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 (SAA) or recurrent aplastic anemia (AA).

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 plus cyclosporine plus eltrombopag. Patients with relapsed/refractory SAA or recurrent AA were enrolled into one of two treatment options: hATG plus 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
  • Hong Kong, Hong Kong, 999077
    • Novartis Investigative Site
• Portugal
  • Lisbon, Portugal, 1649-035
    • Novartis Investigative Site
• Russia
  • Moscow, Russia, 117198
    • Novartis Investigative Site
  • Saint Petersburg, Russia, 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 Childrens 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 Childs Hosp
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5225
      • Indiana University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Childrens Hosp Boston Dept of Heme
  • 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 Childrens 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 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) was supplied as either oral capsules or oral solution, administered twice a day.
Experimental: Cohort A (Option 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) was supplied as either oral capsules or oral solution, administered twice a day.
Experimental: Cohort B; 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) was 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 Parameters: AUCtau, AUClast	AUC tau: Area under the curve calculated to the end of the dosing interval ( tau) (mass*time/volume) AUC last: Area under the curve calculated to the last quantifiable concentration point (Tlast) (mass*time/volume)	at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78
Eltrombopag PK Parameter: Cmax	Cmax is the observed maximum plasma concentration following administration (mass/volume)	at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78
Eltrombopag PK Parameter: Ctrough at the Highest Dose Level	Ctrough is the pre-dose plasma concentration (mass/volume).	at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With an Overall Response Rate and Percentage of Participants With a Platelet Response Rate Based on Per Pediatric Committee of European Medicines Agency (PDCO)	Overall response rate (ORR) is defined as the percentage of participants who have achieved a complete response (CR) or partial response (PR) or No response (NR) by the Investigator. CR criteria: Platelet (PLT) and red blood cell (RBC) transfusion independence, Normal age-adjusted Hgb, PLT >100 × 10^9/L and absolute neutrophil count (ANC) >1.5 × 10^9/L. PR: PLT and RBC Transfusion independence and at least 2 of the following criteria: Reticulocytes >30 × 10^9/L, PLT >30 × 10^9/L, ANC >1.5 x 10^9L. PLT transfusion independence is defined as a period for at least 28 days without PLT transfusion. Platelet response rate (PRR): Platelet response rate is comprised of CR + PR based on the following criteria: CR: PLT >100 × 10^9/L; PR: PLT >30 × 10^9/L; NR: PLT transfusion within 4 weeks or PLT <= 30 × 10^9/L.	Week 12, Week 26, Week 52, Week 78
Hematologic Counts (Platelets (Blood), Neutrophils (Blood))	Individual Platelets (PLT) and neutrophil counts were summarized for all participants.	Week 12, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234
Hematologic Counts (Hemoglobin (Blood))	Individual hemoglobin (Hgb) counts were summarized for all participants.	Week 12, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234
Number of Red Blood Cells (RBC) Transfusions	Number of transfusions during the treatment period refers to total number of RBC transfusions participants have received while on treatment.	From date of first dose to approx. 4.5 years
Frequency of Red Blood Cell (RBC) Transfusions	Frequency of transfusions during the treatment period refers to number of RBC transfusions during the treatment period divided by number of months of treatment duration.	From date of first dose to approx. 4.5 years
Number of Platelet (PLT) Transfusions	Number of transfusions during the treatment period refers to total number of PLT transfusions participants have received while on treatment.	From date of first dose to approx. 4.5 years
Frequency of Platelet (PLT) Transfusions	Frequency of transfusions during the treatment period refers to number of PLT transfusions during the treatment period divided by number of months of treatment duration.	From date of first dose to approx. 4.5 years
Total Duration of Red Blood Cell (RBC) Transfusion Independence During the Treatment Period	RBC transfusion independence is defined as a period of time of at least 56 days without RBC transfusion. Duration of RBC transfusion independence is defined as a period of time of at least 56 days without RBC transfusion. First transfusion duration was calculated as the date of the day before the first transfusion after baseline minus the date of first exposure eltrombopag + 1.	From date of first dose to approx. 4.5 years
Total Duration of Platelet (PLT) Transfusion Independence During the Treatment Period	Platelet transfusion independence during the treatment period is defined as the duration from the first day of the 28-day period without PLT transfusion until the occurrence of a PLT transfusion after the period free from any PLT transfusion. Duration of PLT transfusion independence is defined as a period of time of at least 28 days without platelet transfusion. First transfusion duration was calculated as the date of the day before the first transfusion after baseline minus the date of first exposure eltrombopag + 1.	From date of first dose to approx. 4.5 years
Maximum Duration of Red Blood Cell (RBC) Transfusion Independence	RBC transfusion independence is defined as a period of time of at least 56 days without RBC transfusion. Maximum duration of RBC transfusion independence is defined as the maximum duration among the durations of RBC transfusion independence. First transfusion duration was calculated as the date of first transfusion after baseline minus the date of first exposure eltrombopag + 1.	From date of first dose to approx. 4.5 years
