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

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ClinicalTrials.gov Identifier: NCT02190721
Recruitment Status : Completed
First Posted : July 15, 2014
Results First Posted : July 31, 2018
Last Update Posted : July 31, 2018
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Pharmaceutical Industries, Ltd. )

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.

Condition or disease Intervention/treatment Phase
Neutropenia Drug: tbo-filgrastim Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 12, 2015
Actual Primary Completion Date : April 4, 2017
Actual Study Completion Date : April 4, 2017


Arm Intervention/treatment
Experimental: 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
Drug: tbo-filgrastim
5 μg/kg




Primary Outcome Measures :
  1. Participants With Adverse Events (AEs) [ 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) ]

    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.


  2. Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results [ Time Frame: 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


  3. Participants With Potentially Clinically Significant Abnormal Hematology Results [ Time Frame: 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


  4. Participants With Potentially Clinically Significant Abnormal Vital Signs [ Time Frame: 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.


  5. Participants With Potentially Clinically Significant Abnormal Electrocardiogram Results [ 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) ]

    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.


  6. Participants With Negative Shifts From Baseline to End of Study in Physical Exam Findings [ Time Frame: 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.


  7. Participants With Injection Site Reactions to Tbo-Filgrastim Administration [ Time Frame: 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)

  8. Participants With Negative Shifts From Baseline to End of Study in Spleen Sonography Findings [ Time Frame: 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.


  9. Participants Who Were Alive at the 90 Day Follow-Up [ Time Frame: 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 Outcome Measures :
  1. Participants With Positive Immunogenicity Findings Tested at Four Study Timepoints [ Time Frame: 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.


  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. Participants With Severe Neutropenia [ 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) ]
    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.

  13. Duration of Severe Neutropenia [ 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) ]
    The duration of severe neutropenia was derived by counting the number of days with absolute neutrophil count (ANC) values <0.5 * 10^9/L.

  14. 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) ]
  15. Absolute Neutrophil Count (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) ]
    ANC nadir (measured in 10^9/L) is the lowest ANC recorded.

  16. 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) ]
  17. 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) ]
  18. 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) ]
  19. 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) ]
  20. 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) ]
  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) ]
  22. 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) ]
  23. 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) ]
  24. Participants With Febrile Neutropenia During the First Cycle of Chemotherapy [ Time Frame: (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.



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 chemotherapy (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 × 10^9/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 × 10^9/L and a platelet count >100 × 10^9/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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02190721


  Show 33 Study Locations
Sponsors and Collaborators
Teva Pharmaceutical Industries, Ltd.
Investigators
Study Director: Teva Medical Expert, MD Teva Pharmaceuticals USA
  Study Documents (Full-Text)

Documents provided by Teva Pharmaceutical Industries ( Teva Pharmaceutical Industries, Ltd. ):
Study Protocol  [PDF] February 24, 2016
Statistical Analysis Plan  [PDF] January 26, 2017


Responsible Party: Teva Pharmaceutical Industries, Ltd.
ClinicalTrials.gov Identifier: NCT02190721     History of Changes
Other Study ID Numbers: XM02-ONC-201
2014-001772-55 ( EudraCT Number )
First Posted: July 15, 2014    Key Record Dates
Results First Posted: July 31, 2018
Last Update Posted: July 31, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Teva Pharmaceutical Industries ( Teva Pharmaceutical Industries, Ltd. ):
Neutropenia

Additional relevant MeSH terms:
Neutropenia
Agranulocytosis
Leukopenia
Leukocyte Disorders
Hematologic Diseases
Lenograstim
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs