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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03025698
• Collaborator: (none)
• Enrollment: 51
• Locations: 20
• Arms: 3
• Anticipated Duration (Months): 91.8
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a phase II, open label, multi-center, intra-patient dose escalation study to characterize the pharmacokinetics 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 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].

Condition or Disease	Intervention/Treatment	Phase
Aplastic Anemia	Drug: Eltrombopag; Drug: hATG; Drug: CsA	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Sep 30, 2017
• Actual Primary Completion Date: Apr 22, 2022
• Anticipated Study Completion Date: May 26, 2025

Arms and Interventions

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; 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; 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; 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

Outcome Measures

Primary Outcome Measures

1. Eltrombopag PK parameter: AUCtau [2 weeks and 11 weeks after dose initiation]

   Area under the curve calculated to the end of the dosing interval (tau).

2. Eltrombopag PK parameter: Cmax [2 weeks and 11 weeks after dose initiation]

   Peak concentration of drug

3. Eltrombopag PK parameter: Ctrough [2 weeks and 11 weeks after dose initiation]

   Pre-dose drug concentration in a repeated dose setting.

Secondary Outcome Measures

1. 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)

2. 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

3. Hematologic counts [Week 12, Week 26, Week 52, Week 78, and then annually up to 3 years]

   PLT, Hgb, and neutrophil counts

4. 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.

5. 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.

6. 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 bioptate

7. 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

8. Bone marrow cytogenetics [Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years]

   Chromosomal structure by karyotyping and FISH

9. 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.

10. 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

11. 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

12. 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)

13. PK of eltrombopag at the starting dose (AUCtau) [Week 3 Day 1]

    Pharmacokinetic parameters of eltrombopag (AUCtau)

14. PK of eltrombopag at the starting dose (Cmax) [Week 3 Day 1]

    Pharmacokinetic parameters of eltrombopag (Cmax)

15. PK of eltrombopag at the starting dose (Ctrough) [Week 3 Day 1]

    Pharmacokinetic parameters of eltrombopag (Ctrough)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

1. Diagnosis of SAA at time of enrollment.

2. Patients must not have been previously treated with IST, and must meet all criteria as described in Table 5-1.

3. 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:

1. Age 1 to <18 years.

2. 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.

3. 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.)

4. Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag.

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

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

7. 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:

1. 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.

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital SC	Phoenix	Arizona	United States	85016
2	Arkansas Childrens Hospital SC	Little Rock	Arkansas	United States	72202
3	Childrens Hospital Colorado	Aurora	Colorado	United States	80045
4	Aflac Cancer and Blood Disorders Center	Atlanta	Georgia	United States	30342
5	Ann and Robert H Lurie Childrens Hospital of Chicago SC	Chicago	Illinois	United States	60611
6	Indiana University SC Riley Children's Hospital	Indianapolis	Indiana	United States	46202-5225
7	Childrens Hospital of Boston SC	Boston	Massachusetts	United States	02115
8	University of Michigan Health System SC	Ann Arbor	Michigan	United States	48109
9	Hackensack University Medical Center SC-2	Hackensack	New Jersey	United States	07601
10	Duke University Medical Center SC	Durham	North Carolina	United States	27710
11	Cleveland Clinic Cleveland Clinic (5)	Cleveland	Ohio	United States	44195
12	Texas Children's Cancer and Hematology Center SC	Houston	Texas	United States	77030
13	Novartis Investigative Site	Shatin		Hong Kong
14	Novartis Investigative Site	Lisboa		Portugal	1649-035
15	Novartis Investigative Site	Moscow		Russian Federation	117198
16	Novartis Investigative Site	Saint Petersburg		Russian Federation	197022
17	Novartis Investigative Site	Bangkok noi	Bangkok	Thailand	10700
18	Novartis Investigative Site	Khon Kaen	THA	Thailand	40002
19	Novartis Investigative Site	Bangkok		Thailand	10400
20	Novartis Investigative Site	London		United Kingdom	WC1N 3JH

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03025698
• Other Study ID Numbers: CETB115E2201
• First Posted: Jan 19, 2017
• Last Update Posted: May 20, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Eltrombopag; Horse anti-thymocyte globulin; Cyclosporine; previously untreated or relapsed severe aplastic anemia; recurrent aplastic anemia; Severe aplastic anemia; Pharmacokinetics; Immunosuppressive therapy; ETB115; Refractory
• Additional relevant MeSH terms: Anemia; Anemia, Aplastic

Study Results

No Results Posted as of May 20, 2022