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

A Phase II, Open-label, Non-controlled, Intra-patient Dose-escalation Study to Characterize the Pharmacokinetics After Oral Administration of Eltrombopag in Pediatric Patients With Refractory, Relapsed or Treatment Naive Severe Aplastic Anemia or Recurrent Aplastic Anemia

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.

Study Overview

• Status: Completed
• Conditions: Aplastic Anemia
• Intervention / Treatment: Drug: Eltrombopag; Drug: hATG; Drug: CsA

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].

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hong Kong
  • Shatin, Hong Kong
    • Novartis Investigative Site
• Portugal
  • Lisboa, Portugal, 1649 035
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 117198
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197022
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • THA
    • Khon Kaen, THA, Thailand, 40002
      • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Novartis Investigative Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children s Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Childrens Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Childrens Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Aflac Cancerand Blood Disorders Ctr
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H Lurie Childrens Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5225
      • Indiana University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Childrens Hosp Boston Dept of Hematology
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of MI Health System
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center SC-2
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Cancer and Hematology Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A (Option 1); Regimen 1: hATG (ATGAM®), CsA and eltrombopag begin on Day 1.	Drug: Eltrombopag; Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily; Other Names: ETB115; Drug: hATG; Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP); Drug: CsA; Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day
Experimental: Cohort A (option 2); CsA and eltrombopag begin on Day 1.	Drug: Eltrombopag; Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily; Other Names: ETB115; Drug: CsA; Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day
Experimental: Cohort B; previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen	Drug: Eltrombopag; Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily; Other Names: ETB115; Drug: hATG; Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP); Drug: CsA; Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Eltrombopag PK parameter: AUCtau	Area under the curve calculated to the end of the dosing interval (tau).	at the highest dose level, i.e. 11 weeks after dose initiation
Eltrombopag PK parameter: Cmax	Peak concentration of drug	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.	at the highest dose level, i.e. 11 weeks after dose initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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	Week 12, Week 26, Week 52, and Week 78.
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.	From date of first dose to approx. 3 years
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.	From date of first dose to approx. 3 years
Bone marrow morphology	Percentage of hematopoietic cells in bone marrow aspirate	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.	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	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	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)	Week 12, Week 26, Week 52, and Week 78.
PK of eltrombopag at the starting dose (AUCtau)	Pharmacokinetic parameters of eltrombopag (AUCtau)	Week 3 Day 1
PK of eltrombopag at the starting dose (Cmax)	Pharmacokinetic parameters of eltrombopag (Cmax)	Week 3 Day 1
PK of eltrombopag at the starting dose (Ctrough)	Pharmacokinetic parameters of eltrombopag (Ctrough)	Week 3 Day 1
Hematologic counts	Platelet (PLT), Hgb, and neutrophil counts	Week 12, Week 26, Week 52, Week 78, and then annually up to 3 years
Bone marrow cellularity	Percentage of hematopoietic cells in bone marrow biopsy.	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)	Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2017
• Primary Completion (Actual): April 22, 2022
• Study Completion (Actual): January 27, 2025

Study Registration Dates

• First Submitted: January 12, 2017
• First Submitted That Met QC Criteria: January 16, 2017
• First Posted (Estimated): January 19, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 28, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Refractory; Immunosuppressive therapy; Cyclosporine; Eltrombopag; ETB115; Severe aplastic anemia; Horse anti-thymocyte globulin; previously untreated or relapsed severe aplastic anemia; recurrent aplastic anemia
• Additional Relevant MeSH Terms: Bone Marrow Failure Disorders; Hematologic Diseases; Bone Marrow Diseases; Anemia; Anemia, Aplastic
• Other Study ID Numbers: CETB115E2201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No