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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. )

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition: Neutropenia
Intervention: Drug: tbo-filgrastim

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
A total of 55 patients were screened for this study. Of the 55 patients screened, 50 patients at 33 investigational centers in Central and Eastern Europe met inclusion/exclusion criteria and were considered to be eligible for enrollment into the study.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of the 5 patients who were not enrolled, 2 patients were excluded due to inclusion criteria not met (baseline AST elevation, baseline ANC count was too low), 2 patients were excluded due to exclusion criteria not met (ongoing active infection or history of infectious disease within 2 weeks prior to screening), and 1 patient withdrew consent.

Reporting Groups
  Description
Infants (1 Month to <2 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.
Children (2 to <12 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.
Adolescents (12 to <16 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

Participant Flow:   Overall Study
    Infants (1 Month to <2 Years)   Children (2 to <12 Years)   Adolescents (12 to <16 Years)
STARTED   2   30   18 
Completed Treatment   2   30   18 
Completed 30 Day Follow-up   2   29   18 
Completed 90 Day Follow-up   2   29   18 
COMPLETED   2   29   18 
NOT COMPLETED   0   1   0 
Patient was out of the city                0                1                0 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups
  Description
Infants (1 Month to <2 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.
Children (2 to <12 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.
Adolescents (12 to <16 Years) Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.
Total Total of all reporting groups

Baseline Measures
   Infants (1 Month to <2 Years)   Children (2 to <12 Years)   Adolescents (12 to <16 Years)   Total 
Overall Participants Analyzed 
[Units: Participants]
 2   30   18   50 
Age 
[Units: Years]
Median (Full Range)
 1.65 
 (1.4 to 1.9) 
 6.80 
 (2.4 to 11.5) 
 13.80 
 (12.0 to 15.9) 
 9.05 
 (1.4 to 15.9) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
       
Female      1  50.0%      13  43.3%      6  33.3%      20  40.0% 
Male      1  50.0%      17  56.7%      12  66.7%      30  60.0% 
Ethnicity (NIH/OMB) 
[Units: Participants]
Count of Participants
       
Hispanic or Latino      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Not Hispanic or Latino      2 100.0%      30 100.0%      18 100.0%      50 100.0% 
Unknown or Not Reported      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Race (NIH/OMB) 
[Units: Participants]
Count of Participants
       
American Indian or Alaska Native      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Asian      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Native Hawaiian or Other Pacific Islander      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Black or African American      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
White      2 100.0%      30 100.0%      18 100.0%      50 100.0% 
More than one race      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Unknown or Not Reported      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Weight 
[Units: Kg]
Median (Full Range)
 9.90 
 (9.3 to 10.5) 
 20.25 
 (12.0 to 51.1) 
 53.90 
 (29.5 to 89.5) 
 28.95 
 (9.3 to 89.5) 
Height 
[Units: Cm]
Median (Full Range)
 78.00 
 (76.0 to 80.0) 
 121.00 
 (89.0 to 163.0) 
 161.00 
 (140.0 to 185.0) 
 130.50 
 (76.0 to 185.0) 
Body Mass Index 
[Units: Kg/m^2]
Median (Full Range)
 16.0 
 (16 to 16) 
 15.2 
 (12 to 20) 
 20.7 
 (15 to 28) 
 16.4 
 (12 to 28) 
Chemotherapy Administration [1] 
[Units: Participants]
Count of Participants
       
Mild      0   0.0%      6  20.0%      8  44.4%      14  28.0% 
Moderate      2 100.0%      16  53.3%      7  38.9%      25  50.0% 
Severe      0   0.0%      8  26.7%      3  16.7%      11  22.0% 
[1] The chemotherapy (CTX) regimens administered included at least etoposide, doxorubicin, ifosfamide, or cyclophosphamide. The severity group (mild/moderate/severe) of myelotoxicity of the CTX regimens administered was assigned by a group of clinical experts, based on the scientific literature (Moreau et al 2009) and clinical experience.


  Outcome Measures

1.  Primary:   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) ]

2.  Primary:   Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results   [ Time Frame: Day 1 (start of tbo-filgrastim administration) up to Day 21 ]

3.  Primary:   Participants With Potentially Clinically Significant Abnormal Hematology Results   [ Time Frame: Day 1 (start of tbo-filgrastim administration) up to Day 21 ]

4.  Primary:   Participants With Potentially Clinically Significant Abnormal Vital Signs   [ Time Frame: Day 1 (start of tbo-filgrastim administration) up to Day 21 ]

5.  Primary:   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) ]

6.  Primary:   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) ]

7.  Primary:   Participants With Injection Site Reactions to Tbo-Filgrastim Administration   [ Time Frame: Day 1 (start of tbo-filgrastim administration) up to Day 14 ]

8.  Primary:   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) ]

9.  Primary:   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) ]

10.  Secondary:   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) ]

11.  Secondary:   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 ]

12.  Secondary:   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 ]

13.  Secondary:   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 ]

14.  Secondary:   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 ]

15.  Secondary:   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 ]

16.  Secondary:   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 ]

17.  Secondary:   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 ]

18.  Secondary:   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 ]

19.  Secondary:   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 ]

20.  Secondary:   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 ]

21.  Secondary:   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) ]

22.  Secondary:   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) ]

23.  Secondary:   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) ]

24.  Secondary:   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) ]

25.  Secondary:   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) ]

26.  Secondary:   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) ]

27.  Secondary:   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) ]

28.  Secondary:   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) ]

29.  Secondary:   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) ]

30.  Secondary:   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) ]

31.  Secondary:   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) ]

32.  Secondary:   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) ]

33.  Secondary:   Participants With Febrile Neutropenia During the First Cycle of Chemotherapy   [ Time Frame: (relative to tbo-filgrastim therapy) Days -7 to Day 14 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc.
phone: 215-591-3000
e-mail: USMedInfo@tevapharm.com



Responsible Party: Teva Pharmaceutical Industries ( Teva Pharmaceutical Industries, Ltd. )
ClinicalTrials.gov Identifier: NCT02190721     History of Changes
Other Study ID Numbers: XM02-ONC-201
2014-001772-55 ( EudraCT Number )
First Submitted: July 11, 2014
First Posted: July 15, 2014
Results First Submitted: May 18, 2018
Results First Posted: July 31, 2018
Last Update Posted: July 31, 2018