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

Aplastic Anemia Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03025698
• Other study ID #: CETB115E2201
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 30, 2017
• Est. completion date: January 29, 2025

Study information

• Verified date: February 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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].

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 51
• Est. completion date: January 29, 2025
• Est. primary completion date: April 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

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 Immunosuppressive therapy (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 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.

Related Conditions & MeSH terms

• Anemia
• Anemia, Aplastic
• Aplastic Anemia

Intervention

Drug:
• Eltrombopag
Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily
• hATG
Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP)
• CsA
Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day

Locations

Country	Name	City	State
Hong Kong	Novartis Investigative Site	Shatin
Portugal	Novartis Investigative Site	Lisboa
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Saint Petersburg
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok noi	Bangkok
Thailand	Novartis Investigative Site	Khon Kaen	THA
United Kingdom	Novartis Investigative Site	London
United States	University of MI Health System SC	Ann Arbor	Michigan
United States	Aflac Cancer and Blood Disorders Center	Atlanta	Georgia
United States	Childrens Hospital Colorado .	Aurora	Colorado
United States	Childrens Hospital Boston SC	Boston	Massachusetts
United States	Ann and Robert H Lurie Childrens Hospital of Chicago .	Chicago	Illinois
United States	Cleveland Clinic Foundation Cleveland Clinic (5)	Cleveland	Ohio
United States	Duke University Medical Center SC	Durham	North Carolina
United States	Hackensack University Medical Center SC-2	Hackensack	New Jersey
United States	Texas Children's Cancer and Hematology Center SC	Houston	Texas
United States	Indiana University SC Riley Children's Hospital	Indianapolis	Indiana
United States	Arkansas Childrens Hospital SC	Little Rock	Arkansas
United States	Phoenix Children's Hospital SC	Phoenix	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Hong Kong,  Portugal,  Russian Federation,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Eltrombopag PK parameter: AUCtau	Area under the curve calculated to the end of the dosing interval (tau).	2 weeks and 11 weeks after dose initiation
Primary	Eltrombopag PK parameter: Cmax	Peak concentration of drug	2 weeks and 11 weeks after dose initiation
Primary	Eltrombopag PK parameter: Ctrough	Pre-dose drug concentration in a repeated dose setting.	2 weeks and 11 weeks after dose initiation
Secondary	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.
Secondary	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.
Secondary	Hematologic counts	Platelet (PLT), Hgb, and neutrophil counts	Week 12, Week 26, Week 52, Week 78, and then annually up to 3 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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.
Secondary	PK of eltrombopag at the starting dose (AUCtau)	Pharmacokinetic parameters of eltrombopag (AUCtau)	Week 3 Day 1
Secondary	PK of eltrombopag at the starting dose (Cmax)	Pharmacokinetic parameters of eltrombopag (Cmax)	Week 3 Day 1
Secondary	PK of eltrombopag at the starting dose (Ctrough)	Pharmacokinetic parameters of eltrombopag (Ctrough)	Week 3 Day 1