of >=15 mmHg | 5 Participants |
Secondary
Absolute Neutrophil Count (ANC) Nadir
ANC nadir (measured in 10\^9/L) is the lowest ANC recorded.
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Absolute Neutrophil Count (ANC) Nadir | 0.490 *10^9/L | Standard Deviation 0.4808 |
| Children (2 to <12 Years) | Absolute Neutrophil Count (ANC) Nadir | 0.851 *10^9/L | Standard Deviation 1.3633 |
| Adolescents (12 to <16 Years) | Absolute Neutrophil Count (ANC) Nadir | 0.832 *10^9/L | Standard Deviation 0.6358 |
Secondary
Apparent Clearance (CL/F)
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose of Day 1
Population: PK analysis set. The 12 hour sampling duration limited the ability to characterize the terminal elimination rate of tbo-filgrastim (λz ) and related parameters (t½, AUC0-∞,-∞ %AUCex, CL/F, and Vz/F) for more than half of patients enrolled, especially those with maximum serum concentrations being achieved \>= 6 hours. This included both infants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Children (2 to <12 Years) | Apparent Clearance (CL/F) | 0.98 L/hour | Standard Deviation 0.719 |
| Adolescents (12 to <16 Years) | Apparent Clearance (CL/F) | 1.68 L/hour | Standard Deviation 0.748 |
Secondary
Apparent Volume of Distribution During the Terminal Phase (Vz/F)
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: PK analysis set. The 12 hour sampling duration limited the ability to characterize the terminal elimination rate of tbo-filgrastim (λz ) and related parameters (t½, AUC0-∞,-∞ %AUCex, CL/F, and Vz/F) for more than half of patients enrolled, especially those with maximum serum concentrations being achieved \>= 6 hours. This included both infants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Children (2 to <12 Years) | Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 3.21 liters | Standard Deviation 1.963 |
| Adolescents (12 to <16 Years) | Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 6.13 liters | Standard Deviation 3.094 |
Secondary
Area Under The Serum Concentration-Time Curve From Time 0 To 12 Hours Postdose (AUC0-12)
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: PK analysis set. In 4 participants, serum concentrations of tbo-filgrastim were not obtained through 12 hours and as a result, AUC0-12 could not be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Area Under The Serum Concentration-Time Curve From Time 0 To 12 Hours Postdose (AUC0-12) | 187889.69 hr*pg/mL | Standard Deviation 80122.148 |
| Children (2 to <12 Years) | Area Under The Serum Concentration-Time Curve From Time 0 To 12 Hours Postdose (AUC0-12) | 144109.32 hr*pg/mL | Standard Deviation 63358.011 |
| Adolescents (12 to <16 Years) | Area Under The Serum Concentration-Time Curve From Time 0 To 12 Hours Postdose (AUC0-12) | 140550.22 hr*pg/mL | Standard Deviation 73648.629 |
Secondary
Area Under The Serum Concentration-Time Curve From Time 0 To Time Of Last Quantifiable Concentration (AUClast)
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Area Under The Serum Concentration-Time Curve From Time 0 To Time Of Last Quantifiable Concentration (AUClast) | 187889.69 hr*pg/mL | Standard Deviation 80122.148 |
| Children (2 to <12 Years) | Area Under The Serum Concentration-Time Curve From Time 0 To Time Of Last Quantifiable Concentration (AUClast) | 142124.91 hr*pg/mL | Standard Deviation 63127.42 |
| Adolescents (12 to <16 Years) | Area Under The Serum Concentration-Time Curve From Time 0 To Time Of Last Quantifiable Concentration (AUClast) | 127447.08 hr*pg/mL | Standard Deviation 73894.137 |
Secondary
