Inhibitor Of Nuclear Export Compound Research Articles

A Phase 2b Study of Selinexor in Combination with Carfilzomib, Daratumumab, or Pomalidomide in Patients with Multiple Myeloma Relapsing on Current Therapy

Background: Selinexor is an oral, selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1), leading to retention of tumor suppressor proteins and apoptosis in malignant cells. Preclinical studies suggest synergistic activity when selinexor is combined with other treatments for multiple myeloma (MM). We hypothesize the addition of selinexor can recapture response to patients relapsing on their current carfilzomib (CFZ), pomalidomide (POM) or daratumumab (DARA)-based regimens. Methods: This is an ongoing phase 2b, open-label, multicenter investigator-initiated study to evaluate the safety and efficacy of selinexor plus CFZ, POM, or DARA. MM patients with documented disease progression or refractory disease while on current treatment with any CFZ-containing regimen (Arm 1), any POM-containing regimen (Arm 2), or any DARA-containing regimen (Arm 3) were eligible for this study. Patients were assigned to the respective arm only if their most recent line of therapy contained the specific drug of interest. Arm 1 consists of selinexor 80 mg orally on D1, 8, 15; CFZ 56 mg/m 2 IV on D1, 8, 15; and dexamethasone (DEX) 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. Arm 2 consists of selinexor 60 mg orally on D1, 8, 15; POM 4 mg orally on D1-21; and DEX 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. Arm 3 consists of selinexor 100 mg orally on D1, 8, 15, 22; DARA 16 mg/kg IV or 1,800 mg SQ dosing as per standard of care; and DEX 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. The primary endpoint is overall response rate (ORR), which includes patients who experience partial response (PR), very good partial response (VGPR), complete response (CR), or stringent CR (sCR), based on International Myeloma Working Group response criteria (Kumar 2016). Secondary endpoints include duration of response (DOR), clinical benefit rate (CBR = sCR + CR + VGPR + PR + stable disease [SD]), progression-free survival (PFS), and treatment-emergent adverse events (TEAEs). Results: At data cutoff (July 14, 2023), there were 23 patients enrolled, including 20 patients on trial, 2 screen failures, and 1 in screening. Of the 20 patients on trial, 1 patient was enrolled onto Arm 1, 9 patients onto Arm 2, and 10 patients onto Arm 3. The median age was 66 years (range 52-83), 30% with ISS stage III MM, 75% with high-risk cytogenetics, 90% refractory to the last LOT, 50% triple refractory, and 35% quadruple refractory. Fifteen unique patients had high-risk cytogenetics, which included 9 patients with 1q21 duplication, 7 with t(4;14), 2 with del(17p)/monosomy 17, 4 with TP53 mutation, and 1 with complex karyotype. In 18 patients evaluable for response, the ORR was 33% (6/18; PR, 6 [33%]) and the CBR was 89% (16/18; PR, 6 [33%]; SD, 10 [56%]); 2 patients withdrew consent before response evaluation. For Arm 2, the ORR was 29% (2/7; PR, 2 [29%]) and the CBR was 86% (6/7; PR, 2 [29%]; SD, 4 [57%]). For Arm 3, the ORR was 44% (4/9; PR, 4 [44%]) and the CBR was 100% (9/9; PR, 4 [44%]; SD, 5 [56%]). In the overall cohort, median DOR was 9.46 months (95% CI, 5.1-12.3), and median PFS was 5.98 months (95% CI, 3.9-NR) (Figure 1). There were 18/20 patients who experienced any grade TEAEs (Table 1). No treatment-related deaths occurred. The most common grade 3 TEAEs were neutropenia (25%), thrombocytopenia (15%), pneumonia (10%), and hyperglycemia (10%). One patient experienced a grade 4 TEAE of neutropenia. There were 3 unique patients who experienced SAEs related to study treatment, which included pneumonia (n=2), chest pain (n=1), sepsis (n=1), and lactic acidosis (n=1). Seventeen patients discontinued treatment due to disease progression (n=12) and withdrawal of consent (n=5). Two patients are deceased: one patient died during long-term follow-up unrelated to treatment of disease; and one patient was hospitalized for dehydration, anorexia, and hyponatremia after C1D8 of KCD then experienced progressive cytopenias upon discharge likely due to disease progression. Conclusions: Preliminary results suggest selinexor plus CFZ, POM, or DARA is safe and restores sensitivity to therapy in relapsed/refractory MM patients. In this population of heavily pretreated MM patients relapsing on their most recent line of therapy, the ORR of 33% and CBR 89% highlights the clinical potential and generally manageable side effect profile of selinexor as an add-on drug for patients with relapsed/refractory MM in combination with CFZ, POM, and DARA. Clinical trial information: NCT04661137.

