A phase II dose escalation study: use of eltrombopag in pediatric patients with severe aplastic anemia or recurrent aplastic anemia

• Register: EUCTR
• Last refreshed on: 13 October 2020
• Main ID: EUCTR2015-003166-91-GB
• Date of registration: 05/07/2017
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma AG
• Public title: A phase II dose escalation study: use of eltrombopag in pediatric patients with severe aplastic anemia or recurrent aplastic anemia
• Scientific 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 naïve severe aplastic anemia or recurrent aplastic anemia.
• Date of first enrolment: 22/05/2019
• Target sample size: 60
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003166-91
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Medica Information Services
• Affiliation: Novartis Pharmaceuticals UK Limited

• Name: Medica Information Services
• Affiliation: Novartis Pharmaceuticals UK Limited

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion Criteria specific to Cohort A (patients with relapsed/refractory SAA or recurrent AA):
1. Prior history of diagnosis of SAA.
2. Diagnosis of relapsed/refractory SAA or recurrent AA following IST for SAA at the time of enrollment. Patients with
recurrent AA (e.g., losing their response) are exempt from meeting the diagnostic criteria for relapsed SAA at the time of 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.

Inclusion Criteria specific to Cohort B (patients with previously untreated SAA):
4. Diagnosis of SAA at the time of enrollment.
5. Patients must not have been previously treated for SAA
6. Patients must agree to treatment with hATG + CsA concurrent with
eltrombopag.

Inclusion Criteria for all patients regardless of cohort:
7. Age 1 to <18 years
8. Where appropriate, 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 available or suitable as a treatment option or has been refused by the patient. (Candidacy for HSCT will be determined as per local practice.)
10. Bone marrow aspirate/biopsy at any time during the 4 weeks prior to first dose of eltrombopag
[11. Removed]
12. Performance status score: Karnofsky =50 or Lansky =50 (depending on age)
[13. Removed]
[14. Removed]
15. Written informed consent 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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 60
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
2. Prior and/or active medical history of:
• Fanconi anemia (via chromosomal breakage test or growth arrest by flow cytometry)
• Other known underlying congenital/inherited marrow failure syndromes (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 PMN 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. Any out of range lab values:
• Serum Creatinine >2.5 × upper limit of normal (ULN),
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × ULN.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Refractory, relapsed or treatment naïve severe aplastic anemia (SAA) or recurrent aplastic anemia (AA)
MedDRA version: 20.0 Level: PT Classification code 10002967 Term: Aplastic anaemia System Organ Class: 10005329 - Blood and lymphatic system disorders

Intervention(s)

Trade Name: REVOLADE
Product Name: Eltrombopag
Product Code: ETB115
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ELTROMBOPAG
CAS Number: 496775-61-2
Current Sponsor code: ETB115
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 12.5-

Trade Name: REVOLADE
Product Name: Eltrombopag
Product Code: ETB115
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ELTROMBOPAG
CAS Number: 496775-61-2
Current Sponsor code: ETB115
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Trade Name: REVOLADE
Product Name: Eltrombopag
Product Code: ETB115
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ELTROMBOPAG
CAS Number: 496775-61-2
Current Sponsor code: ETB115
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Trade Name: REVOLADE
Product Name: Eltrombopag
Product Code: ETB115
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ELTROMBOPAG
CAS Number: 496775-61-2
Current Sponsor code: ETB115
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 75-

Trade Name: REVOLADE
Product Name: Eltrombopag
Product Code: ETB115
Pharmaceutical Form: Powder for oral suspension
INN or Proposed INN: ELTROMBOPAG
CAS Number: 496775-61-2
Current Sponsor code: ETB115
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Trade Name: REVOLADE
Product Name: Eltrombopag
Product Code: ETB115
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ELTROMBOPAG
CAS Number: 496775-61-2
Current Sponsor code: ETB115
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 12.5-

Trade Name: REVOLADE
Product Name: Eltrombopag
Product Code: ETB115
Pharmaceutical Form:

Primary Outcome(s)

Secondary Objective: Key secondary objectives:
1. To determine the safety and tolerability of eltrombopag given orally in pediatric patients with SAA.
2. To assess the efficacy defined as overall response (ORR).
Other secondary endpoints:
3. To assess hematologic counts.
4. To evaluate PLT and RBC transfusion independence.
5. To assess bone marrow cellularity, morphology (trephine biopsy) and cytogenetics.
6. To assess the acceptability and palatability for the PfOS.
7. To assess clonal evolution to PNH.
8. To characterize the exposure-response relationship of eltrombopag and overall response and PLT response.
9. To assess the efficacy defined as the alternate overall response (aORR).
10. To characterize the PK of eltrombopag at the starting dose

Timepoint(s) of evaluation of this end point: 11 weeks (Week 12 Day 1) after initiation of eltrombopag treatment, or later, as applicable.

Primary end point(s): Cohort A and Cohort B: eltrombopag PK parameters, including AUCtau, Cmax and Ctrough at the highest dose level

Main Objective: To characterize the PK of eltrombopag at the highest dose after oral administration in pediatric patients with SAA.

Secondary Outcome(s)

Secondary end point(s): a) To determine the safety and tolerability of eltrombopag given orally in pediatric patients with SAA.
b) To assess the efficacy of eltrombopag defined as overall response rate (ORR)

Timepoint(s) of evaluation of this end point: a) Assessed throughout the study.
b) At Week 12, Week 26, Week 52, and Week 78.

Secondary ID(s)

CETB115E2201

NCT03025698

Source(s) of Monetary Support

Novartis Pharma AG

Ethics review

Status: Approved
Approval date: 22/05/2019
Contact: