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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

Primary Purpose

Aplastic Anemia

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Eltrombopag
hATG
CsA
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aplastic Anemia focused on measuring Eltrombopag, Horse anti-thymocyte globulin, Cyclosporine, previously untreated or relapsed severe aplastic anemia, recurrent aplastic anemia, Severe aplastic anemia, Pharmacokinetics, Immunosuppressive therapy, ETB115, Refractory

Eligibility Criteria

1 Year - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

For Cohort A patients:

  1. History of prior diagnosis of SAA,
  2. 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.
  3. Agree to concurrent eltrombopag treatment with appropriate, investigator-selected IST with either hATG + CsA or CsA.

    For Cohort B patients:

  4. Diagnosis of SAA at time of enrollment.
  5. Patients must not have been previously treated with IST, and must meet all criteria as described in Table 5-1.
  6. 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:

  7. Age 1 to <18 years.
  8. 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.
  9. 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.)
  10. Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag.

12. Performance status score: Karnofsky ≥50 for patients 16 years of age and older or Lansky ≥50 for patients below 16 years of age.

15. Written informed consent must be signed by a parent or legal guardian prior to initiation of any study specific procedure.

16. 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:

2. 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 WBC or RBC at time of enrollment.
  • Any cytogenetic abnormalities by karyotyping or FISH.
  • Myelodysplastic syndrome (MDS)
  • Other known or suspected underlying primary immunodeficiency
  • Any malignancy 3. Active infection not responding to appropriate therapy. 4. Prior eltrombopag or other thrombopoietin receptor (TPO-R) agonist treatment for at least 2 months and a lack of response.

    5. 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. 6. 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.

Sites / Locations

  • Phoenix Children's Hospital SC
  • Arkansas Childrens Hospital SC
  • Childrens Hospital Colorado .
  • Aflac Cancer and Blood Disorders Center
  • Ann and Robert H Lurie Childrens Hospital of Chicago SC
  • Indiana University SC Riley Children's Hospital
  • Childrens Hospital of Boston SC
  • University of Michigan Health System SC
  • Hackensack University Medical Center SC-2
  • Duke University Medical Center SC
  • Cleveland Clinic Cleveland Clinic (5)
  • Texas Children's Cancer and Hematology Center SC
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort A (Option 1)

Cohort A (option 2)

Cohort B

Arm Description

Regimen 1: hATG (ATGAM®), CsA and eltrombopag begin on Day 1.

CsA and eltrombopag begin on Day 1.

previously untreated SAA), hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen

Outcomes

Primary Outcome Measures

Eltrombopag PK parameter: AUCtau
Area under the curve calculated to the end of the dosing interval (tau).
Eltrombopag PK parameter: Cmax
Peak concentration of drug
Eltrombopag PK parameter: Ctrough
Pre-dose drug concentration in a repeated dose setting.

Secondary Outcome Measures

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)
Percentage of participants with a platelet response
Percentage of participants who have achieved a complete or partial platelet response
Hematologic counts
Platelet (PLT), Hgb, and neutrophil counts
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.
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.
Bone marrow cellularity
Percentage of hematopoietic cells in bone marrow biopsy.
Bone marrow morphology
Percentage of hematopoietic cells in bone marrow aspirate
Bone marrow cytogenetics
Chromosomal structure by karyotyping and Fluorescence in situ hybridization (FISH)
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.
Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)
Percentage of participants with PNH clones
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
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)
PK of eltrombopag at the starting dose (AUCtau)
Pharmacokinetic parameters of eltrombopag (AUCtau)
PK of eltrombopag at the starting dose (Cmax)
Pharmacokinetic parameters of eltrombopag (Cmax)
PK of eltrombopag at the starting dose (Ctrough)
Pharmacokinetic parameters of eltrombopag (Ctrough)

Full Information

First Posted
January 12, 2017
Last Updated
September 11, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT03025698
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 30, 2017 (Actual)
Primary Completion Date
April 22, 2022 (Actual)
Study Completion Date
April 9, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 will be treated with eltrombopag for the 26-week Treatment Period, followed by a 52-week Follow-Up Period. Patients who have been previously untreated with immunosuppressive therapy will be treated according to the standard of care, hATG/cyclosporine, in addition to eltrombopag. Patients with relapsed/refractory SAA or recurrent AA will be enrolled into one of two treatment options: hATG/cyclosporine plus eltrombopag or cyclosporine plus eltrombopag, depending on prior treatment with immunosuppressive therapy. After initiating treatment with eltrombopag, patients will have their dose assessed and modified as tolerated, until the targeted platelet count or maximum dose is achieved. Pharmacokinetic assessments will be 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 will be 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].

