Selective Inhibitor Of Nuclear Export Research Articles

Selinexor Combined with Ibrutinib Demonstrates Tolerability and Efficacy in Advanced B-Cell Malignancies: A Phase I Study

Selinexor Combined with Ibrutinib Demonstrates Tolerability and Efficacy in Advanced B-Cell Malignancies: A Phase I Study

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome

Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (e.g. p53, IκB), and promotes the translation of eIF4E-bound mRNAs coding oncoproteins (e.g. c-MYC, BCL-2, AR). Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Eltanexor (elta), a second-generation SINE compound, has demonstrated reduced brain penetration and improved tolerability compared to selinexor in non-clinical animal models, and preliminary anti-tumor activity in clinical trials of hematologic and solid tumor malignancies. The primary objective of this study was to assess the safety, tolerability and anti-tumor activity of elta in patients (pts) with higher risk (HR)-Myelodysplastic Syndrome (MDS). Methods: This is part of a Phase 1/2 study (NCT02649790) to determine the safety, tolerability and anti-tumor activity of elta in advance malignancies. This trial planned to evaluate single agent activity of elta in an expansion cohort of 20 pts with HR-MDS (intermediate-2 [Int-2] or high-risk by the International Prognostic Scoring System [IPSS]). Other key eligibility criteria included: age ≥18, ECOG ≥1, adequate organ function, and documented evidence of progressive disease as defined by the 2006 International Working Group (IWG) Response Criteria for MDS, which includes hypomethylating agent (HMA) failure. The dose levels evaluated in the MDS cohort were 10 and 20 mg elta taken orally once daily for 5 consecutive days per week in a 28-day cycle. A key efficacy endpoint is overall response rate (ORR) which includes complete response (CR), partial response (PR), marrow CR (mCR), and hematologic improvement (HI) using the 2006 IWG Response Criteria for MDS. Results: Twenty pts (median age 77 years-old; range 62-89; 55% male) were enrolled as of 15 July 2018 (n=15 at 20 mg and n=5 at 10 mg). All pts were refractory to HMA with a median of 2 prior therapies (range 1 - 5) and 90% high risk via IPSS (11 pts high, 7 pts Int-2, 2 pts Int-1 [IPSS-R high]). Fourteen of 20 pts were evaluable for response, 2 are pending disease reassessment and 4 were not evaluable (NE). Preliminary efficacy demonstrated best responses of 4 mCR (29%) and 6 stable disease (SD; 43%) and 4 progressive disease (PD; 29%). The disease control rate (mCR + SD) was 71%. The median time on treatment for all pts was 69 days (range 5+ - 379) with a median time on study of 115 days (range 5+ - 400). The most frequent (≥3 pts) treatment-related adverse events (TRAEs) any grade (Gr) included nausea (53%), decreased appetite (33%), diarrhea (27%), thrombocytopenia, anemia, neutropenia, vomiting and dysgeusia (20% each). The most frequent Gr≥3 TRAEs included thrombocytopenia and anemia which are expected in this immune compromised patient population. All AEs were reversible and manageable by supportive care and dose modification. The 4 pts NE for response were pts who discontinued from treatment before having the first disease response reassessment due to: Gr3 diarrhea related to eltanexor, Gr5 sepsis not related per investigator, Gr3 pneumonia not related, and withdrawal by pt. Conclusion: Oral eltanexor demonstrated preliminary anti-tumor activity as a single agent in elderly pts with HMA-refractory HR-MDS, including mCRs or disease stabilization, and a manageable tolerability profile. Further evaluation of efficacy and safety in HR-MDS is on-going. Disclosures Lee: Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Bhatnagar:Karyopharm Therapeutics: Other: Research support; Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties. Baloglu:Karyopharm Therapeutics Inc: Equity Ownership, Patents & Royalties; resTORbio: Employment. Wang:Karyopharm Therapeutics Inc: Employment. Shah:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Effect of Age on the Safety and Efficacy of Selinexor in Patients with Relapsed Refractory Multiple Myeloma: A Post-hoc Analysis of the STORM Study

The advent of newer therapies has significantly improved the outcomes in patients (pts) with refractory multiple myeloma (MM). However, the treatment of elderly pts remains challenging. Selinexor (SEL) is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. SEL plus low dose dexamethasone (SEL-DEX) induced an overall response rate (ORR) of 26.2% in pts with penta-exposed, triple-class refractory MM. Side effects were generally reversible without evidence of major organ toxicities.

Improvements in Renal Function with Selinexor in Relapsed/Refractory Multiple Myeloma: Post-hoc Analyses from the STORM Study

There is an unmet need for effective therapies in patients (pts) with adverse prognostic factors such as renal impairment, a common complication of multiple myeloma (MM). Selinexor (SEL), a novel, oral selective inhibitor of nuclear export (SINE) blocks XPO1, forcing nuclear activation of tumor suppressor proteins. In the STORM study, SEL plus low dose dexamethasone (SEL-DEX) induced an overall response rate (ORR) of 26.2% in pts with penta-exposed, triple-class refractory MM. Side effects were generally reversible without evidence of major organ toxicities.

Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma. Selinexor (SEL) is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. SEL in combination with dexamethasone (DEX) has demonstrated an overall response rate (ORR) of 26.2% in patients (pts) with triple class refractory MM. Lenalidomide (LEN) in combination with DEX is approved for the treatment of RRMM with an overall response rate (ORR) of 60-76%.

EBV-Positive Primary Large B-cell Lymphoma: Highlighting the Role of XPO1 in the Diagnosis of Mediastinal Lymphomas

Abstract Background Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is described to be almost always negative for EBV in the current WHO. In the context of a mediastinal lymphoma, the distinction between PMBL, classic Hodgkin lymphoma (CHL), diffuse large B-cell lymphoma, and mediastinal gray-zone lymphoma can be very difficult; hence, EBV positivity often aids in pointing away from a diagnosis of PMBL. However, since EBV positivity can occur in rare PMBLs, it should not be the deciding factor in the diagnosis; assistance from molecular studies is emerging in these difficult cases. Case Presentation We present a 19-year-old male patient with a 2-week history of cough, vocal changes, and occasional dysphagia who was found upon imaging to have a 6-cm mediastinal mass. The biopsy of this mass was morphologically consistent with PMBL but the tumor was EBV positive by in situ hybridization. Methods We performed next-generation sequencing using Oncomine Comprehensive Assay v3 (ThermoFisher Scientific) on formalin-fixed, paraffin-embedded tumor tissue with a buccal swab sample for germline control. Variant calling, filtering, and annotation were performed by the Yale Tumor Profiling Laboratory. Results We found somatic mutations in XPO1, SMARCB1, and MYC. Along with classic immunophenotype of PMBL including positivity for MAL, OCT2, BOB1, BCL6, CD79a, MUM1, CD20, and subset weak CD30, the diagnosis was confirmed to be PMBL. Conclusion This is the first EBV-positive PMBL in which molecular profiling was performed. XPO1, specifically the mutation hotspot (E571K), found in our case is involved in PMBL and CHL. This was clinically helpful in confirming the histopathologic diagnosis and also opening up a targeted therapeutic option. Selective inhibitors of nuclear export (SINEs) that block the binding of XPO1 to its cargo are in clinical development as antineoplastic agents and have shown promising activity against some hematologic malignancies.

PL3.5 Efficacy and safety of selinexor in recurrent glioblastoma

Abstract BACKGROUND New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N=8). We now report updated results following completion of accrual to non-surgical cohorts (N=68). MATERIALS AND METHODS This is an open-label, multicenter, phase 2 study of selinexor monotherapy. Patients (pts) not undergoing surgery for measurable rGBM per response assessment neuro-oncology criteria (RANO) were enrolled in one of 3 arms encompassing different dosing schedules of selinexor (50 mg/m2 [~ 85 mg] BIW, 60 mg BIW, and 80 mg QW). Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan-Meier method. RESULTS 76 pts were enrolled; 24, 14 and 30 pts on doses of ~85 mg BIW, 60 mg BIW, and 80 mg QW, respectively. Median age was 56 years (range 21–78). Median number of prior treatments was 2 (range 1–7) At the end of the 6 cycles, 30.2% pts on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 18.9%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Complete and partial responses were durable: the complete and a partial responder remain on selinexor for 393 and 1093 days respectively, as of the cut-off date. Median duration of response was 10.8 months. The most common related adverse events (all grades) in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/63%), leukopenia (38%/7%/43%), fatigue (71%/71%/47%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). CONCLUSION Selinexor demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, selinexor at a dose of 80 mg QW is recommended for further development in rGBM.

