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Preliminary phase II results of Ara-C and idarubicin in combination with selective inhibitor of nuclear export (SINE) compound selinexor (KPT-330) in patients with relapsed or refractory AML

Fiedler, W., Heuser, M., Ottmann, Oliver, Kebenko, M., Thol, F., Trummer, A., Brandts, C., Bokemeyer, C., Theile, S. and Kranich, A. 2015. Preliminary phase II results of Ara-C and idarubicin in combination with selective inhibitor of nuclear export (SINE) compound selinexor (KPT-330) in patients with relapsed or refractory AML. Haematologica 100 , p. 221.

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Abstract

Background Acute myeloid leukemia (AML) is one of the most common leukemia’s affecting adults. Although 70-80% of patients achieve a complete remission (CR), patients with AML who fail to achieve a CR after the first cycle of induction therapy and those with relapsed disease have a bleak prognosis. Currently no standard regimen exists for the treatment of patients with relapsed AML and a great clinical need exists for new treatment options. Selinexor, an oral first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, inhibits XPO1 mediated nuclear export to induce cytotoxicity in cells with genomic damage such as tumor cells. In Vivo model with selinexor alone or combination with AraC significantly prolonged the survival of leukemic mice from a median survival of 24 days (APL + vehicle) to 39 days, respectively (P < 0.0001). Combination therapy prolonged survival (P < 0.0001), with some mice being cured of the disease. Phase I clinical study demonstrates encouraging results in AML patient. The role of selinexor as a mono therapy is currently under investigation in phase II. Aims This phase II trial explores the efficacy & tolerability of Ara-C and idarubicin in combination with selinexor in patients with relapsed or refractory AML. Methods Patients with relapsed/refractory AML are treated with Ara-C (100 mg/m2, continuous infusion, day 1-7), idarubicin (10 mg/m2, day 1, 3, 5) every 4 weeks. In the majority of the patients selinexor is administered twice weekly orally starting on day 2 (40 mg/m2). A small cohort of patients received selinexor after registration and before first induction cycle for correlative studies. The primary endpoint is percentage of patients achieving a complete response or complete remission without normalization of peripheral blood counts (CRi). Other endpoints are partial response rate, percentage of patients undergoing subsequent allogeneic stem cell transplant, early death rate, overall survival (OS), event-free survival and toxicity. Results As of 20-April-2015, 18 patients with AML have been enrolled in 3 sites. Informed consent was obtained from all patients. Median age was 56 years. Out of 18 patients, 17 patients received ≥ 1 induction and 15 patients (9 male, 6 female) were evaluable for efficacy at the time of analysis. In average, patients received 2.4 therapies prior to study start. Overall response rate was 53% (13% of patients achieved CR, 40% of patients achieved CRi). Stable disease was observed in 13% of patients. Sixty-seven percent of patients received or were planned for stem cell transplant or donor lymphocyte infusion. Drug related AEs comprised 61% of all CTC Grade 3/4 and 46% of all CTC Grade 1/2 events. Grade 3/4 drug related adverse events (AEs) include febrile neutropenia (71%), diarrhea (71%), anorexia (57%), thrombocytopenia (43%), leukopenia (43%), anemia (29%) and nausea (29%). Grade 1/2 drug related AEs include: diarrhea (86%), vomiting (71%), nausea (71%), anorexia (43%), constipation (43%), fatigue (29%) and oral mucositis (29%). No drug-related deaths occurred. Summary The prognosis of relapsed/refractory AML patients is remarkably poor. Our findings suggest that treatment with Ara-C and idarubicin in combination with selinexor might be a potentially effective strategy for patients with relapsed/refractory AML without unexpected toxicities. Most common AEs were of low CTC grade.

Item Type: Article
Date Type: Publication
Status: Published
Publisher: Ferrata Storti Foundation
ISSN: 0390-6078
Last Modified: 04 Jun 2017 09:33
URI: http://orca-mwe.cf.ac.uk/id/eprint/96774

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