1. No category

Preliminary Phase II Results of Ara-­‐C and Idarubicin in Combina9on with Selec9ve Inhibitor of Nuclear Export (SINE) Compound Selinexor (KPT-­‐330) in Pa9ents with Relapsed or Refractory AML Walter Fiedler1, Michael Heuser2, Maxim Kebenko1, Felicitas Thol2, Arne Trummer2, Chris<an Brandts3, Carsten Bokemeyer1, Susann Theile4, Anne Kranich5 1Department of Internal Medicine II and Clinic (Oncology Center), University Medical Center Hamburg-­‐Eppendorf, Hamburg, Germany, 2Department of Hematology, Hemostasis, Oncology and Stem Cell Transplanta<on, Hannover Medical School, Hannover, Germany, 3Department of Medicine II, University Hospital Frankfurt, Frankfurt, Germany, 4GSO Hamburg, Hamburg, Germany, 5GSO Global, Amsterdam, Netherlands Background Acute myeloid leukemia (AML) is the most frequent acute leukemia in adults. Although 70-­‐80% of pa<ents achieve a complete remission (CR), pa<ents with AML who fail to achieve a CR a[er the first cycle of induc<on therapy and those with relapsed disease have a bleak prognosis (1). Currently no standard regimen exists for the treatment of pa<ents with relapsed AML and a great clinical need exists for new treatment op<ons (2). Selinexor, an oral first-­‐in-­‐class Selec<ve Inhibitor of Nuclear Export (SINE) compound, inhibits XPO1 mediated nuclear export to induce cytotoxicity in cells with genomic damage such as tumor cells (3). In an in-­‐vivo model, selinexor shows high ac<vity against AML cells of leukemic mice without toxicity to normal hematopoie<c cells (4). This Phase I clinical study demonstrates encouraging results in AML pa<ents. The role of selinexor as a mono therapy is currently under inves<ga<on in Phase II. 2 Study Design Study Objec9ves: •  This Phase II trial explores the efficacy & tolerability of Ara-­‐C and idarubicin in combina<on with selinexor in pa<ents with relapsed or refractory AML. Study Methods: •  Pa<ents with relapsed/refractory AML are treated with Ara-­‐C (100 mg/m2, con<nuous infusion, day 1-­‐7), idarubicin (10 mg/m2, day 1, 3, 5) every 4 weeks. In a majority of the pa<ents selinexor was administered orally, twice weekly, star<ng on Day 2 (40 mg/m2). •  A small cohort of pa<ents received selinexor a[er registra<on and before first induc<on cycle for correla<ve studies. The study flow chart is shown in Figure 1. •  The primary endpoint is percentage of pa<ents achieving a complete response (CR) or complete remission without normaliza<on of peripheral blood counts (CRi). Other endpoints are par<al response (PR) rate, percentage of pa<ents undergoing subsequent allogeneic stem cell transplant (SCT), early death rate, overall survival (OS), event-­‐free survival and toxicity. 3 Figure 1: Study Flow Chart Baseline(Transla+onal(Research(
prior(to(first(induc+on(cycle(
(op+onal):(
Bone(marrow(aspirates(pre;(and(
24(hr;post(single(Selinexor(dose(
2.(Induc+on(4(weeks(
D(9,(11,(16,(18,(23,(25(
Selinexor((twice(weekly)(
PR(
Non;responders/PD(
CR(
CR(
1.(Induc+on(4(weeks(
D1;7(
con+nuous(
Ara;C((
D1,(3,(5(
Idarubicin(
D2,4(
Selinexor(
Recommend:(
Allogeneic(stem(cell(transplanta+on((SCT)(
EOT(
D1;7(
con+nuous(
Ara;C((
D1,(3(
Idarubicin(
D2,4(
Selinexor(
D(9,(11,(16,(18,(23,(25(
Selinexor((twice(weekly)(
CR(and(not(eligible(
for(allogeneic(SCT(
>(50%(
blast(
reduc+on(
Maintenance(
Selinexor((twice(weekly)(
un+l(PD((or(maximal(1(
year(aJer(start((of(
treatment(
PD(
Any(other(
EOT(
PD(
Consolida+on((3(x(4(weeks)(
EOT(
D1;3(
6(doses(of(Ara;C(
D(2,(4,(9,(11,(16,(18,(23,(25(
Selinexor((twice(weekly)(
Maintenance(
Selinexor((twice(weekly)(un+l(
relapse((or(maximal(1(year(
aJer(start((of(treatment(
4 Pa9ent Characteris9cs Pa#ent'characteris#cs'
'
Median'age''''''''''''''''''''57'(+/H'15)'
'
Gender'
Male''''''''''''''''''''''''''''''''10'(56%)'
Female''''''''''''''''''''''''''''8'(44%)'
'
Prior'therapy'
Prior'chemotherapy'''''2'(+/H'0.8)'
Prior'SCT/DLi''''''''''''''''''39%'(6%'n.n.)'
