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 (CETB115E2201)

Immunosuppressive treatment (IST) is the standard of care for the treatment of
aplastic anemia patients who are not candidate for HSCT with an HLA identical
donor. Related to SKION children are treated with a combination of cyclosporine
A and hATG (horse ATG). This treatment was chosen because of results of the NCI
(Scheinberg et.al. Horse versus rabbit antithymocyte globulin in acquired
aplastic anemia, NEJM, 365:430*438) showing that horse ATG has better remision
percentages compared to rabbit ATG.
There are several limitations of IST in severe aplastic anemia (SAA), e.g. the
majority of the responses observed following initial IST are partial with only
a few patients achieving normal blood counts, 1/3 of patients are refractory to
initial IST, hematologic relapses occur in 35% of responders following initial
response to IST, among relapsed patients chronic use of cyclosporine A is not
infrequent which often leads to toxicities and clonal evolution is still
observed in 10-15% of patients.
In order to address these limitations, efforts to improve initial IST in
treatment-naïve patients with the addition of mycophenolate mofetil and
sirolimus to standard horse anti-thymocyte globulin (hATG) /cyclosporine or use
of lymphocytotoxic agents have not yielded the expected better outcomes when
compared to standard (h-ATG/cyclosporine).
The most important advance in SAA in the recent years has been the seminal
observation that a thrombopoietin receptor agonist, eltrombopag, has activity
in SAA, as recenty published: Townsley et.al. Eltrombopag added to standard
immunosuppression for aplastic anemia, NEJM, 376;16, april 20 2017. Eltrombopag
is registered for adults with SAA. In this study the same will be done in
children.
Previous research focusing on safety and dosing of eltrombopag was done in
children with ITP. Eltrombopag is registered for this indication for children
older than 1 year.
The lack of availability of anti-thymocyte globulin (hATG) in several countries
has left a large proportion of patients with SAA with limited treatment options
and poor outcome. In this context, the combination of cyclosporine and
eltrombopag, 2 therapies with different modes of action, is an attractive
therapeutic option to address this unmet medical need, with the possible
addition of hATG. In the Netherlands hATG is available and part of the standard
of care.
The main objective of this study is to assess the safety and efficacy of
eltrombopag and cyclosporine and in the Netherlands with the addition of hATG
for the treatment-naïve SAA patients and subject with relapsed or recurrent
disease.

To characterize the PK of eltrombopag at steady state after oral administration
in pediatric patients with SAA.
Secondary (key only, see protocol page 40-41 for all objectives):
Safety and tolerability. Efficacy (overall response rate ORR).

Phase II, open-label, non-controlled, intra-patient dose-escalation study.
Eltrombopag plus cyclosporine plus or minus hATG. Escalation part (eltrombopag)
10 weeks, maintenance up to 6 months. Evaluation of efficacy at 6 months.
Responders may remain on eltrombopag plus cyclosporine up to at least month 54.
3 cohorts (approx. 20 subjects each):
* A.
1. For subjects who have been pretreated for SAA. Eltrombopag plus cyclosporine
plus ATG. ATG only during first 4 days. I.V., duration 4 to 8 hours, max. up to
24 hours. On day 1 of the treatment period treatment with eltrombopag and
cyclosporine will be initiated as well. Eltrombopag as tablets or soluble
powder. Cyclosporine in capsules or in a drinkable liquid.
2. For subjects who have been pretreated for SAA. Eltrombopag plus
cyclosporine. For the rest cohort A1 will be treated in the same way as cohort
A1. Investigator chooses allocation of the subject to Cohort A1 or A2.
* B. For treatment-naive subjects with SAA. Eltrombopag plus cyclosporine plus
ATG. Cohort B will be treated in the same way as cohort A1.
Non-responders will stop study medication at week 26 and will enter the
follow-up period, followed by the long-term follow-up period (4 years in
total).
Approx. 60 subjects.

Treatment with eltrombopag, cyclosporine and possibly hATG.

Risk: Adverse effects of eltrombopag in combination with cyclosporine ± hATG.
Burden: Screening 4 weeks, treatment with eltrombopag and cyclosporine (as long
as subjects benefits from treatment) ± hATG (for first 4 days). Total study
duration approx. 4,5 years.
35 visits in 4,5 years.Duration mostly 4 hours.
Physical examination: 34 times.
Blood tests: safety every visit (5-10 ml/occasion); biomarkers approx. 9 times
( 2,0 ml/occasion); PK approx. 30 ml in total); cyclosporine levels 14 times (5
ml/occasion).
Pregnancy test urine (if relevant): 29 times.
Bone marrow sample: 9 times.
ECG: cycle 4 times.
Questionnaire: 10 times.
Optional storage and use of the remaining blood and tissue for future research.