The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice.

Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that is caused by the loss of functional dystrophin protein in cardiac and skeletal muscles. DMD patient muscles become weakened, leading to eventual myofiber breakdown and replacement with fibrotic and adipose tissues. Inflammation drives the pathogenic processes through releasing inflammatory cytokines and other factors that promote skeletal muscle degeneration and contributing to the loss of motor function. Selective inhibitors of nuclear export (SINEs) are a class of compounds that function by inhibiting the nuclear export protein exportin 1 (XPO1). The XPO1 protein is an important regulator of key inflammatory and neurological factors that drive inflammation and neurotoxicity in various neurological and neuromuscular diseases. Here, we demonstrate that SINE compound KPT-350 can ameliorate dystrophic-associated pathologies in the muscles of DMD models of zebrafish and mice. Thus, SINE compounds are a promising novel strategy for blocking dystrophic symptoms and could be used in combinatorial treatments for DMD.

TRAIL responses are enhanced by nuclear export inhibition in osteosarcoma

Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-tumour agent that induces apoptosis of malignant cells through activation of death receptors. Death receptor agonistic antibodies are in clinical trials as TRAIL-mimetics, however, along with TRAIL monotherapy, there is limited efficacy due to the rapid emergence of TRAIL resistance, or due to existing TRAIL-insensitive disease. TRAIL-sensitisers, which enhance TRAIL activity or overcome TRAIL resistance, may facilitate death receptor agonists as viable anti-tumour strategies. In this study we demonstrate that the nuclear export inhibitor Leptomycin B, is a potent in vitro TRAIL-sensitiser in osteosarcoma cell lines. Leptomycin B works synergistically with both TRAIL and death receptor 5 agonistic antibodies to induce apoptosis in TRAIL sensitive cell lines. Further, Leptomycin B sensitises TRAIL-insensitive cell lines to TRAIL and death receptor agonistic antibody mediated apoptosis. We also confirmed that aldehyde dehydrogenase (ALDH) positive cells are not resistant to the apoptotic effects of TRAIL and Leptomycin B, an important observation since ALDH positive cells can have enhanced tumorigenicity and are implicated in disease recurrence and metastasis. The nuclear export pathway in combination with death receptor agonists, is a potential therapeutic strategy in osteosarcoma and warrants further research on clinically relevant selective inhibitors of nuclear export.

Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy

Immune checkpoint pathways active in Acute Myeloid Leukemia (AML) patients, especially during the course of remission induction chemotherapy, have not been well studied. Although dominant in mediating T cell dysfunction in cancer, it is now well-accepted that interruption of PD-1/PD-L1 axes alone does not always completely restore T cell function, indicating the involvement of additional negative regulatory pathways, such as TIM-3/Gal-9, in promoting T cell exhaustion.Here, we characterized these pathways in AML patients enrolled in a phase I dose escalation trial that combined Selinexor, a Selective Inhibitor of Nuclear Export (SINE), with high-dose cytarabine (HiDAC) and mitoxantrone (Mito) (NCT02573363) as induction therapy.To monitor changes in expression of immune checkpoint receptors, multi-parameter flow cytometry was performed on peripheral blood and bone marrow biopsy specimens at diagnosis and following induction therapy in 26 AML patients. Expression of CD47, PD-L1, PD-L2 and Gal9 was assessed on CD34+ AML blasts, as well as on CD34− cell populations. In parallel, we evaluated expression of inhibitory (PD1, CTLA4, LAG3, TIM-3) and stimulatory (CD28, ICOS, CD137, OX40, CD40L, HLA-DR) co-receptors on CD4+ and CD8+ T cell subsets.Compared to baseline, the frequency of Gal9+ CD34− cells was significantly higher in patients with treatment failure (TF) than in those in complete remission (CR), and this finding correlated with increased TIM-3 expression on marrow-resident T cells in TF patients. Moreover, when we measured the expression level of PD-1 and TIM-3 in bone marrow samples compared to peripheral blood, TIM-3 was significantly higher in BM specimens.Our results suggest that targeting the Gal9/Tim-3 axis could be effective in combination with induction chemotherapy to increase the likelihood of complete remission in AML patients.

