A Phase II Dose-escalation Study Characterizing the PK of Eltrombopag in Pediatric Patients With Previously Untreated or Relapsed Severe Aplastic Anemia or Recurrent Aplastic Anemia

Phase 2

Completed

Conditions: Aplastic Anemia

Interventions: Drug: Eltrombopag
Drug: hATG
Drug: CsA

Registration Number: NCT03025698

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: 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 \[at Week 78\].

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 51

Inclusion Criteria

For Cohort A patients:

History of prior diagnosis of SAA,
Diagnosis of relapsed/refractory SAA or recurrent AA following treatment for SAA, as per Section 5.1. Patients with recurrent AA (e.g., losing their response) are exempt from meeting the diagnostic criteria for SAA relapse at the time of study enrollment, but must have been previously diagnosed with SAA.
Agree to concurrent eltrombopag treatment with appropriate, investigator-selected Immunosuppressive therapy (IST) with either hATG + CsA or CsA.

For Cohort B patients:

Diagnosis of SAA at time of enrollment.
Patients must not have been previously treated with IST, and must meet all criteria as described in Table 5-1.
Patients must agree to treatment with hATG + CsA concurrent with eltrombopag.

All patients eligible for inclusion in this study must meet all of the following criteria:

Age 1 to <18 years.
Assessments to rule out congenital/inherited bone marrow failure syndromes and other causes of immune-mediated pancytopenia, which may be treated with transplant, must be completed prior to enrollment.
Hematopoietic stem cell transplantation (HSCT) is not suitable or available as a treatment option or has been refused by the patient. (Candidacy for HSCT will be determined as per local practices or national guidelines.)
Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag.
Performance status score: Karnofsky ≥50 for patients 16 years of age and older or Lansky ≥50 for patients below 16 years of age.
Written informed consent must be signed by a parent or legal guardian prior to initiation of any study specific procedure.
Normal karyotype within 4 weeks prior to first dose of eltrombopag. If there are insufficient metaphases (< 10) to determine karyotype, a repeat marrow aspirate is required. If upon repeat bone marrow aspirate, the number of metaphases is insufficient (< 10), then FISH probes performed in marrow aspirate as per protocol must be normal.

Exclusion Criteria

Prior and/or active medical history of:
- Fanconi anemia (via chromosome breakage test or growth arrest by flow cytometry)
- Other known underlying inherited marrow failure syndrome (such as but not limited to Dyskeratosis Congenita, Congenital Amegakaryocytic Thrombocytopenia, or Shwachman-Diamond Syndrome).
Symptomatic Paroxysmal Nocturnal Hemoglobinuria (PNH) and/or PNH clones >50% of White blood cell (WBC) or Red blood cell (RBC) at time of enrollment.
- Any cytogenetic abnormalities by karyotyping or FISH.
- Myelodysplastic syndrome (MDS)
- Other known or suspected underlying primary immunodeficiency
- Any malignancy
Active infection not responding to appropriate therapy.
Prior eltrombopag or other thrombopoietin receptor (TPO-R) agonist treatment for at least 2 months and a lack of response.
Have any of the following out-of-range laboratory values:
- Serum Creatinine >2.5 × upper limit of normal (ULN),
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × ULN.
Concurrent participation in an investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer. Note: a parallel enrollment in a registry for patients with SAA or AA is acceptable.

Pregnant or nursing (lactating) women.

Female patients of childbearing potential (e.g., are menstruating or could reach menarche during the study, this usually includes girls 9 years and older) who do not agree to abstinence or, if sexually active, do not agree to the use of contraception as defined in Section 7.2.1.2.6 (pregnancy section) of the protocol. If local regulations are more stringent than the contraception methods listed in this protocol to prevent pregnancy, local regulations apply and will be described in the ICF.
Male patients who are sexually active and do not agree to abstinence or to use a condom during intercourse while taking eltrombopag, and for 13 weeks after stopping treatment.
Patients, who in the investigators' opinion may be unwilling, are unable or unlikely to comply with the requirements of the study protocol.
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or its excipient, CSA, or hATG that contraindicates patient participation.
History of major surgery, serious illness, or traumatic injury within 4 weeks of first dose of study treatment.
Patients with known history of HIV positivity.
Patients with known history of hepatitis B or C positivity.
Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol, such as:

