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

Neutropenia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02190721
• Other study ID #: XM02-ONC-201
• Secondary ID: 2014-001772-55
• Status: Completed
• Phase: Phase 2
• Start date: May 12, 2015
• Est. completion date: April 4, 2017

Study information

• Verified date: December 2021
• Source: Teva Branded Pharmaceutical Products R&D, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: April 4, 2017
• Est. primary completion date: April 4, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 16 Years

Eligibility

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.

Related Conditions & MeSH terms

• Neutropenia

Intervention

Drug:
• tbo-filgrastim
5 µg/kg

Locations

Country	Name	City	State
Bulgaria	Teva Investigational Site 59104	Sofia
Bulgaria	Teva Investigational Site 59105	Varna
Croatia	Teva Investigational Site 60015	Rijeka
Croatia	Teva Investigational Site 60014	Zagreb
Croatia	Teva Investigational Site 60016	Zagreb
Hungary	Teva Investigational Site 51185	Budapest
Hungary	Teva Investigational Site 51186	Budapest
Hungary	Teva Investigational Site 51184	Szeged
Poland	Teva Investigational Site 53249	Gdansk
Poland	Teva Investigational Site 53248	Lublin
Poland	Teva Investigational Site 53245	Warszawa
Poland	Teva Investigational Site 53246	Warszawa
Poland	Teva Investigational Site 53247	Wroclaw
Romania	Teva Investigational Site 52063	Bucharest
Romania	Teva Investigational Site 52064	Cluj-Napoca, Cluj
Romania	Teva Investigational Site 52065	Timisoara
Russian Federation	Teva Investigational Site 50282	Chelyabinsk
Russian Federation	Teva Investigational Site 50281	Krasnodar
Russian Federation	Teva Investigational Site 50284	Moscow
Russian Federation	Teva Investigational Site 50280	St. Petersburg
Russian Federation	Teva Investigational Site 50283	Volgograd
Ukraine	Teva Investigational Site 58147	Kharkiv
Ukraine	Teva Investigational Site 58145	Kyiv
Ukraine	Teva Investigational Site 58148	Lviv
Ukraine	Teva Investigational Site 58146	Vinnytsya
Ukraine	Teva Investigational Site 58149	Vinnytsya
United States	Teva Investigational Site 12960	Columbus	Ohio
United States	Teva Investigational Site 12957	Houston	Texas
United States	Teva Investigational Site 12954	Jackson	Mississippi
United States	Teva Investigational Site 12953	Las Vegas	Nevada
United States	Teva Investigational Site 12958	Long Beach	California
United States	Teva Investigational Site 12951	Los Angeles	California
United States	Teva Investigational Site 12959	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
Teva Branded Pharmaceutical Products R&D, Inc.

Countries where clinical trial is conducted

United States,  Bulgaria,  Croatia,  Hungary,  Poland,  Romania,  Russian Federation,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	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)
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	Day 1 (start of tbo-filgrastim administration) up to Day 21
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	Day 1 (start of tbo-filgrastim administration) up to Day 21
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.	Day 1 (start of tbo-filgrastim administration) up to Day 21
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.	Day 1 (start of tbo-filgrastim administration) pre-dose, 4 hours post dose and 6 hours post dose; Day 21 (end of study visit)
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.	Baseline: Day -21, Day 21 (end of study visit)
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)	Day 1 (start of tbo-filgrastim administration) up to Day 14
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.	Baseline: Day -21, Day 21 (end of study visit)
Primary	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	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of the AUC0-8 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
Secondary	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
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.	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)
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.	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
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.	(relative to tbo-filgrastim therapy) Days -7 to Day 14