A Study to Evaluate 5 μg/kg Tbo-filgrastim in Infants, Children and Adolescents With Solid Tumors Without Bone Marrow Involvement

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Efficacy, and Immunogenicity of Daily Subcutaneous Administration of 5 ?g/kg Tbo-filgrastim in Infants, Children and Adolescents With Solid Tumors Without Bone Marrow Involvement

Conditions
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Neutropenia

Intervention / Treatment
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* Drug: tbo-filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion: Male or female infants, children and adolescents aged 1 month to <16 years. Patients with solid tumors without bone marrow involvement, who are scheduled to receive myelosuppressive CTX. Body weight ≥5 kg. 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 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. Normal cardiac, renal, and hepatic function. All subjects must have a life expectancy of 12 weeks or more. Performance Status: Lansky performance score >60 (age 1 to <16 years). More criteria may apply, please contact the investigator for more information. Exclusion: Bone marrow involvement. Active myelogenous leukemia or history of myelogenous leukemia. 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. History of congenital neutropenia or cyclic neutropenia. Pregnant or nursing female patients. 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. Ongoing active infection or history of infectious disease within 2 weeks prior to the screening visit. Treatment with lithium at screening or planned during the study More criteria may apply, please contact the investigator for more information.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 16 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tbo-filgrastim<br>Patients will receive subcutaneous doses of tbo-filgrastim 5 μg/kg body weight daily; each daily dose, to be administered at the investigative site | Drug: tbo-filgrastim<br>* 5 μg/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 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 | 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. | 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. | 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. | 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) | 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. | 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. | 90 days post end of study visit (111 days from start of tbo-filgrastim administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 |  | 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 | 
| 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 | 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. | 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. | 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) |  | 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. | 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 |  | 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 |  | 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 |  | 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 | 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. | (relative to tbo-filgrastim therapy) Days -7 to Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neutropenia