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aplastic Anemia
Keywords
Eltrombopag, Horse anti-thymocyte globulin, Cyclosporine, previously untreated or relapsed severe aplastic anemia, recurrent aplastic anemia, Severe aplastic anemia, Pharmacokinetics, Immunosuppressive therapy, ETB115, Refractory

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
51 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort A (Option 1)
Arm Type
Experimental
Arm Description
Regimen 1: hATG (ATGAM®), CsA and eltrombopag begin on Day 1.
Arm Title
Cohort A (option 2)
Arm Type
Experimental
Arm Description
CsA and eltrombopag begin on Day 1.
Arm Title
Cohort B
Arm Type
Experimental
Arm Description
previously untreated SAA), hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen
Intervention Type
Drug
Intervention Name(s)
Eltrombopag
Other Intervention Name(s)
ETB115
Intervention Description
Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily
Intervention Type
Drug
Intervention Name(s)
hATG
Intervention Description
Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP)
Intervention Type
Drug
Intervention Name(s)
CsA
Intervention Description
Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day
Primary Outcome Measure Information:
Title
Eltrombopag PK parameter: AUCtau
Description
Area under the curve calculated to the end of the dosing interval (tau).
Time Frame
2 weeks and 11 weeks after dose initiation
Title
Eltrombopag PK parameter: Cmax
Description
Peak concentration of drug
Time Frame
2 weeks and 11 weeks after dose initiation
Title
Eltrombopag PK parameter: Ctrough
Description
Pre-dose drug concentration in a repeated dose setting.
Time Frame
2 weeks and 11 weeks after dose initiation
Secondary Outcome Measure Information:
Title
Percentage of participants who have achieved a complete (CR) or partial response (PR)
Description
Percentage of participants who have achieved a complete (CR) or partial response (PR)
Time Frame
Week 12, Week 26, Week 52, and Week 78.
Title
Percentage of participants with a platelet response
Description
Percentage of participants who have achieved a complete or partial platelet response
Time Frame
Week 12, Week 26, Week 52, and Week 78.
Title
Hematologic counts
Description
Platelet (PLT), Hgb, and neutrophil counts
Time Frame
Week 12, Week 26, Week 52, Week 78, and then annually up to 3 years
Title
Red Blood Cell (RBC) transfusion independence
Description
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
Title
Platelet transfusion independence
Description
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
Title
Bone marrow cellularity
Description
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
Title
Bone marrow morphology
Description
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
Title
Bone marrow cytogenetics
Description
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
Title
Acceptability and palatability for both tablets and powder for oral suspension
Description
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
Title
Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)
Description
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.
Title
Exposure-response relationship of eltrombopag and overall response and platelet response
Description
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
Title
Alternate Overall response (aOR)
Description
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.
Title
PK of eltrombopag at the starting dose (AUCtau)
Description
Pharmacokinetic parameters of eltrombopag (AUCtau)
Time Frame
Week 3 Day 1
Title
PK of eltrombopag at the starting dose (Cmax)
Description
Pharmacokinetic parameters of eltrombopag (Cmax)
Time Frame
Week 3 Day 1
Title
PK of eltrombopag at the starting dose (Ctrough)
Description
Pharmacokinetic parameters of eltrombopag (Ctrough)
Time Frame
Week 3 Day 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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. 12. Performance status score: Karnofsky ≥50 for patients 16 years of age and older or Lansky ≥50 for patients below 16 years of age. 15. Written informed consent must be signed by a parent or legal guardian prior to initiation of any study specific procedure. 16. 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: 2. 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 3. Active infection not responding to appropriate therapy. 4. Prior eltrombopag or other thrombopoietin receptor (TPO-R) agonist treatment for at least 2 months and a lack of response. 5. 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. 6. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Phoenix Children's Hospital SC
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Facility Name
Arkansas Childrens Hospital SC
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202
Country
United States
Facility Name
Childrens Hospital Colorado .
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Aflac Cancer and Blood Disorders Center
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Ann and Robert H Lurie Childrens Hospital of Chicago SC
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Indiana University SC Riley Children's Hospital
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202-5225
Country
United States
Facility Name
Childrens Hospital of Boston SC
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Michigan Health System SC
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Hackensack University Medical Center SC-2
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Duke University Medical Center SC
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Cleveland Clinic Cleveland Clinic (5)
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Texas Children's Cancer and Hematology Center SC
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Novartis Investigative Site
City
Shatin
Country
Hong Kong
Facility Name
Novartis Investigative Site
City
Lisboa
ZIP/Postal Code
1649-035
Country
Portugal
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
117198
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Saint Petersburg
ZIP/Postal Code
197022
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Bangkok noi
State/Province
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Novartis Investigative Site
City
Khon Kaen
State/Province
THA
ZIP/Postal Code
40002
Country
Thailand
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10400
Country
Thailand
Facility Name
Novartis Investigative Site
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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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

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