Selective Inhibitor Of Nuclear Export Research Articles

Impact of Prior Therapies on the Safety and Efficacy of Once Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the Boston Study

Impact of Prior Therapies on the Safety and Efficacy of Once Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the Boston Study

A Phase I Study of Selinexor and R-ICE in Patients with Relapsed/Refractory Aggressive B-Cell Lymphomas

A Phase I Study of Selinexor and R-ICE in Patients with Relapsed/Refractory Aggressive B-Cell Lymphomas

A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers

PurposeSelinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population. Patients and methodsThis phase I, 3 + 3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m2 or 60 mg plus CP at AUC 5 and 175 mg/m2 or 80 mg/m2, respectively) for 6–10 cycles (1 cycle = 21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks. ResultsTwenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers. ConclusionsCombination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers.

Multiple Myeloma: An Overview of the Current and Novel Therapeutic Approaches in 2020.

The survival rate of multiple myeloma (MM) patients has drastically increased recently as a result of the wide treatment options now available. Younger patients truly benefit from these innovations as they can support more intensive treatment, such as autologous stem cell transplant or multiple drug association (triplet, quadruplet). The emergence of immunotherapy allowed new combinations principally based on monoclonal anti-CD38 antibodies for these patients. Still, the optimal induction treatment has not been found yet. While consolidation is still debated, maintenance treatment is now well acknowledged to prolong survival. Lenalidomide monotherapy is the only drug approved in that setting, but many innovations are expected. Older patients, now logically named not transplant-eligible, also took advantage of these breakthrough innovations as most of the recent drugs have a more acceptable safety profile than previous cytotoxic agents. For this heterogenous subgroup, geriatric assessment has become an essential tool to identify frail patients and provide tailored strategies. At relapse, options are now numerous, especially for patients who were not treated with lenalidomide, or not refractory at least. Concerning lenalidomide refractory patients, approved combinations are lacking, but many trials are ongoing to fill that space. Moreover, innovative therapeutics are increasingly being developed with modern immunotherapy, such as chimeric antigen receptor T-cells (CAR-T cells), bispecific antibodies, or antibody-drug conjugates. For now, these treatments are usually reserved to heavily pre-treated patients with a poor outcome. MM drug classes have tremendously extended from historical alkylating agents to current dominant associations with proteasome inhibitors, immunomodulatory agents, and monoclonal anti-CD38/anti SLAMF7 antibodies. Plus, in only a couple of years, several new classes will enter the MM armamentarium, such as cereblon E3 ligase modulators (CELMoDs), selective inhibitors of nuclear export, and peptide-drug conjugates. Among the questions that will need to be answered in the years to come is the position of these new treatments in the therapeutic strategy, as well as the role of minimal residual disease-driven strategies which will be a key issue to elucidate. Through this review, we chose to enumerate and comment on the most recent advances in MM therapeutics which have undergone major transformations over the past decade.

Selinexor Sensitizes TRAIL-R2-Positive TNBC Cells to the Activity of TRAIL-R2xCD3 Bispecific Antibody.

Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific antibodies (BsAbs), able to redirect T cells against tumors, has shown promising results. In particular, a BsAb that uses TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) as a target was constructed and demonstrated good results in redirecting CD3+ T cells to kill TRAIL-R2-expressing TNBC cells. In the present study, we investigated whether treatment with selinexor, a selective inhibitor of nuclear export (SINE) targeting exportin-1/chromosome maintenance protein 1 (XPO1/CRM1), could potentiate the antitumor activity of this BsAb. In combination experiments, we found that selinexor-exposed TNBC cells exhibited greater growth inhibition when treated with the TRAIL-R2xCD3 BsAb than that expected by simple additivity. Similarly, the apoptosis rate in selinexor/TRAIL-R2xCD3 BsAb-treated TNBC cells was significantly higher than that observed after exposure to either single agent. Together, our results suggest that the combination of selinexor and TRAIL-R2xCD3 BsAb can be a viable anticancer strategy and indicate this treatment as a promising therapeutic option for TNBC patients.

Glucocorticoid receptor expression in multiple myeloma patients is a predictor of survival

Multiple myeloma (MM) is a blood neoplasia characterized by abnormal proliferation of plasma cells. Various treatments such as stem cell transplant (SCT), proteasome inhibitors, immune-modulating drugs, monoclonal antibodies and selective inhibitors of nuclear export have been routinely used to treat MM. However, relapse and treatment resistance are common problems in MM patients. Treatments are enhanced by Dexamethasone (Dex), a synthetic steroid that activates the glucocorticoid receptor (GR) which leads to apoptosis. To evaluate the potential impact of GR expression on overall survival, MM patient data from the CoMMpass study of 650 patients were analyzed. Multivariate modeling results show that increased GR expression at diagnosis is associated with a decreased risk of dying relative to those with lower levels of expression.

