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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
5 μg/kg
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)
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
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
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Teva Investigational Site 12958
Long Beach, California, United States
Teva Investigational Site 12951
Los Angeles, California, United States
Teva Investigational Site 12954
Jackson, Mississippi, United States
Teva Investigational Site 12953
Las Vegas, Nevada, United States
Teva Investigational Site 12959
Valhalla, New York, United States
Teva Investigational Site 12960
Columbus, Ohio, United States
Teva Investigational Site 12957
Houston, Texas, United States
Teva Investigational Site 59104
Sofia, Bulgaria
Teva Investigational Site 59105
Varna, Bulgaria
Teva Investigational Site 60015
Rijeka, Croatia
...and 23 more locations
Time frame: Day 1 (start of tbo-filgrastim administration) up to Day 21
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
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)
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)
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
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)
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)
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)
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
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
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
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
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
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
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
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
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
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
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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