Area Under The Serum Drug Concentration By Time Curve Of Absolute Neutrophil Count (AUC ANC)
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Area Under The Serum Drug Concentration By Time Curve Of Absolute Neutrophil Count (AUC ANC) | 20.465 *10^9/L * days | Standard Deviation 6.1235 |
| Children (2 to <12 Years) | Area Under The Serum Drug Concentration By Time Curve Of Absolute Neutrophil Count (AUC ANC) | 53.931 *10^9/L * days | Standard Deviation 44.8741 |
| Adolescents (12 to <16 Years) | Area Under The Serum Drug Concentration By Time Curve Of Absolute Neutrophil Count (AUC ANC) | 87.098 *10^9/L * days | Standard Deviation 61.1857 |
Secondary
AUC From Time 0 to Infinity (AUC0-inf)
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: PK analysis set. The 12 hour sampling duration limited the ability to characterize the terminal elimination rate of tbo-filgrastim (λz ) and related parameters (t½, AUC0-∞,-∞ %AUCex, CL/F, and Vz/F) for more than half of patients enrolled, especially those with maximum serum concentrations being achieved \>= 6 hours. This included both infants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Children (2 to <12 Years) | AUC From Time 0 to Infinity (AUC0-inf) | 161964.32 hr*pg/mL | Standard Deviation 87205.04 |
| Adolescents (12 to <16 Years) | AUC From Time 0 to Infinity (AUC0-inf) | 198470.33 hr*pg/mL | Standard Deviation 80773.023 |
Secondary
Duration of Severe Neutropenia
The duration of severe neutropenia was derived by counting the number of days with absolute neutrophil count (ANC) values \<0.5 \* 10\^9/L.
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Duration of Severe Neutropenia | 1.5 days | Standard Deviation 2.12 |
| Children (2 to <12 Years) | Duration of Severe Neutropenia | 2.5 days | Standard Deviation 2.46 |
| Adolescents (12 to <16 Years) | Duration of Severe Neutropenia | 0.7 days | Standard Deviation 1.14 |
Secondary
Elimination Half-life (t1/2)
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: PK analysis set. The 12 hour sampling duration limited the ability to characterize the terminal elimination rate of tbo-filgrastim (λz ) and related parameters (t½, AUC0-∞,-∞ %AUCex, CL/F, and Vz/F) for more than half of patients enrolled, especially those with maximum serum concentrations being achieved \>= 6 hours. This included both infants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Children (2 to <12 Years) | Elimination Half-life (t1/2) | 2.41 hours | Standard Deviation 0.549 |
| Adolescents (12 to <16 Years) | Elimination Half-life (t1/2) | 2.52 hours | Standard Deviation 0.561 |
Secondary
Maximum Observed Serum Concentration (Cmax) of Tbo-Filgrastim
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: Pharmacokinetic (PK) analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Maximum Observed Serum Concentration (Cmax) of Tbo-Filgrastim | 26087.95 pg/mL | Standard Deviation 8647.562 |
| Children (2 to <12 Years) | Maximum Observed Serum Concentration (Cmax) of Tbo-Filgrastim | 20048.27 pg/mL | Standard Deviation 9232.446 |
| Adolescents (12 to <16 Years) | Maximum Observed Serum Concentration (Cmax) of Tbo-Filgrastim | 19032.60 pg/mL | Standard Deviation 11086.273 |
Secondary
Participants With Febrile Neutropenia During the First Cycle of Chemotherapy
Febrile neutropenia was defined as an axillary or external ear temperature \>38.3°C (100.94°F) or 2 consecutive readings \>37.8°C (100.04°F) at least 2 hours apart and an ANC \<0.5 \* 10\^9/L. The efficacy variable was evaluated for up to 21 days from the start of the first cycle of chemotherapy.
