A Phase I/II open-label, single-arm, multi-center study of
ruxolitinib added to corticosteroids in pediatric patients
with grade II-IV acute graft vs. host disease after allogeneic
hematopoietic stem cell transplantation

An allogenic stem cell transplantation bears the risk of the development of a
graft-versus-host disease (GvHD). In a
GvHD the donor cells are acting against the body of the patient. Immune cells
of the donor attack the patient*s cells as
they are considered foreign. A acute graft-versus-host disease (cGvHD) develops
starting after the transplantation till 3
months. The disease may appear in all body parts. In most cases the disease is
present in the skin, liver and GI tract.
The disease damages tissues and organs and weakens the immune system of the
body. This is why aGvHD patients
are more susceptible for infections.
Systemic steroids alone or in combination with calcineurin inhibitor have
remained SOC as
initial systemic treatment of aGvHD grades II-IV over 3 decades (Ruutu 2014).
Unfortunately,
only 30*50% of children respond to corticosteroids as initial therapy, and
optimal initial or
second-line therapies have not yet been determined (Carpenter and Macmillan
2010).
Treatments that are currently used for Grade II-IV steroid refractory aGvHD
(SR-aGvHD) are
mostly off-label and although they demonstrate initial responses in
approximately 50% of
patients, they are associated with aGvHD flare during attempted steroid taper.
These second
line treatments include the following: ATG, extracorporeal photopheresis (ECP),
mesenchymal
stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF),
mTOR
inhibitors (everolimus or sirolimus), etanercept, or infliximab. Management of
aGvHD flare
necessitates administration of further high dose systemic corticosteroids over
a more prolonged
time period and/or additional new systemic immunosuppressive therapy leading to
lifethreatening
infections, and/or malignancy recurrence, with resultant two year survival rates
ranging only approximately 20-30% (Martin et al 2012). As such, more effective
treatment for
aGvHD and SR-aGvHD grades II-IV in pediatric patients represents a very high
unmet medical
need.

The purpose of the study intends to assess safety, activity and
pharmacokinetics of ruxolitinib treatment with corticosteroids in
treatment-naïve and steroid refractory (SR)- acute Graft versus Host Disease
(aGvHD) patients aged *28 days to <18 years of age.
The rationale of the study is based on current knowledge of acute graft vs.
host disease pathophysiology and published studies showing that ruxolitinib
impairs antigen presenting cell function, inhibits donor T cell proliferation,
suppresses adverse cytokine production,
and improves survival and disease manifestations in GvHD mouse models. Further,
published data has shown that ruxolitinib has evidence of clinical efficacy
when added to immunosuppressive therapy in patients with steroid refractory
acute graft vs. host disease.
Clinical studies using ruxolitinib (10mg BID) alone or in comparison to best
available therapy are currently underway in the SR-aGvHD setting for adult
patients and adolescents * 12 years of age. Recent data with ruxolitinib in
SR-aGvHD pediatric patients (ages 1.6 y/o-16.4 y/o) have shown encouraging
overall response rates compared to corticosteroids +/- CNI alone (Khandelwal
2017).

This trial is a Phase I/II open-label, single-arm, multi-center study of
ruxolitinib added to corticosteroids in pediatric allogeneic stem cell
transplant (alloSCT) recipients with grade II-IV acute graft vs. host disease.
Patients will be enrolled into 4 groups based on age (Group 1 (Age *12 years to
< 18 years), Group 2 (Age *6 years to < 12 years), Group 3 (Age *2 years to < 6
years) and Group 4 (Age *28 days to <2 years) to allow appropriate
dosing based on available data. Group 1, being treated with the same dose as
the ongoing registration trial (CINC424C2301 using 10mg BID), will be enrolled
directly into the Phase II. The remaining groups will be enrolled in Phase I:
Group 2 will have a starting dose of 5mg BID, Group 3 will have a starting dose
of 4mg/m2 BID, and the starting dose of Group 4 will be determined based on the
PK data collected from Groups 1-3.During the Phase I, the PK, safety and
activity data for Groups 2-4 will be reviewed by the data monitoring committee
(DMC). Should all of these parameters be considered appropriate by the DMC, the
starting dose for each group will be confirmed as the RP2D for each age group,
and
then used as the starting dose for all future patients of that age group
enrolled into the Phase II.All patients enrolled in the study will be treated
for 24 weeks(approximately 6 months) or until early discontinuation. All
patients will also be followed for additional 18 months (total duration of
study = up to 2 years from enrollment). Should the occurrence of aGvHD flare
require treatment re-initiation or should ruxolitinib not be discontinued by the
end of 24 weeks due to extended tapering, patients may continue to taper
ruxolitinib beyond 24 weeks up to a maximum of 48 weeks (approximately 12
months).

treatment with ruxolitinib

Risk: side effects of ruxolitinib
Burden:
Treatment phase: screening followed by 4-week cycles. Weekly visits during
cycle 1 and 2. Visits on day 1 of each cycle (cycle 3-6). Total duration of
treatment phase is 24 weeks after randomization.
The follow-up phase will follow after end of treatment and safety follow-up.
Follow-up phase visit on day 1 of month 12 (after randomization), month 18 and
month 24.
Total 16 visits. Duration per visit is usually 2-3 hours in treatment phase.
Physical examination: every visit in treatment phase.
Blood tests (11-25 ml / times): each visit in treatment phase.
Blood for biomarkers: quantity depending on age cohort
Dexa scan: 4 visits
Questionnaire (1): 3 visits (only if patient is given medication in oral
solution form)