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A Phase I Study of Selinexor in Combination with High-Dose Cytarabine and Mitoxantrone for Remission Induction in Patients with Acute Myeloid Leukemia Amy Y

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A Phase I Study of Selinexor in Combination with High-Dose Cytarabine and Mitoxantrone for Remission Induction in Patients with Acute Myeloid Leukemia Amy Y Wang et al. Journal of Hematology & Oncology (2018) 11:4 DOI 10.1186/s13045-017-0550-8 RESEARCH Open Access A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia Amy Y. Wang1, Howard Weiner2, Margaret Green2, Hua Chang3, Noreen Fulton2, Richard A. Larson2, Olatoyosi Odenike2, Andrew S. Artz2, Michael R. Bishop2, Lucy A. Godley2, Michael J. Thirman2, Satyajit Kosuri2, Jane E. Churpek2, Emily Curran2, Kristen Pettit4, Wendy Stock2 and Hongtao Liu2* Abstract Background: Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents. Methods: We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito). Results: Three (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m2), and 17 (85%) received the target level of 80 mg (~ 50 mg/m2). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%) , cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction. Conclusion: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/ m2/day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination. Trial registration: ClinicalTrials.gov, NCT02573363. Registered October 5, 2015 Keywords: AML, Selinexor, Induction chemotherapy, XPO1/CRM1 * Correspondence: [email protected] 2Department of Medicine, Section of Hematology/Oncology, University of Chicago Medicine, 5841 S. Maryland, MC 2115, Chicago, IL 60637-1470, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Journal of Hematology & Oncology (2018) 11:4 Page 2 of 10 Background Based on phase I safety and efficacy data of selinexor Acute myeloid leukemia (AML) is the most common acute in patients with AML, the promising results with leukemia in adults and is characterized by a poor prognosis HiDAC/Mito induction, and the in vivo and in vitro data with a 5-year survival rate of approximately 30% [1]. Even suggesting synergistic killing of AML cell lines by com- patients who achieve remission to initial therapy often re- bining selinexor and anthracyclines, we hypothesized lapse, and certain subgroups such as those with therapy- that selinexor would sensitize AML cells to the cytotoxic related AML, older patients, and those with relapsed or effects of HiDAC/Mito. We monitored the impact on refractory disease have a particularly poor outcome [2, 3]. minimal residual disease (MRD) by tracking the level of Novel agents that are active and able to be widely applied Wilms tumor 1 (WT1) expression. WT1 levels in the are imperative. Selinexor (KPT-330), an exportin 1 (XPO1) peripheral blood predict relapse after remission, and inhibitor,maybesuchanagent. their levels after consolidation therapy are closely corre- XPO1 is the exclusive, nuclear exporter of most major lated with survival and early relapse [18, 19]. In this tumor suppressor proteins (TSP) and growth regulatory phase I study, we describe the safety, tolerability, correla- proteins (GRP), including p53, p21, p73, FOXO1, and tive molecular studies, and activity of selinexor in com- NPM1 [4–6]. In leukemia and solid tumors, XPO1 is bination with HiDAC/Mito for remission induction in overexpressed leading to enhanced transport of these patients with previously untreated or relapsed/refractory proteins to the cytoplasm, thereby neutralizing their (R/R) AML. anti-neoplastic functions and functionally inactivating TSP/GRP. Elevated levels of XPO1 have been independ- Methods ently associated with a worse prognosis in adults with Study subjects and design AML [7, 8]. These findings presented an attractive target We performed a phase I dose escalation trial with co- for the development of a novel class of XPO1 inhibitors. hort expansion that combined increasing doses of seli- However, the earliest compounds of XPO1 inhibitors nexor with age-adjusted HiDAC/Mito (NCT02573363). had faced significant toxicities in phase I clinical trials The trial was approved by the Institutional Review requiring discontinuation, while others were never studied Board at The University of Chicago (IRB15-0412). Pa- in a clinical setting [9]. tients with newly diagnosed or R/R AML, except acute Selinexor (KPT-330) is an oral, first-in-class, slowly promyelocytic leukemia, were eligible to enroll if they reversible, and potent agent that was among the next had adequate performance status (ECOG ≤ 2), cardiac group of selective inhibitor of nuclear export (SINE) function (ejection fraction > 50%), renal function (cre- compounds to be developed, which also included KPT- atinine clearance > 30cm3/min), and hepatic function 335, KPT-185, KPT-276, and KPT-251, many of which (transaminases ≤ 3.0 times upper limit of normal). Ex- have since been studied in clinical trials. The SINE com- clusion criteria included active central nervous system pounds bind to residue Cys528 of XPO1 and blocks the (CNS) leukemia, pregnancy, recent treatment with any transport of cargo proteins [5]. In both AML primary investigational agent, recent major surgery, concurrent samples and murine xenograft models, SINE compounds malignancy under active treatment, active infection, or have been shown to reduce XPO1 levels and enhance recent seizure or stroke. Dose escalation of selinexor the nuclear accumulation of p53 [10, 11]. A phase I clin- was performed according to a 3 + 3 design [20]. Patient ical trial of selinexor in patients with advanced AML enrollment began in October 2015. demonstrated it to have a manageable safety profile at 35 mg/m2 (60 mg) and to be efficacious in a single-agent Treatment regimen setting [12]. Figure 1 shows the study schematic. HiDAC (3 g/m2,or In vivo and in vitro evidence suggest synergistic activity 2 g/m2 if > 70 years, intravenously over 4 h) followed im- against leukemic cells by combining selinexor with anthra- mediately by Mito (30 mg/m2, or 20 mg/m2 if > 70 years, cyclines or DNA-damaging agents [13]. The combination intravenously over 1 h) were administered on days 1 and of high-dose cytarabine (HiDAC) with the anthracycline 5. This regimen was based on several studies demon- mitoxantrone (Mito) is an effective induction regimen for strating efficacy in response and leukemia cell dynamics patients with AML [14–17] and is frequently utilized at [14, 15]. Selinexor was given orally on days 2, 4, 9, and the University of Chicago as frontline therapy for patients 11. Initial selinexor dose was 60 mg (~ 35 mg/m2 for an with high-risk AML, either de novo or relapsed/refractory. average adult) followed by dose escalation to a target The HiDAC/Mito regimen demonstrated an overall re- level of 80 mg (~ 50 mg/m2). Patients who failed to sponse rate (ORR) of 55% in the high-risk AML popula- achieve remission after induction were taken off the tion at this institution [16] and an ORR of 82% in another study. A second cycle of induction was not given. Pa- study of previously untreated patients with therapy- tients who entered remission proceeded to allogeneic related myeloid neoplasms [17]. hematopoietic cell transplantation (HCT), if feasible, or Wang et al. Journal of Hematology & Oncology (2018) 11:4 Page 3 of 10 Fig. 1 Study schematic. Schematic of phase 1 dose escalation study. Selinexor dosing remained unchanged for all phases, except for 2 patients who received reduced selinexor dosing during consolidation. Twenty patients entered induction, and 14 achieved a response. No patients received a second cycle of induction. No patients withdrew. Six patients entered consolidation, but 1 soon proceeded to allogeneic HCT. Ultimately, 8 underwent allogeneic HCT. One patient quickly relapsed after induction prior to starting the next phase of therapy. HCT = hematopoietic cell transplantation consolidation chemotherapy with
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