Safety and Efficacy of Selinexor Sequential Azacytidine in Newly Diagnosed Patients with Myelodysplastic Syndromes EB1 or EB2: A Single-Center, Single-Arm, Phase Ib/II Trial

Background: Azacytidine is one of the hypomethylating agents (HMAs) for the treatment of higher-risk myelodysplastic syndromes (MDS). However, clinical outcomes of patients treated with azacytidine monotherapy were far from satisfactory with overall response rate (ORR) of 41%-59% and overall survival (OS) of 15-18 months. Selinexor is an oral, first-in-class selective inhibitor of nuclear export compound that inhibits exportin 1 (XPO1). Preclinical studies have shown that inhibition of XPO1 causes nuclear accumulation of p53 and disruption of NF-κB signaling, both relevant targets for myelodysplastic syndromes. Prior study reported an ORR of 26% and mOS of 8.7 months with selinexor in HMAs-refractory MDS patients. We therefore aimed to assess the safety and efficacy of selinexor sequential azacytidine in newly diagnosed patients with MDS-EB1 or EB2. Methods: The effectiveness of simultaneous and sequential treatment of azacytidine and selinexor was measured by cell death rate, cell cycle and colony formation rate in vitro. Western Blot was performed to detect the sublocation of p53. MOLM-13-luciferase xenograft murine model was established to verify the synergetic effect in vivo. Based on the experiments, we conducted a single-center, single-arm, phase Ib/II trial, which included newly diagnosed patients 18 years or older with MDS-EB1 or EB2. Eligible patients received 2-4 weeks long cycles of oral selinexor (40mg qw for 4 weeks; 40mg biw for 2 weeks; 60mg qw for 4 weeks). The primary endpoints were to find the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD). The secondary endpoint was ORR including complete remission (CR), partial remission (PR), marrow complete remission (mCR), and hematological improvement (HI). This trial was registered with the Chinese Clinical Trial Registry (#ChiCTR2200065167). Results: First we treated three AML cell lines: AML-OCI2, THP1, MV4-11 and three MDS cell lines: SKM-1, MOLM-13, MDSL with azacitidine and selinexor simultaneously or sequentially. Sequential treatment showed stronger synergetic effect (Figure 1A) and reduced colony formation by 90% in SKM-1 and MOLM-13 (Figure 1B). Cell cycle arrest were induced and the percentage of Annexin V cells obviously increased with sequential treatment (Figure 1C). Sequential treatment decreased leukemia burden and prolonged survival of MOLM-13-luciferase xenograft murine model (Figure 1D, E). Mechanistically, pretreatment of azacitidine on SKM-1 and MOLM-13 upregulated the expression level of p53, and selinexor led to massive nuclear accumulation of p53, resulted in better vulnerability lethal to MDS cells (Figure 1F). Secondly, 15 patients were enrolled in our trial with a median age of 57. 26.7% of patients were MDS-EB1, 73.3% were EB2. 93.3% of patients were high or very high risk by the Revised International Prognositic Scoring System (IPSS-R) (see the Table). At Phase Ib, the following selinexor dosages were administered: 40mg qw (n=3), 40mg biw (n=3) and 60mg qw (n=3). One patient in the 60mg qw group discontinued treatment because of nausea, vomiting, fatigue and Herpes simplex virus infection. Subsequently, in order to find RP2D, an extension cohort of 3 additional patients were treated with 40mg qw and 40mg biw, respectively. Therefore, 14 patients were evaluable for efficacy assessment. ORR was 78.6% in 11 patients including CR in 3 patients (21.4%); mCR+HI in 1 patient (7.1%); and mCR in 7 patients (50.0%) (see the swimmer plot). Especially, among the TP53 mutated patients (n=3), one achieved CR, the other two achieved mCR. The common adverse events were neutropenia (93.3%), anemia (86.7%), thrombocytopenia (80.0%), fatigue (53.3%), nausea (26.7%), dizziness (26.7%), vomiting (20.0%) and decreased appetite (20.0%). There were no treatment related deaths. Conclusion: We verified the activity of selinexor sequential azacytidine in MDS both in vitro and in vivo. The treatment showed with encouraging efficacy in newly diagnosed patients with MDS-EB1 or EB2. Adverse events were manageable with supportive care implementation. Enrollment is ongoing to assess the efficacy and safety of this sequential therapy, which may be a new treatment option for EB subjects.