Time frame: (relative to tbo-filgrastim therapy) Days -7 to Day 14
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Febrile Neutropenia During the First Cycle of Chemotherapy | Participants with event | 1 Participants |
| Infants (1 Month to <2 Years) | Participants With Febrile Neutropenia During the First Cycle of Chemotherapy | Participants without event | 1 Participants |
| Children (2 to <12 Years) | Participants With Febrile Neutropenia During the First Cycle of Chemotherapy | Participants with event | 9 Participants |
| Children (2 to <12 Years) | Participants With Febrile Neutropenia During the First Cycle of Chemotherapy | Participants without event | 21 Participants |
| Adolescents (12 to <16 Years) | Participants With Febrile Neutropenia During the First Cycle of Chemotherapy | Participants with event | 3 Participants |
| Adolescents (12 to <16 Years) | Participants With Febrile Neutropenia During the First Cycle of Chemotherapy | Participants without event | 15 Participants |
Secondary
Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints
Blood was drawn for the assessment of anti-drug antibody (ADA) at screening, at the end-of-study visit, and at 30 and 90 days after the last administration of tbo-filgrastim in chemotherapy (CTX) cycle 1. The main endpoint from the assessment was the presence of antibodies in the sample, reported as positive or negative. Participants with positive results are summarized.
Time frame: Baseline (Day -21), Day 21 (end of study visit), Day 51 (30 Day follow-up) and Day 111 (90 Day follow-up)
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | Screening | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | End of Study visit | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | 30 Day Follow-up | 0 Participants |
| Infants (1 Month to <2 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | 90 Day Follow-up | 0 Participants |
| Children (2 to <12 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | 90 Day Follow-up | 0 Participants |
| Children (2 to <12 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | Screening | 0 Participants |
| Children (2 to <12 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | 30 Day Follow-up | 0 Participants |
| Children (2 to <12 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | End of Study visit | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | 90 Day Follow-up | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | End of Study visit | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | 30 Day Follow-up | 0 Participants |
| Adolescents (12 to <16 Years) | Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints | Screening | 0 Participants |
Secondary
Participants With Severe Neutropenia
Count of participants who had an incidence of severe neutropenia, defined as any value of absolute neutrophil count (ANC) \<0.5 \* 10\^9/L at any time.
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: The Full Analysis Set (FAS) included all patients in the ITT population who received at least 1 dose of tbo-filgrastim and had at least 1 post baseline efficacy assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Participants With Severe Neutropenia | Participants with event | 1 Participants |
| Infants (1 Month to <2 Years) | Participants With Severe Neutropenia | Participants without event | 1 Participants |
| Children (2 to <12 Years) | Participants With Severe Neutropenia | Participants with event | 19 Participants |
| Children (2 to <12 Years) | Participants With Severe Neutropenia | Participants without event | 11 Participants |
| Adolescents (12 to <16 Years) | Participants With Severe Neutropenia | Participants with event | 6 Participants |
| Adolescents (12 to <16 Years) | Participants With Severe Neutropenia | Participants without event | 12 Participants |
Secondary
Percentage of the AUC0-∞ That Is Due To the Extrapolation (%AUCext)
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: PK analysis set. The 12 hour sampling duration limited the ability to characterize the terminal elimination rate of tbo-filgrastim (λz ) and related parameters (t½, AUC0-∞,-∞ %AUCex, CL/F, and Vz/F) for more than half of patients enrolled, especially those with maximum serum concentrations being achieved \>= 6 hours. This included both infants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Children (2 to <12 Years) | Percentage of the AUC0-∞ That Is Due To the Extrapolation (%AUCext) | 7.97 percent of AUC0-∞ | Standard Deviation 4.179 |
| Adolescents (12 to <16 Years) | Percentage of the AUC0-∞ That Is Due To the Extrapolation (%AUCext) | 8.19 percent of AUC0-∞ | Standard Deviation 4.424 |
Secondary
Terminal Elimination Rate (Lambda-z)