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome),Active skin, mucosa, ocular or GI disorders of Grade > 1.
Impaired cardiac function, such as:
- Patients with a history of congenital long QT syndrome or known family history of long QTc syndrome,
- Corrected QTc >450 msec using Fridericia correction (QTcF) on the screening ECG (using triplicate ECGs),
- Ventricular arrhythmias and or other cardiac arrhythmia not controlled with medication,
- Other clinically significant cardio-vascular disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension),
- History of known structural abnormalities (e.g., cardiomyopathy).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A (Option 1)	Eltrombopag	Regimen 1: hATG (ATGAM®), CsA and eltrombopag begin on Day 1.
Cohort A (Option 1)	CsA	Regimen 1: hATG (ATGAM®), CsA and eltrombopag begin on Day 1.
Cohort A (option 2)	Eltrombopag	CsA and eltrombopag begin on Day 1.
Cohort A (option 2)	CsA	CsA and eltrombopag begin on Day 1.
Cohort B	Eltrombopag	previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen
Cohort B	CsA	previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen
Cohort A (Option 1)	hATG	Regimen 1: hATG (ATGAM®), CsA and eltrombopag begin on Day 1.
Cohort B	hATG	previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen

Primary Outcome Measures

Name	Time	Method
Eltrombopag PK parameter: AUCtau	at the highest dose level, i.e. 11 weeks after dose initiation	Area under the curve calculated to the end of the dosing interval (tau).
Eltrombopag PK parameter: Cmax	at the highest dose level, i.e. 11 weeks after dose initiation	Peak concentration of drug
Eltrombopag PK parameter: Ctrough	at the highest dose level, i.e. 11 weeks after dose initiation	Pre-dose drug concentration in a repeated dose setting.

Secondary Outcome Measures

Name	Time	Method
Percentage of participants who have achieved a complete (CR) or partial response (PR)	Week 12, Week 26, Week 52, and Week 78.	Percentage of participants who have achieved a complete (CR) or partial response (PR)
Hematologic counts	Week 12, Week 26, Week 52, Week 78, and then annually up to 3 years	Platelet (PLT), Hgb, and neutrophil counts
PK of eltrombopag at the starting dose (Cmax)	Week 3 Day 1	Pharmacokinetic parameters of eltrombopag (Cmax)
Percentage of participants with a platelet response	Week 12, Week 26, Week 52, and Week 78.	Percentage of participants who have achieved a complete or partial platelet response
Bone marrow morphology	Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years	Percentage of hematopoietic cells in bone marrow aspirate
Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)	Baseline, Week 12, 26, 52, 78 and annually for up to 3 years to at time of disease progression.	Percentage of participants with PNH clones
Alternate Overall response (aOR)	Week 12, Week 26, Week 52, and Week 78.	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)
Platelet transfusion independence	From date of first dose to approx. 3 years	Number and frequency of participants with platelet transfusion independence defined as a period of time of at least 28 days without PLT transfusion.
Bone marrow cellularity	Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years	Percentage of hematopoietic cells in bone marrow biopsy.
PK of eltrombopag at the starting dose (AUCtau)	Week 3 Day 1	Pharmacokinetic parameters of eltrombopag (AUCtau)
Acceptability and palatability for both tablets and powder for oral suspension	Week 1, Week 2, Week 3, Week 4, Week, 12, Week 26, Week 78	Standardized (total) summary score, ranged from 0-100 will be derived from all items from the questionnaire based on a scoring matrix.
Exposure-response relationship of eltrombopag and overall response and platelet response	Week 12 or up to Week 26 when the PK highest dose has been achieved	Pharmacokinetic parameters of eltrombopag at the highest dose by the best overall response and platelet response
Red Blood Cell (RBC) transfusion independence	From date of first dose to approx. 3 years	Number and frequency of participants with RBC transfusion independence defined as a period of time of at least 56 days without RBC transfusion.
Bone marrow cytogenetics	Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years	Chromosomal structure by karyotyping and Fluorescence in situ hybridization (FISH)
PK of eltrombopag at the starting dose (Ctrough)	Week 3 Day 1	Pharmacokinetic parameters of eltrombopag (Ctrough)

Trial Locations

Locations (13): Aflac Cancerand Blood Disorders Ctr
🇺🇸
Atlanta, Georgia, United States
Phoenix Children s Hospital
🇺🇸
Phoenix, Arizona, United States
Arkansas Childrens Hospital
🇺🇸
Little Rock, Arkansas, United States
Childrens Hospital Colorado
🇺🇸
Aurora, Colorado, 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
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Texas Children's Cancer and Hematology Center
🇺🇸
Houston, Texas, United States
Novartis Investigative Site
🇬🇧
London, United Kingdom