A phase IIb study of selinexor in combination with carfilzomib, daratumumab, or pomalidomide in patients with multiple myeloma relapsing on current therapy.

e20042 Background: Selinexor is an oral, selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1), leading to retention of tumor suppressor proteins and apoptosis in malignant cells. Preclinical studies suggest synergistic activity when selinexor is combined with other treatments for MM. We hypothesize the addition of selinexor can recapture response to patients relapsing or refractory on carfilzomib (CFZ), pomalidomide (POM) or daratumumab (DARA)-based regimens. Methods: This is an ongoing phase IIb, open-label, multicenter study to evaluate the safety and efficacy of selinexor plus CFZ, POM, or DARA in patients with MM. Patients were enrolled to each arm only if their disease was refractory to the specific drug of interest (CFZ for Arm 1, POM for Arm 2, and DARA for Arm 3). Arm 1 (n=1) consists of selinexor 80 mg orally on D1, 8, 15; CFZ 56 mg/m2 IV on D1, 8, 15; and dexamethasone (DEX) on D1, 8, 15, 22. Arm 2 (n=7) consists of selinexor 60 mg orally on D1, 8, 15; POM 4 mg orally on D1-21; and DEX on D1, 8, 15, 22. Arm 3 (n=7) consists of selinexor 100 mg orally on D1, 8, 15, 22; DARA 16 mg/kg IV or 1,800 mg SQ on D1, 8, 15, 22 for C1-2; D1 and 15 for C3-6; D1 for ≥C7; and DEX on D1, 8, 15, 22. The primary endpoint is ORR and secondary endpoints include PFS, OS, MRD negativity and TEAEs. Results: At data cutoff (Feb 6 2023), 15 patients were enrolled with a median age of 64 years (range 60-83), 27% with ISS stage III MM, 73% with high-risk cytogenetics, 93% refractory to the last LOT, 47% triple refractory, and 33% quadruple refractory (Table). The ORR was 33% (4/12; 4 PR) and the CBR was 92% (11/12; 7 SD); 3 patients are pending. The most common grade 3-4 TEAEs (n=34) were neutropenia (32%), hypophosphatemia (9%), pneumonia (6%), hyperglycemia (6%), and fatigue (6%). Ten patients discontinued treatment due to PD (n=5), withdrawal of consent (n=2), or TEAEs (n=3; fall, diarrhea, and RSV pneumonia), of whom 1 patient died while hospitalized for diarrhea and weakness. Conclusions: Preliminary results show selinexor plus CFZ, POM, or DARA is safe and restores sensitivity to therapy in relapsed/refractory MM patients. In this population of heavily pretreated MM patients, the ORR (33%) and CBR (92%) observed are higher compared to those seen with single-agent selinexor (ORR 4% and CBR 21%) (Chen C et al, Blood 2018). Clinical trial information: NCT04661137 . [Table: see text]

Selinexor: Targeting a novel pathway in multiple myeloma.

Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin-1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor-based therapy has been approved for the treatment of relapsed/refractory MM (RRMM), with selinexor-dexamethasone approved in the later-relapse setting for penta-refractory patients and selinexor-bortezomib-dexamethasone approved for patients who have received ≥1 prior therapy. Here, we provide a comprehensive review of the clinical data on selinexor-based regimens, including recent updates from the 2022 American Society of Hematology annual meeting, and summarise ongoing studies of this novel targeted agent in newly diagnosed MM and RRMM.

Selinexor in Combination with R-GDP for Patients with Relapsed/Refractory B-Cell Lymphoma: Results of the Selinda Phase Ib Lysa Study

Selinexor in Combination with R-GDP for Patients with Relapsed/Refractory B-Cell Lymphoma: Results of the Selinda Phase Ib Lysa Study

Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies

AbstractThe selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies. However, many tumors are not responsive to venetoclax. We used models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) to determine in vitro and in vivo responses to treatment with venetoclax and SINE compounds combined. Cotreatment with venetoclax and SINE compounds demonstrated loss of viability in multiple cell lines. Further in vitro analyses showed that this enhanced cell death was the result of an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays, coinciding with activation of p53 and loss of MCL1. Treatment with SINE compounds and venetoclax combined led to a reduction in tumor growth in both AML and DLBCL xenografts. Immunohistochemical analysis of tissue sections revealed that the reduction in tumor cells was partly the result of an induction of apoptosis. The enhanced effects of this combination were validated in primary AML and DLBCL patient cells. Our studies reveal synergy with SINE compounds and venetoclax in aggressive hematologic malignancies and provide a rationale for pursuing this approach in a clinical trial.

Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma

BackgroundSelinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.MethodsWe administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.ResultsA total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.ConclusionsSelinexor–dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.)

Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis

AbstractSelinexor is the first oral selective inhibitor of nuclear export compound tested for cancer treatment. Selinexor has demonstrated a safety therapy profile with broad antitumor activity against solid and hematological malignancies in phases 2 and 3 clinical trials (#NCT03071276, #NCT02343042, #NCT02227251, #NCT03110562, and #NCT02606461). Although selinexor shows promising efficacy, its primary adverse effect is high-grade thrombocytopenia. Therefore, we aimed to identify the mechanism of selinexor-induced thrombocytopenia to relieve it and improve its clinical management. We determined that selinexor causes thrombocytopenia by blocking thrombopoietin (TPO) signaling and therefore differentiation of stem cells into megakaryocytes. We then used both in vitro and in vivo models and patient samples to show that selinexor-induced thrombocytopenia is indeed reversible when TPO agonists are administered in the absence of selinexor (drug holiday). In sum, these data reveal (1) the mechanism of selinexor-induced thrombocytopenia, (2) an effective way to reverse the dose-limiting thrombocytopenia, and (3) a novel role for XPO1 in megakaryopoiesis. The improved selinexor dosing regimen described herein is crucial to help reduce thrombocytopenia in selinexor patients, allowing them to continue their course of chemotherapy and have the best chance of survival. This trial was registered at www.clinicaltrials.gov as #NCT01607905.

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors.

Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry-based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors. Cancer Res; 77(20); 5614-27. ©2017 AACR.

Abstract 464: Novel role of xpo1 in regulating MicroRNAs related to pancreatic ductal adenocarcinoma invasion and metastasis

Abstract Objective: There are no known reports on the role of exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) in microRNA biology. In this study, we for the first time demonstrate that interfering with XPO1 machinery can influence miRNA signaling leading to suppression of pancreatic ductal adenocarcinoma (PDAC) proliferation, invasion and metastasis. Methods: miRNA arrays (LCSciences, Houston, TX) were performed on total RNA samples from PDAC cell lines (HPAC, MiaPaCa-2, AsPc-1 and L3.6pl) and normal human pancreatic ductal epithelial (HPDE) cells. PDAC cells were treated with XPO1 inhibitor (Selinexor) or transfected with control siRNA, XPO1 siRNA (Santa Cruz), miR-control or miR-145 mimic (Applied biosystems) all at a final concentration of 20 nM using DharmaFact Transfection Reagent (Dharmacon, Lafayette. CO). The total RNA and total protein from treated or transfected cells were subjected to real-time PCR or immunoblot analysis in order to measure expression level of miR-145, let-7d, miR-34c, miR-320, miR-205, and miR-145 target or downstream genes including EGFR, MMP1, MT-MMP, c-Myc, Sox-2, and PAK4. The impact of XPO1 inhibitor Selinexor on PDAC growth, proliferation, invasion and migrations was also evaluated using MTT and scratch assay. Results: In this study, we show that PDAC cells have significantly reduced expression of miR-145 when compared to normal pancreatic duct epithelial cells. Similarly, forced expression of miR-145 in PDAC cells inhibited cell proliferation and migration. Conversely, we demonstrate that RNAi of XPO1 by siRNA knockdown or chemical inhibition of XPO1 by selective inhibitor of nuclear export compound (Selinexor) restores miR-145 expression in PDAC cells ultimately leading to inhibition of cell proliferation and migration. In addition, we show that the inhibition of cell proliferation and migration by Selinexor is mediated through the down-regulation of known miR-145 signals including EGFR, MMP1, MT-MMP, c-Myc, PAK4 and Sox-2. Selinexor also induced the expression of two important tumor suppressive miRNAs, miR-34c and let-7d, leading to the up-regulation of p21WAF1. We also observed the down-regulation of oncomir mir-205. Conclusions: These results are the first to show that targeted inhibition of the nuclear exporter protein XPO1 by RNAi or Selinexor could restore tumor suppressive miRs in PDAC. Citation Format: Asfar S. Azmi, Yiwei Li, Irfana Muqbil, Amro Aboukameel, William Senapedis, Erkan Baloglu, Yosef Landesman, Michael Kauffman, Sharon Shacham, Philip A. Philip, Ramzi M. Mohammad. Novel role of xpo1 in regulating MicroRNAs related to pancreatic ductal adenocarcinoma invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 464. doi:10.1158/1538-7445.AM2017-464

A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia

AbstractSelinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m(2), 50 mg/m(2), or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes. The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma. Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.

Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc.

The Selective Inhibitor of Nuclear Export Compound, Selinexor, Inhibits NF-κB and Induces Anti-Non-Small Cell Lung Cancer Activity Regardless of p53 Status

The Selective Inhibitor of Nuclear Export Compound, Selinexor, Inhibits NF-κB and Induces Anti-Non-Small Cell Lung Cancer Activity Regardless of p53 Status