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: PK analysis set. The 12 hour sampling duration limited the ability to characterize the terminal elimination rate of tbo-filgrastim (λz ) and related parameters (t½, AUC0-∞,-∞ %AUCex, CL/F, and Vz/F) for more than half of patients enrolled, especially those with maximum serum concentrations being achieved \>= 6 hours. This included both infants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Children (2 to <12 Years) | Terminal Elimination Rate (Lambda-z) | .30 1/hr | Standard Deviation 0.077 |
| Adolescents (12 to <16 Years) | Terminal Elimination Rate (Lambda-z) | .29 1/hr | Standard Deviation 0.067 |
Secondary
Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Chemotherapy
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Chemotherapy | 6.5 days | Standard Deviation 2.12 |
| Children (2 to <12 Years) | Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Chemotherapy | 10.3 days | Standard Deviation 2.86 |
| Adolescents (12 to <16 Years) | Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Chemotherapy | 11.2 days | Standard Deviation 2.31 |
Secondary
Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Tbo-filgrastim Administration
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Tbo-filgrastim Administration | 3.0 days | Standard Deviation 4.24 |
| Children (2 to <12 Years) | Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Tbo-filgrastim Administration | 6.9 days | Standard Deviation 2.55 |
| Adolescents (12 to <16 Years) | Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Tbo-filgrastim Administration | 7.3 days | Standard Deviation 2.72 |
Secondary
Time to ANC Recovery To ≥1.0 * 10^9/L From ANC Nadir
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From ANC Nadir | 10.0 days | Standard Deviation 7.07 |
| Children (2 to <12 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From ANC Nadir | 2.2 days | Standard Deviation 2.02 |
| Adolescents (12 to <16 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From ANC Nadir | 1.0 days | Standard Deviation 1.19 |
Secondary
Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Chemotherapy
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Chemotherapy | 16.5 days | Standard Deviation 4.95 |
| Children (2 to <12 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Chemotherapy | 10.2 days | Standard Deviation 5.98 |
| Adolescents (12 to <16 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Chemotherapy | 7.4 days | Standard Deviation 7.09 |
Secondary
Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Tbo-filgrastim Administration
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Tbo-filgrastim Administration | 13.0 days | Standard Deviation 2.83 |
| Children (2 to <12 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Tbo-filgrastim Administration | 7.3 days | Standard Deviation 4.43 |
| Adolescents (12 to <16 Years) | Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Tbo-filgrastim Administration | 5.1 days | Standard Deviation 5.3 |
Secondary
Time to ANC Recovery To ≥2.0 * 10^9/L From ANC Nadir
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From ANC Nadir | 13.0 days | Standard Deviation 2.83 |
| Children (2 to <12 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From ANC Nadir | 3.0 days | Standard Deviation 3.09 |
| Adolescents (12 to <16 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From ANC Nadir | 2.8 days | Standard Deviation 2.09 |
Secondary
Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Chemotherapy
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Chemotherapy | 19.5 days | Standard Deviation 0.71 |
| Children (2 to <12 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Chemotherapy | 11.0 days | Standard Deviation 6.52 |
| Adolescents (12 to <16 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Chemotherapy | 14.0 days | Standard Deviation 3.73 |
Secondary
Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Tbo-filgrastim Administration
Time frame: ANC blood samples collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, 15 and at the end of study visit (up to Day 21)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infants (1 Month to <2 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Tbo-filgrastim Administration | 16.0 days | Standard Deviation 1.41 |
| Children (2 to <12 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Tbo-filgrastim Administration | 8.1 days | Standard Deviation 5.2 |
| Adolescents (12 to <16 Years) | Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Tbo-filgrastim Administration | 10.2 days | Standard Deviation 4.22 |
Secondary
Time to Maximum Observed Serum Concentration (Tmax) of Tbo-Filgrastim
Time frame: Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
Population: PK analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infants (1 Month to <2 Years) | Time to Maximum Observed Serum Concentration (Tmax) of Tbo-Filgrastim | 6.00 Hours |
| Children (2 to <12 Years) | Time to Maximum Observed Serum Concentration (Tmax) of Tbo-Filgrastim | 4.07 Hours |
| Adolescents (12 to <16 Years) | Time to Maximum Observed Serum Concentration (Tmax) of Tbo-Filgrastim | 4.00 Hours |