Abstract 3476: Evaluable antitumor activity in metastatic pancreatic adenocarcinoma with specific inhibitor of nuclear export based treatment

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease in urgent need of newer therapeutic modalities. Earlier we have shown that in PDAC, the over-expression of the nuclear exporter protein Exportin-1 (XPO1) leads to functional inactivation of tumor suppressor proteins (TSPs; FOXO3a, p27, Par-4 etc.) through mis-localization. We demonstrated that inhibition of XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) Selinexor and analogs restores the anti-tumor function of multiple TSPs leading to PDAC cell death and tumor inhibition in orthotopic models. Methods: Here we evaluate the synergy between SINE compounds and standard of care gemcitabine-nab-paclitaxel in PDAC models in vitro, in vivo and in a Phase Ib/2 trial (NCT02178436). Results: Selinexor and second generation SINE compound eltanexor synergized with gemcitabine (GEM) and nab-paclitaxel leading to suppression of PDAC growth, induction of apoptosis, and superior spheroid disintegration of PDAC derived cancer stem cells (CSCs). The observed synergy was due in part to enhanced nuclear localization of TSPs and suppression of both CSCs and epithelial-to-mesenchymal transition (EMT) markers. Label-Free quantitative (LFQ) proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. The protein class with highest percent of nuclear retention were DNA binders. Selinexor and eltanexor as single agent (used at MTD) inhibited the growth of PDAC-CSC and two patient derived (Pdx) sub-cutaneous xenografts (p<0.01). In combination experiment, selinexor-GEM-nab-paclitaxel used at sub-MTD dose could significantly suppress the growth of PDx tumors. Molecularly, we observed down-regulation of CRM1 and target TSPs ex vivo. In a Phase 1b/2 study examining patients with metastatic pancreatic cancer, 9 patients were exposed to selinexor (60 mg oral) with GEM (1000 mg/m2 IV) and nab-paclitaxel (125 mg/m2 IV) once weekly (Mondays) for 3 weeks. Evaluable responses were observed in patients on this trial. 2 patients showed partial response (PR) and 2 had stable disease. Outstanding objective response was observed in 1 patient who demonstrated remission for 16 months and remained alive for 22 months. Remarkable and sustained reduction in CA19-9 levels were observed in the responding patient. Conclusions: These results rationally fortify selinexor-gemcitabine-nab-paclitaxel as new and effective therapy for metastatic PDAC and strengthen our ongoing Phase II study. Citation Format: Asfar S. Azmi, Yosef Landesman, Michael Kauffman, Sharon Shacham, Gabriel Mpilla, Amro Aboukameel, Steve Kim, Mandana Kamgar, Anteneh Tesfaye, Ramzi M. Mohammad, Philip A. Philip. Evaluable antitumor activity in metastatic pancreatic adenocarcinoma with specific inhibitor of nuclear export based treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3476.

Abstract 1998: Selinexor effectively inhibits tumor growth in a triple negative breast cancer brain metastasis mouse model

