Published OnlineFirst October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-2169 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Phase I Clinical Trial of Selinexor in Combination with Daunorubicin and Cytarabine in Previously Untreated Poor-Risk Acute Myeloid Leukemia Kendra Sweet1, Rami Komrokji1, Eric Padron1, Christopher L. Cubitt2, Joel G. Turner3, Junmin Zhou4, Alan F. List1, David A. Sallman1, Jana L. Dawson5, Daniel M. Sullivan3, Julio Chavez1, Bijal D. Shah1, and Jeffrey E. Lancet1 ABSTRACT ◥ Purpose: Induction chemotherapy results in complete and recommended phase II dose of selinexor were the primary remission (CR) rates of 20% to 50% among patients with endpoints. poor-risk AML. Selinexor is an oral selective inhibitor of Results: Twenty-one patients with poor-risk AML were nuclear export with promising single-agent activity. By inhi- enrolled. All 21 patients were included in the safety evaluations biting the primary export protein, XPO1, selinexor localizes and survival analyses (4 in each of 2 cohorts; 13 in the expansion); and activates tumor suppressor proteins in the nucleus and 8 (53%) of the 19 patients evaluable for response achieved CR/CRi. inhibits DNA damage repair, rationalizing combination with MTD was not reached. Selinexor 80 mg (orally, twice weekly) was DNA-damaging agents. used in the expansion phase. The most common grade 3/4 Patients and Methods: This was a single-arm phase I nonhematologic treatment-emergent adverse events were febrile clinical trial of selinexor combined with cytarabine and dau- neutropenia (67%), diarrhea (29%), hyponatremia (29%), and norubicin (7þ3). Dose escalation was selinexor alone (3þ3) sepsis (14%). At median follow-up (28.9 months), 38% of patients with an expansion at the MTD. Cohorts 1 and 2 received 60 were alive. Median overall survival was 10.3 months. and 80 mg orally, respectively, twice weekly during induction. Conclusions: Selinexor plus 7þ3 is a safe regimen for patients Consolidation cycles ( 2) with selinexor at induction dose with newly diagnosed poor-risk AML and warrants further inves- plus 5þ2 were allowed for patients who achieved CR. MTD tigation in a larger clinical trial. Introduction the inactivation of TSPs, allowing malignant cells to evade apopto- sis (3). XPO1 is overexpressed in AML cells, and increased levels of Acute myeloid leukemia (AML) is a clonal hematopoietic disorder XPO1 are inversely correlated with overall survival (OS) in patients characterized by a block in myeloid differentiation and aberrant with AML (4). proliferation of immature myeloid progenitors. An inherent feature Selective inhibitors of nuclear export (SINE) compounds are orally of these self-renewing leukemia-initiating cells is their resistance to bioavailable small molecules that function by covalently binding to chemotherapy, which contributes to disease relapse (1). Nuclear– cysteine 528 in the cargo-binding pocket of the XPO1 protein. This cytoplasmic protein transport is required to maintain normal intra- prevents XPO1 from binding to the nuclear export signal of proteins, cellular signaling and cell-cycle regulation (2). Exportin 1 (XPO1/ thereby preventing the loading and nuclear export of cargo proteins. CRM1) is the sole nuclear export protein responsible for the cyto- The resulting nuclear retention, accumulation, and activation of TSPs plasmic translocation of nearly all tumor suppressor proteins (TSP) restore the tumor suppressor function, leading to apoptosis and cell- and growth regulators, including p53, p21, p27, forkhead box O3 cycle arrest of tumor cells, as well as forced differentiation of myeloid (FOXO3), and nucleophosmin 1 (NPM1). This nuclear export leads to blasts. These effects are seen in bulk tumor cells and leukemia- initiating cells (1, 5–8). Another client of XPO1 is the protein topo- isomerase IIa. Cytoplasmic localization of topoisomerase IIa is a well- 1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and documented mechanism of chemotherapy resistance in multiple Research Institute, Tampa, Florida. 