Maximum Duration of Platelet (PLT) Transfusion Independence	Maximum duration of PLT transfusion independence is defined as the maximum duration among the durations of PLT transfusion independence. First transfusion duration was calculated as the date of first transfusion after baseline minus the date of first exposure eltrombopag + 1.	From date of first dose to approx. 4.5 years
Overall Bone Marrow Cellularity	Percentage of cells in bone marrow biopsy - a comprehensive diagnostic evaluation to distinguish between the various bone marrow disorders.	Screening, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234
Bone Marrow Morphology	Percentage of morphology (erythropoiesis, granulopoiesis, megakaryopoiesis, CD34+ (blast cells) cells in bone marrow aspirate - a comprehensive diagnostic evaluation to distinguish between the various bone marrow disorders.	Screening, Week, 26, Week 52, Week 78, Week 130, Week 182, Week 234
Bone Marrow Cytogenetics	Number of bone marrow cytogenetics (chromosomal structure) by kryotyping and Fluorescence in situ hybridization (FISH). This is a comprehensive diagnostic evaluation to distinguish between the various bone marrow disorders.	Screening, Week 12, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234
Acceptability and Palatability for Both Tablets and Powder Formulation for Oral Solution (PfOS)	Standardized (total) summary score, ranged from 0-100, (where 0 means worst and 100 means the best), was derived from all items from the questionnaire based on a scoring matrix. The questionnaire was completed by parents and caregivers of patients under 12 years of age (ObsRO) and a questionnaire completed by patients 12 years and older (PRO).	any day from Day 1 of drug initiation up to Week 78
Clonal Evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)	Percentage of participants with clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH).	Baseline, Week (W) 26 Day (D) 1, W52D1, W78D1, W130D1, W182D1, W234D1
Exposure (AUCtau) - Response Relationship of Eltrombopag and Best Overall Response Rate by Age Groups	Pharmacokinetic parameter (AUCtau) of eltrombopag at the highest dose in relationship to best overall response rate in regard to complete response (CR), partial response (PR) and no response (NR). AUC tau: Area under the curve calculated to the end of the dosing interval (tau) (mass*time/volume)	at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78
Exposure (Cmax, Ctrough) - Response Relationship of Eltrombopag and Best Overall Response Rate by Age Groups	Pharmacokinetic parameters (Cmax and Ctrough) of eltrombopag at the highest dose in relationship to overall response rate in regard to complete response (CR), partial response (PR) and no response (NR). Cmax is the observed maximum plasma concentration following administration (mass/volume). Ctrough is the pre-dose plasma concentration (mass/volume).	at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78
Exposure (AUCtau) - Response Relationship of Eltrombopag and Best Platelet Response Rate by Age Groups	Pharmacokinetic parameter (AUCtau) of eltrombopag at the highest dose in relationship to platelet response rate. AUC tau: Area under the curve calculated to the end of the dosing interval ( tau) (mass*time/volume)	at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78
Exposure (Cmax, Ctrough) - Response Relationship of Eltrombopag and Best Platelet Response Rate by Age Groups	Pharmacokinetic parameters (Cmax and Ctrough) of eltrombopag at the highest dose in relationship to platelet response rate. Cmax is the observed maximum plasma concentration following administration (mass/volume). Ctrough is the pre-dose plasma concentration (mass/volume).	at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78
Alternate Overall Response Rate (aORR)	Alternate overall responses were derived using hematological parameters (i.e., hemoglobin, platelet, reticulocyte, and ANC). aORR is defined as the percentage of participants who achieved an alternate complete response (aCR) or an alternate partial response (aPR)	Week 12, Week 26, Week 52, Week 78
Pharmacokinetics (PK) of Eltrombopag at the Starting Dose (AUCtau)	PK parameter, AUCtau. AUC tau: Area under the curve calculated to the end of the dosing interval (tau) (mass*time/volume)	Week 3 Day 1
PK of Eltrombopag at the Starting Dose (Cmax)	PK parameter, Cmax Cmax is the observed maximum plasma concentration following administration (mass/volume)	Week 3 Day 1
PK of Eltrombopag at the Starting Dose (Ctrough)	PK parameter, Ctrough Ctrough is the pre-dose plasma concentration (mass/volume).	Week 3 Day 1

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Shimamura A, Maschan A, Bennett C, Samarasinghe S, Farrar JE, Li CK, Sirachainan N, Pongtanakul B, Komvilaisak P, Zubarovskaya L, Rothman JA, Walkovich K, Nakano TA, Bertuch AA, Ferrao A, Bhat R, Hanna R, Overholt K, Boklan J, Wong TF, Wang Q, Urban P, Strahm B, Wang W, Vlachos A, Williams DA. Eltrombopag in combination with immunosuppressive therapy in pediatric severe aplastic anemia: phase 2 ESCALATE trial. Blood Adv. 2025 Aug 12;9(15):3728-3738. doi: 10.1182/bloodadvances.2024015102.

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): August 10, 2026
• Last Update Submitted That Met QC Criteria: July 16, 2026
• Last Verified: July 1, 2026

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; Hemic and Lymphatic Diseases; Anemia, Aplastic; eltrombopag
• Other Study ID Numbers: CETB115E2201; 2015-003166-91 (EudraCT Number)

Plan for Individual participant data (IPD)

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

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

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