Abstract Introduction: Breast cancer brain metastasis (BCBM) is a devastating disease and remains largely incurable. Patients with triple negative breast cancer (TNBC) develop brain metastasis at a significantly higher incidence (46%) than patients with other breast cancer subtypes. Median survival after brain metastases in TNBC can be as short as 5 months. Selinexor is a first-in-class oral SINE (Selective Inhibitor of Nuclear Export) drug that inhibits XPO1 (exportin-1/ CRM1) activity and exhibits remarkable anti-cancer activity in advanced clinical trials. Moreover, selinexor can penetrate the blood-brain barrier and shows promising anti-tumor activity in animal models of glioblastoma and central nervous system lymphoma. Previous studies have shown that most TNBC cell lines tested in vitro and in vivo are sensitive to selinexor-induced growth inhibition and cell death. To explore the possibility of using selinexor as an effective treatment for TNBC brain metastasis, a mouse model was established and tested. Methods: TNBC cell line HCC1806 (ATCC# CRL-2335) was transformed with RediFect Red-Fluc-Puromycin and selected using puromycin to generate HCC1806-Fluc cells that expressed both puromycin resistance gene and a luciferase gene. Twenty-four nu/nu mice were inoculated intracranially with 1 x 104 HCC1806-Fluc cells. Four days post implant, mice were allocated to three groups of eight mice and treated with either vehicle, selinexor 10 mg/kg, or selinexor 15 mg/kg through oral gavage, three times per week (Mon, Wed, Fri). Body weight and condition of animals were recorded daily, and tumors were imaged twice per week (Tue and Thu). Brain tissues were collected at the end of study and analyzed by immunohistochemistry (IHC). Results: HCC1806-Fluc cells injected intracranially successfully implanted in the brains of host mice. All mice survived the duration of the study (day 16 after treatment initiation) and no significant difference in body weight was observed between different treatment groups. Mice treated with selinexor had a significant reduction in tumor area relative to vehicle controls. Tumor growth inhibition (TGI) was 103% for selinexor at 10 mg/kg and 97% for selinexor at 15 mg/kg compared to vehicle controls. IHC showed reduced tumor cell proliferation, decreased expression of Myc and Survivin, and increased nuclear expression of p21 and p27 in tumor samples from the brain of mice treated with selinexor as compared to that of controls. Decreased expression of HDAC1 and HDAC5 was also observed in brain tumor samples from selinexor-treated mice. Conclusions: Oral intake of selinexor effectively inhibited TNBC cell growth in a mouse model of brain metastasis. The anti-cancer effect is likely achieved through multiple signaling pathways, including cell cycle regulation, down-regulation of oncogenes and HDACs. Citation Format: Hua Chang, Marsha Crochiere, Sophie Debler, Trinayan Kashyap, Thaddeus J. Unger, Erkan Baloglu, William Senapedis, Sharon Shacham, Yosef Landesman. Selinexor effectively inhibits tumor growth in a triple negative breast cancer brain metastasis mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1998.

Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia.

Chemoresistance is a major cause of recurrence and death from T-cell acute lymphoblastic leukemia (T-ALL), both in adult and pediatric patients. In the majority of cases, drug-resistant disease is treated by selecting a combination of other drugs, without understanding the molecular mechanisms by which malignant cells escape chemotherapeutic treatments, even though a more detailed genomic characterization and the identification of actionable disease targets may enable informed decision of new agents to improve patient outcomes. In this work, we describe pathways of resistance to common chemotherapeutic agents including glucocorticoids and review the resistance mechanisms to targeted therapy such as IL7R, PI3K-AKT-mTOR, NOTCH1, BRD4/MYC, Cyclin D3: CDK4/CDK6, BCL2 inhibitors, and selective inhibitors of nuclear export (SINE). Finally, to overcome the limitations of the current trial-and-error method, we summarize the experiences of anti-cancer drug sensitivity resistance profiling (DSRP) approaches as a rapid and relevant strategy to infer drug activity and provide functional information to assist clinical decision one patient at a time.

S1606 SAFETY AND EFFICACY OF COMBINATION OF SELINEXOR, DARATUMUMAB, AND DEXAMETHASONE (SDD) IN PATIENTS WITH MULTIPLE MYELOMA (MM) PREVIOUSLY EXPOSED TO PROTEASOME INHIBITORS AND IMMUNOMODULATORY DRUGS

