A Study to Evaluate 5 μg/kg Tbo-filgrastim in Infants, Children and Adolescents With Solid Tumors Without Bone Marrow Involvement
- Registration Number
- NCT02190721
- Lead Sponsor
- Teva Branded Pharmaceutical Products R&D, Inc.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 50
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description tbo-filgrastim tbo-filgrastim Patients will receive subcutaneous doses of tbo-filgrastim 5 μg/kg body weight daily; each daily dose, to be administered at the investigative site
- Primary Outcome Measures
Name Time Method 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 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 normalParticipants 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 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 normalParticipants 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 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.
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 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)
- Secondary Outcome Measures
Name Time Method 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 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 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 ≥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) 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 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 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) 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) 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 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 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.
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 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 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 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 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 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.
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 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 ≥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) 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)
Trial Locations
- Locations (33)
Teva Investigational Site 52063
🇷🇴Bucharest, Romania
Teva Investigational Site 12957
🇺🇸Houston, Texas, United States
Teva Investigational Site 51186
🇭🇺Budapest, Hungary
Teva Investigational Site 12960
🇺🇸Columbus, Ohio, United States
Teva Investigational Site 12953
🇺🇸Las Vegas, Nevada, United States
Teva Investigational Site 12954
🇺🇸Jackson, Mississippi, United States
Teva Investigational Site 53246
🇵🇱Warszawa, Poland
Teva Investigational Site 52064
🇷🇴Cluj-Napoca, Cluj, Romania
Teva Investigational Site 50282
🇷🇺Chelyabinsk, Russian Federation
Teva Investigational Site 58147
🇺🇦Kharkiv, Ukraine
Teva Investigational Site 51185
🇭🇺Budapest, Hungary
Teva Investigational Site 58146
🇺🇦Vinnytsya, Ukraine
Teva Investigational Site 60014
🇭🇷Zagreb, Croatia
Teva Investigational Site 52065
🇷🇴Timisoara, Romania
Teva Investigational Site 50280
🇷🇺St. Petersburg, Russian Federation
Teva Investigational Site 60016
🇭🇷Zagreb, Croatia
Teva Investigational Site 53247
🇵🇱Wroclaw, Poland
Teva Investigational Site 51184
🇭🇺Szeged, Hungary
Teva Investigational Site 53249
🇵🇱Gdansk, Poland
Teva Investigational Site 58145
🇺🇦Kyiv, Ukraine
Teva Investigational Site 50284
🇷🇺Moscow, Russian Federation
Teva Investigational Site 53248
🇵🇱Lublin, Poland
Teva Investigational Site 53245
🇵🇱Warszawa, Poland
Teva Investigational Site 12951
🇺🇸Los Angeles, California, United States
Teva Investigational Site 12959
🇺🇸Valhalla, New York, United States
Teva Investigational Site 12958
🇺🇸Long Beach, California, United States
Teva Investigational Site 59104
🇧🇬Sofia, Bulgaria
Teva Investigational Site 59105
🇧🇬Varna, Bulgaria
Teva Investigational Site 60015
🇭🇷Rijeka, Croatia
Teva Investigational Site 58148
🇺🇦Lviv, Ukraine
Teva Investigational Site 50281
🇷🇺Krasnodar, Russian Federation
Teva Investigational Site 50283
🇷🇺Volgograd, Russian Federation
Teva Investigational Site 58149
🇺🇦Vinnytsya, Ukraine