2Department of Translational Research, H. myeloma and AML (9). Selinexor (KPT-330) is a SINE compound Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 3Department that has been extensively studied in laboratories by using AML cell of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt lines, AML patient cells, and mouse models. Selinexor is reported to 4 Cancer Center and Research Institute, Tampa, Florida. Department of Immu- block XPO1, leading to nuclear retention of cargo proteins, including nology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 5Department of Experimental Therapeutics, H. Lee Moffitt Cancer Center and TSPs, and restore their functions. Selinexor also restores topoisom- Research Institute, Tampa, Florida. erase IIa in the nucleus and synergistically sensitizes cells to topo- isomerase II inhibitors, such as idarubicin, daunorubicin, etoposide, Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). and mitoxantrone (3, 6, 10). The nuclear retention of topoisomerase IIa causes downregulation of DNA repair proteins, such as Rad51 and Corresponding Author: Kendra L. Sweet, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612. Phone: 813-745- Chk1, and results in increased lethal DNA double-strand breaks in the 6841; Fax: 813-745-3071; E-mail: kendra.sweet@moffitt.org presence of topoisomerase II inhibitors (10). When given sequentially with chemotherapy, selinexor appears to synergize with many DNA- Clin Cancer Res 2019;XX:XX–XX damaging agents (including idarubicin, daunorubicin, mitoxantrone, doi: 10.1158/1078-0432.CCR-19-2169 etoposide, and fludarabine), especially when the selinexor exposure Ó2019 American Association for Cancer Research. precedes that of the other drugs. Preclinical studies completed at our AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-2169 Sweet et al. Selinexor was given 2 hours before daunorubicin on days 1 and 3 on the Translational Relevance basis of preclinical studies, suggesting that selinexor sensitizes leuke- This clinical trial studied a group of patients with AML with very mic blasts to chemotherapy (3). During the dose escalation phase, poor-risk disease. Treatment options for these patients are limited patients who did not receive at least 5 doses of selinexor, in the absence and are often ineffective. The preclinical rationale for the combi- of a dose-limiting toxicity (DLT), were replaced. nation of drugs used was strong. This is the first clinical trial Reinduction was permitted for patients with residual leukemia seen completed using this combination in this clinical setting, and the on a day 21 bone marrow biopsy, provided a 50% reduction in the results are encouraging. The safety profile of this treatment com- total blast count from baseline was observed. Reinduction consisted of bination was acceptable for this particular group of patients, and administration of daunorubicin (45 mg/m2/day) on days 1 and 2 and the clinical responses suggest that the combination therapy may be cytarabine (100 mg/m2/day) as a continuous intravenous infusion on more effective than standard chemotherapy regimens alone. The days 1 through 5 (5þ2 regimen). Selinexor was given at the same dose results of this clinical trial justify a larger clinical trial with this as induction on days 1, 3, 8, and 10. On day 1, selinexor was given combination therapy. 2 hours before daunorubicin administration. Patients who achieved complete remission (CR) or CR with incom- plete blood count recovery (CRi) were allowed to receive up to 2 cycles of consolidation therapy, consisting of 5þ2 with selinexor given at the institution using AML cell lines and AML patient cells indicated strong same dose as induction on days 1, 3, 8, and 10. synergistic interactions between selinexor and daunorubicin, and these Patients were permitted to discontinue their participation in the data rationalized the development of this clinical trial (Supplementary study and proceed to allogeneic hematopoietic stem cell transplant Figs. S1 and S2; Supplementary Table S1). Several early-phase trials (HSCT) at any time after achieving CR/CRi. Patients who did not have studied selinexor in AML both as a single agent and in combi- undergo HSCT could subsequently receive maintenance therapy nation with chemotherapy and report encouraging results (6, 11–13). consisting of selinexor at the same dose as induction on days 1 and This phase I study (NCT02403310) was conducted to further assess 8 of a 21 day cycle for up to 17 cycles (12 months). the role of selinexor in patients with previously untreated, poor-risk Supportive care measures were established to manage side-effects. AML when administered in combination with cytarabine and dau- These included the use of prophylactic antibiotics, antifungal agents, norubicin. The aim of the study was to identify the MTD and the and antivirals. Nausea was managed with antiemetics as needed and, recommended phase II dose (RP2D) of selinexor and to assess the for some patients, nausea management consisted of empiric treatment safety profile and preliminary signals of efficacy with this combination. with olanzapine (5 mg) taken orally at bedtime beginning 24