Background:Selinexor is a first‐in‐class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor in combination with dexamethasone (dex) has demonstrated a 26.2% overall response rate (ORR) in patients (pts) with triple‐class refractory myeloma (defined as refractory to an immunomodulatory drug (IMiD), proteasome inhibitor (PI), and CD‐38 monoclonal antibody [mAb]) including deep responses with very good partial response (VGPR) and 2 pts in a stringent complete response (sCR) (minimal residual disease negative). Daratumumab (Dara), an anti‐CD38 mAb, is approved for the treatment of heavily pretreated MM is limited by short progression‐free survival (PFS) and an ORR of ∼21% in quad‐refractory MM.Aims:The objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, and preliminary efficacy of the combination of SDd in pts with PI/IMiD refractory MM.Methods:This is amulticenter, open‐label, phase 1/2b study with a dose escalation and expansion phase.Pts were eligible if they had received ≥3 prior lines of anti‐myeloma therapy, including a PI and an IMiD or whose MM is refractory to a PI and IMiD. In the expansion phase, pts’ prior dara therapy was exclusionary. Selinexor was dose‐escalated in 2 concurrent cohorts: once‐weekly (QW, at 100 mg) or twice‐weekly (BIW, at 60 mg). Dara was administered at 16 mg/kg IV (recommended schedule) and dex at 40 mg QW or 20 mg BIW. In the expansion phase, pts were to receive the RP2D.Results:As of February 20th2019, 30 pts (16 male/14 female) have been enrolled. Three pts have been enrolled into the 60 mg BIW and 27 pts in the 100 mg QW cohorts. The median age was 69 years and the median number of prior treatment regimens was 3 (range, 2 – 10). Common treatment‐related adverse events (all grades, Grades 3/4) included: thrombocytopenia (66%, 48%), nausea (66%, 3%), fatigue (55%, 14%), anemia (52%, 31%), leukopenia (48%, 31%), and neutropenia (48%, 24%). Two dose‐limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: Grade 3 thrombocytopenia and Grade 2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort (n = 6), no DLTs occured.Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, dara 16 mg/kg, and dex 40 mg, administered QW. A total of 28 pts were evaluable for response.In dara naïve pts (n = 26), the ORR was 77% (9 VGPR, 8 partial response, 3 unconfirmed partial response). In the 2 pts with dara refractory MM, there was one progressive disease and one stable disease.Summary/Conclusion:Selinexor 100 mg QW can be combined safely with dara (per approved dosing) and dex to produce a deep and durable response warranting further investigation in pts with relapsed refractory MM. The ORR was 77% in pts who had not received prior dara or selinexor. Enrollment in the expansion arm is expected to be completed in March 2019 and full study results will be presented.