'
100'
90'
80'
70'
60'
50'
40'
30'
20'
10'
0'
Percentage'of'pa#ents'with'specified'
molecular'changes'(%)'
B'
C'
Percentage'of'pa#ents'(%)'
A'
NPMH1mut' FLT3mut'
FLT3mut;'
NPMH1mut'
100'
90'
80'
70'
60'
50'
40'
30'
20'
10'
0'
unkown'
late'relapse'
early'relapse'
primary'
refractory'
Response'to'
prior'therapy'
unkown'
unfavorable'
intermediate'
favorable'
Risk'group'
Figure'2'–'pa,ent'characteris,cs'
A)'Pa#ent'demographics'(n.n.'='not'known,'n=18).'B)'Percentage'of'pa#ents'with'specific'molecular'abnormali#es'(n=18).'C)'Disease'status'at'study'entry'and'
risk'category'according'to'karyotype'(n=18).'
A) Pa<ent demographics (n.n. = not known, n=18). B) Percentage of pa<ents with specific molecular abnormali<es (n=18). C) Disease status at study entry and risk category according 'to karyotype (n=18). As of 27-­‐April-­‐2015, 18 pa<ents with AML have been enrolled in 3 sites. Median age was 57 years with 56% male and 44% female pa<ents. Over 40% of pa<ents showed molecular changes. On average, pa<ents had received 2 chemotherapies prior to study start and 39% had prior stem cell transplanta<ons (SCT) and donor lymphocyte infusion (DLi). 22% of pa<ents were primary refractory while 33% of pa<ents showed early relapse within 12 month and 39% of pa<ents late relapse. 44% of pa<ents were categorized as unfavourable. 5 Safety Drug'related'adverse'events'(percentage'of'pa6ents)'
Event&
Anemia'
Diarrhea'
Cons6pa6on'
Nausea'
Vomi6ng'
Fa6gue'
Thrombocytopenia'
Leukopenia'
Hypokalemia'
Anorexia'
CTC&grade&3+4&
18%'
45%'
0%'
18%'
9%'
18%'
27%'
27%'
9%'
45%'
CTC&grade&1+2&
0%'
36%'
18%'
45%'
55%'
27%'
0%'
0%'
9%'
18%'
Out of 18 pa<ents, 11 pa<ents were evaluable for tolerability at <me of analysis. Drug related adverse events comprised 43% of all CTC grade 3 and 4 and 51% of all CTC grade 1 and 2 events. The most common grade 3 and 4 drug related adverse events and grade 1 and 2 drug related adverse events are shown above. No drug related deaths occurred. 6 Percentage(and(number(of(pa4ents(with(
specified(response(
"
Overall"response"rate"""""""""10"(56%)""
CR(((((((((((((((((((((((((((((((((((((((((((3((17%)(
CRi((((((((((((((((((((((((((((((((((((((((((6((33%)(
PR(((((((((((((((((((((((((((((((((((((((((((1((6%)(
(
SD(((((((((((((((((((((((((((((((((((((((((((2((11%)(
(
PD(((((((((((((((((((((((((((((((((((((((((((6((33%)(
(
B"
Percentage(of(pa4ents(receiving(
subsequent(SCT/DLi((%)(
A"
Efficacy 100(
90(
80(
70(
60(
50(
40(
30(
20(
10(
0(
SCT/DLi(
n.n.(
A) Percentage of pa<ents showing complete remission (CR), complete remission with incomplete blood count recovery (CRi), par<al remission (PR), stable disease (SD) and disease progression (PD) is presented (n=18). B) Percentage of pa<ents receiving or planned for stem cell transplanta<ons (SCT) / donor lymphocyte infusion (DLi) are shown (n.n. = not known) (n=18). Overall response rate was 56% (17% CR, 33% CRi, 6% PR,). Fi[y-­‐six percent of pa<ents received or were planned for SCT / DLi. 7 Conclusions •  The prognosis of relapsed/refractory AML pa9ents is remarkably poor. •  Our findings suggest that treatment with Ara-­‐C and idarubicin in combina9on with selinexor shows a promising complete response rate and may serve as a bridge to transplant for pa9ents with relapsed/refractory AML. •  No unexpected toxici9es were encountered. References 1) Ofran et al., Current opinion in hematology, 2012 2) Ferrara et al., Haematologica, 2004 3) Parikh et al., Journal of hematology & oncology, 2014 4) Etchin et al., Bri<sh journal of haematology, 2013 8