This is a phase II, open label, multi-center, intra-patient dose escalation study to characterize the pharmacokinetics (PK) after oral administration of eltrombopag in combination with immunosuppressive therapy in pediatric patients with previously untreated or relapsed/refractory severe aplastic anemia or recurrent aplastic anemia.
All patients were treated with eltrombopag for the 26-week Treatment Period, followed by a 52-week Follow-Up Period. Patients who had been previously untreated with immunosuppressive therapy were treated according to the standard of care, hATG/cyclosporine, in addition to eltrombopag. Patients with relapsed/refractory SAA or recurrent AA were enrolled into one of two treatment options: hATG/cyclosporine plus eltrombopag or cyclosporine plus eltrombopag, depending on prior treatment with immunosuppressive therapy. Patients could receive eltrombopag beyond 26 weeks if the investigator thought that the patient was still receiving clinical benefit from the drug. After initiating treatment with eltrombopag, patients had their dose assessed and modified as tolerated, until the targeted platelet count or maximum dose was achieved. Pharmacokinetic assessments were performed at time points intended to capture steady state PK of the starting dose and highest dose achieved. There are four separate periods of this study: Screening (signing of written informed consent through Day -1), Treatment (for 26 weeks), Follow-up (additional 52 weeks), and Long-term Follow-up (for additional 3 years). The first 3 periods were considered the Core phase of the study. Study completion (Core) will occur when the last patient completes the 26-week treatment and 52-week Follow-up Period \[at Week 78\].
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
51
Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily
Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP)
Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day
Phoenix Children s Hospital
Phoenix, Arizona, United States
Arkansas Childrens Hospital
Little Rock, Arkansas, United States
Eltrombopag PK parameter: AUCtau
Area under the curve calculated to the end of the dosing interval (tau).
Time frame: at the highest dose level, i.e. 11 weeks after dose initiation
Eltrombopag PK parameter: Cmax
Peak concentration of drug
Time frame: at the highest dose level, i.e. 11 weeks after dose initiation
Eltrombopag PK parameter: Ctrough
Pre-dose drug concentration in a repeated dose setting.
Time frame: at the highest dose level, i.e. 11 weeks after dose initiation
Percentage of participants who have achieved a complete (CR) or partial response (PR)
Percentage of participants who have achieved a complete (CR) or partial response (PR)
Time frame: Week 12, Week 26, Week 52, and Week 78.
Percentage of participants with a platelet response
Percentage of participants who have achieved a complete or partial platelet response
Time frame: Week 12, Week 26, Week 52, and Week 78.
Hematologic counts
Platelet (PLT), Hgb, and neutrophil counts
Time frame: Week 12, Week 26, Week 52, Week 78, and then annually up to 3 years
Red Blood Cell (RBC) transfusion independence
Number and frequency of participants with RBC transfusion independence defined as a period of time of at least 56 days without RBC transfusion.
Time frame: From date of first dose to approx. 3 years
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Childrens Hospital Colorado
Aurora, Colorado, United States
Aflac Cancerand Blood Disorders Ctr
Atlanta, Georgia, United States
Ann and Robert H Lurie Childrens Hospital of Chicago
Chicago, Illinois, United States
Indiana University
Indianapolis, Indiana, United States
Childrens Hosp Boston Dept of Hematology
Boston, Massachusetts, United States
University of MI Health System
Ann Arbor, Michigan, United States
Hackensack University Medical Center SC-2
Hackensack, New Jersey, United States
Duke University Medical Center
Durham, North Carolina, United States
...and 10 more locations
Platelet transfusion independence
Number and frequency of participants with platelet transfusion independence defined as a period of time of at least 28 days without PLT transfusion.
Time frame: From date of first dose to approx. 3 years
Bone marrow cellularity
Percentage of hematopoietic cells in bone marrow biopsy.
Time frame: Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years
Bone marrow morphology
Percentage of hematopoietic cells in bone marrow aspirate
Time frame: Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years
Bone marrow cytogenetics
Chromosomal structure by karyotyping and Fluorescence in situ hybridization (FISH)
Time frame: Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years
Acceptability and palatability for both tablets and powder for oral suspension
Standardized (total) summary score, ranged from 0-100 will be derived from all items from the questionnaire based on a scoring matrix.
Time frame: Week 1, Week 2, Week 3, Week 4, Week, 12, Week 26, Week 78
Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)
Percentage of participants with PNH clones
Time frame: Baseline, Week 12, 26, 52, 78 and annually for up to 3 years to at time of disease progression.
Exposure-response relationship of eltrombopag and overall response and platelet response
Pharmacokinetic parameters of eltrombopag at the highest dose by the best overall response and platelet response
Time frame: Week 12 or up to Week 26 when the PK highest dose has been achieved
Alternate Overall response (aOR)
Percentage of participants with alternate overall response rate (aORR) defined as the proportion of patients who have achieved an alternate complete response (aCR) or an alternate partial response (aPR)
Time frame: Week 12, Week 26, Week 52, and Week 78.
PK of eltrombopag at the starting dose (AUCtau)
Pharmacokinetic parameters of eltrombopag (AUCtau)
Time frame: Week 3 Day 1
PK of eltrombopag at the starting dose (Cmax)
Pharmacokinetic parameters of eltrombopag (Cmax)
Time frame: Week 3 Day 1
PK of eltrombopag at the starting dose (Ctrough)
Pharmacokinetic parameters of eltrombopag (Ctrough)
Time frame: Week 3 Day 1