PF587 SELINEXOR, POMALIDOMIDE, AND DEXAMETHASONE (SPD) IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA

Background:The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM) and associated with poor prognosis. Selinexor is a first‐in‐class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, therefore forces the nuclear retention and re‐activation of cell cycle regulators such as p53, FOXO, IkB, and Rb. Pomalidomide/dexamethasone (Pd) achieved an overall response rate (ORR) of 31% and progression‐free survival (PFS) rate of <4 months in patients (pts) refractory to prior bortezomib and lenalidomide (Richardson et al, Blood 2014). Methods to increase response rate and depth are needed. Selinexor in combination with dexamethasone (dex) has demonstrated a 26.2% ORR in pts with triple‐class refractory myeloma including deep responses with very good partial response (VGPR) and 2 pts in a stringent complete response/minimal residual disease negative. It is hypothesized that the combination of SPd may improve the ORR, depth of response, and PFS.Aims:The primary objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, and preliminary efficacy of the combination of SPd in pts with RRMM.Methods:STOMP is amulticenter, open‐label, phase 1/2b, dose escalation study with an expansion phase.Eligiblity included pts with RRMM who received ≥2 prior therapies including lenalidomide (len) and a proteasome inhibitor (PI). Oral (PO) selinexor was evaluated in 2 different dosing schedules of once‐weekly (QW, 60 or 80 mg) or twice‐weekly (BIW, 60 or 80 mg), with escalating doses of pomalidomide (pom)2, 3, or 4 mg PO on Days 1–21, and low dose dexamethasone (dex) 20 mg BIW or 40 mg QW. In the expansion phase, all pts were pom naïve.Results:As of February 20th2019, 43 pts (22 male/21 female) have been enrolled. The median age is 61 years and pts received a median of 4 (range, 2 – 9) prior treatment regimens. Thirty‐nine pts were immunomodulatory imide drug (IMiD) refractory (26 refractory to len, 13 pts refractory to pom and len). The phase 1 dose escalation is ongoing. Enrollment is ongoing in 2 difference schedules: selinexor 80 mg/pom 2 mg and selinexor 60 mg/pom 4 mg in combination with dex. Six dose‐limiting toxicities (DLTs) were observed (see Table 1). Common hematologic SPd treatment‐related adverse events (TRAE) included (all grades, Grades 3/4): neutropenia (54%, 49%), thrombocytopenia (51%, 30%), anemia (47%, 30%). Common non‐hematologic TRAE were predominantly Grade 1/2 and include nausea (51%, 0%), fatigue (47%, 9%), anorexia (42%, 0%). Thirty‐seven pts were evaluable for response. Among pts who were pom naïve (n = 27), the ORR was 52% (5 VGPR, 9 partial response [PR]) and the median progression‐free survival (PFS) was 12.2 months. Among pts refractory to len/pom (n = 10) the ORR was 30% (2 PR, 1 unconfirmed PR) and the median PFS was 5.5 months.Summary/Conclusion:Once weekly selinexor can be safely combined with pom/dex. The all oral SPd combination is durable and active with a 52% ORR in pom‐naïve pts with heavily pretreated MM compared to previously published data of 31% ORR for pom/dex. The median PFS on SPd of 12.2 months in pom naïve pts is significantly longer than that observed with pom/dex (<4 months). No unexpected adverse events were noted. Cytopenias were expected and known with IMiD use. Non‐hematologic side effects were limited to Grade 1/2 events. The RP2D will be presented at the meeting and supports future phase 2/3 studies in RRMM.image

Phase 1b study of selinexor, a first-in-class selective inhibitor of nuclear export (SINE) compound, in combination with doxorubicin in patients (pts) with locally advanced or metastatic soft tissue sarcoma (STS).

3123 Background: Selinexor is a first-in-class SINE compound with single-agent activity in STS. We undertook this study to determine the safety, tolerability and efficacy of selinexor in combination with doxorubicin in pts with incurable STS. Methods: This phase 1b study was conducted using a bayesian model (modified toxicity probability index). Patients with locally advanced or metastatic STS received selinexor at either 60 or 80mg weekly PO plus doxorubicin (75mg/m2 IV q21 days, max 6 cycles). Pts with stable disease (SD) or better (per RECIST 1.1 criteria) after 6 cycles of combination treatment received selinexor monotherapy until disease progression or unacceptable toxicity. Disease assessments were made with standard imaging after every 2 cycles. Results: 24 pts (19F/5M, ECOG 0/1: 12/12, median age 58.5 years [range 34-74]) were enrolled. Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumor (n = 3) and other sarcomas (n = 15). Three pts at 60mg selinexor and 21 pts at 80mg selinexor were treated. The most common G3 drug related adverse events were hematological, neutropenia n = 13 (54%), anemia n = 6 (25%). There were 4 dose-limiting toxicities (2 febrile neutropenia, 1 vomiting and 1 unresolved fatigue) all at the 80mg dose level, but does not satisfy criteria for maximum tolerated dose. Two patients had clinically significant and relevant drop in ejection fraction, presenting with cardiac symptoms. Of the 24 evaluable pts 4 (17%) had a partial response, 16 (67%) had SD as best response and SD > 16 weeks was seen in 13 pts (54%). PK analysis of selinexor did not demonstrate changes compared to single agent profile. The estimated median PFS and OS are 5.5 (95% CI:4.1-7.0) and 9.4 (6.6-13.8) months. Conclusions: Our initial data demonstrate that the combination of selinexor at 80mg with doxorubicin is tolerable and is associated with clinical benefit. Longer term follow up of available patients will be needed to understand toxicity profile. Clinical trial information: NCT03042819.

Efficacy and safety of selinexor in recurrent glioblastoma.

2005 Background: New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor (SEL) is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N = 8). We now report updated results following completion of accrual to non-surgical cohorts (N = 68). Methods: This is an open-label, multicenter, phase 2 study of SEL monotherapy. Patients (pts) not undergoing surgery for measurable rGBM (per RANO) were enrolled in one of 3 arms encompassing different dosing schedules. Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan Meier method. Results: A total of 76 pts were enrolled. Median age was 56 years (range 21-78). Median number of prior treatments was 2 (range 1-7). At the end of the 6 cycles, 30.2% patients on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 15.1%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Median duration of response was 10.8 months. The most common related adverse events in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/60%), leukopenia (38%/7%/43%), fatigue (71%/71%/43%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). Conclusions: SEL demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, SEL at a dose of 80 mg QW is recommended for further development in rGBM. Clinical trial information: NCT01986348. [Table: see text]

Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).

197 Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound oncoprotein mRNAs (eg. c-MYC). XPO1 inhibition reduces total androgen receptor levels, including ARv7, and may re-sensitize prostate cancer (PC) cells to androgen deprivation therapy. Selinexor, the first-in-human SINE compound, showed anticancer activity in patients (pts) with mCRPC. Eltanexor (ELTA), a second-generation SINE compound, showed promising anticancer activity in preclinical models of PC, including in abiraterone (ABI) resistant cell lines. Therefore, ELTA ± ABI was evaluated in mCRPC. Methods: This was part of a phase 1/2 study to determine the safety, preliminary efficacy, and recommended phase 2 doseof ELTA in pts with advanced cancers. Pts with mCRPC received oral ELTA once daily for 5 days per week over a 28-day cycle in 4 cohorts: single-agent (20 mg; n=7 or 30 mg; n=6) or in combination with ABI (20 mg; n=13 or 30 mg; n=4). Pts may have prior exposure to chemotherapy. Pts receiving ELTA + ABI had prior response to ABI then progressed. Response was evaluated by PCWG3 / RECIST v1.1. Results: As of 17 Sept 2018, 30 pts were treated with ELTA ± ABI with a median age of 71 and a median of 4 prior regimens; (87% ABI, 60% enzalutamide, and 57% chemotherapy). Twenty-one pts with mCRPC were evaluable for efficacy: 2 partial response (10%), 15 stable disease (71%), and 4 progressive disease (19%). The median treatment duration is 75.5 days; 4 pts still on treatment. Treatment-related adverse events (TRAEs) occurring in ≥30% of the pts: fatigue (67%; 13% Gr≥3), nausea (63.3%; 0% Gr≥3), decreased appetite (57%; 0% Gr≥3), diarrhea (47%; 3% Gr≥3), weight decreased (43%; 3% Gr≥3), vomiting (37%; 7% Gr≥3), anemia (33%; 7% Gr≥3), and dysgeusia (33%; 0% Gr≥3). The 2 Gr4 TRAEs were neutropenia and elevated AST. Conclusions: ELTA± ABI is well-tolerated with AEs mostly limited to Gr 1/2 and demonstrates preliminary anti-tumor activity in patients with mCRPC. With enrollment complete, these results warrant further investigation of ELTA ± ABIin mCPRC. Clinical trial information: NCT02649790.

XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB.

Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader antitumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell-cycle arrest and XPO-1 knockdown also retarded cell growth. Furthermore, downregulation of the NFκB gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NFκB was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IκB that was accompanied by the reduction of DNA-binding activity of NFκB, suggesting that NFκB is trapped in an inhibitory complex. Coimmunoprecipitation confirmed that p65 of NFκB and IκB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IκB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NFκB pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NFκB inhibition.

Results of the Pivotal STORM Study (Part 2) in Penta-Refractory Multiple Myeloma (MM): Deep and Durable Responses with Oral Selinexor Plus Low Dose Dexamethasone in Patients with Penta-Refractory MM

Results of the Pivotal STORM Study (Part 2) in Penta-Refractory Multiple Myeloma (MM): Deep and Durable Responses with Oral Selinexor Plus Low Dose Dexamethasone in Patients with Penta-Refractory MM