In vivo KPT-350 treatment decreases cortical hyperexcitability following traumatic brain injury

ABSTRACT Primary Objective We tested whether KPT-350, a novel selective inhibitor of nuclear export, could attenuate cortical network hyperexcitability, a major risk factor for developing post-traumatic epilepsy (PTE) following traumatic brain injury (TBI). Research Design All mice in this study underwent TBI and were subsequently treated with either KPT-350 or vehicle during the post-injury latent period. Half of the animal cohort was used for electrophysiology while the other half was used for immunohistochemical analysis. Methods and Procedures TBI was induced using the controlled cortical impact (CCI) model. Cortical network activity was recorded by evoking field potentials from deep layers of the cortex and analyzed using Matlab software. Immunohistochemistry coupled with fluorescence microscopy and Image J analysis detected changes in neuronal and glial markers. Main Outcomes and Results KPT-350 attenuated TBI-associated epileptiform activity and restored disrupted input-output responses in cortical brain slices. In vivo KPT-350 treatment reduced the loss of parvalbumin-(+) GABAergic interneurons after CCI but did not significantly change CCI-induced loss of somatostatin-(+) GABAergic interneurons, nor did it reduce reactivity of GFAP and Iba1 glial markers. Conclusion KPT-350 can prevent cortical hyperexcitability and reduce the loss of parvalbumin-(+) GABAergic inhibitory neurons, making it a potential therapeutic option for preventing PTE.

Abstract 3086: SINE compounds demonstrated potent anti-cancer activity in PDX mouse models of chordoma

Abstract Introduction: Chordoma is an ultra-rare cancer found in the base of the skull and the mobile spine that originates from embryonic remnants of the notochord. It is often resistant to standard chemotherapy and most systemic anti-cancer treatment, and surgical removal followed by radiation therapy remains the mainstay of current treatment. However, due to the difficult location of chordoma, complete surgical removal is not always possible. In addition, chordoma has a high rate of metastasis and recurrence. Therefore, novel and effective treatment options for chordoma are needed. Selective inhibitor of nuclear export (SINE) compounds selinexor and eltanexor are a class of novel oral drugs that target XPO1 (exportin-1/ CRM1) and exhibit anti-cancer activity across a wide range of solid and hematological malignancies. In July 2019, selinexor was approved by the US FDA to treat patients with multiple myeloma. To investigate the preclinical efficacy and tolerability of SINE compounds in chordoma, two PDX (patient derived xenograft) mouse models of chordoma were tested. Methods: Two SINE drugs, selinexor at 5 mg/kg x 4 times a week and eltanexor at 10 mg/kg x 5 times a week, alone or in combination with bortezomib were used to treat chordoma CF466 and SF8894 PDX mouse models. CF466 PDX was derived from a patient with metastatic sacral chordoma whereas SF8894 PDX was derived from a patient with recurrent clival chordoma. Tumor volume and mouse body weight were monitored during the study. Tumors were collected at the end of 6 weeks of the study for histological, and immunohistochemistry (IHC)-based biomarker analyses. Results: Both selinexor and eltanexor demonstrated potent anti-cancer activity compared to controls. Tumor growth inhibition (TGI) of selinexor was 58% and 78% in the CF466 and SF8894 models, respectively, and TGI of eltanexor was 55% in the SF8894 model. No significant difference in body weight was observed among different treatment groups. Bortezomib did not exhibit anti-tumor activity in these models nor did it have additive/synergistic effects when combined with selinexor or eltanexor. CF466 tumors from mice treated with selinexor showed increased apoptosis, decreased cell proliferation and lowered cell density when compared with the controls. In addition, IHC analysis showed that selinexor treatment increased nuclear retention of eIF4E and tumor suppressor proteins APC, SMAD4 and FOXO3A, and decreased the expression of proteins that may play a role in chordoma tumor biology, such as SHH, GLI1 and SOX9. Conclusions: SINE compounds effectively inhibit tumor growth in PDX mouse models of chordoma. The anti-cancer effects are likely achieved through regulation of multiple signaling pathways. Further investigation of SINE compounds as treatment options for chordoma is warranted. Citation Format: Hua Chang, Leah Henegar, Trinayan Kashyap, Thaddeus J. Unger, Sharon Shacham, Josh Sommer, Patty Cogswell, Stacy Fechner, Michael J. Wick, Joan Levy, Yosef Landesman. SINE compounds demonstrated potent anti-cancer activity in PDX mouse models of chordoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3086.

Abstract 4181: The XPO1 inhibitior, eltanexor, exhibits potent in vivo activity against a broad range of pediatric acute lymphoblastic leukemia subtypes

Abstract Introduction: Exportin 1 (XPO1/CRM1) plays a central role in the export of proteins from the nucleus including those with tumor suppressor and growth regulatory activity. Eltanexor (KPT-8602) is a second-generation Selective Inhibitor of Nuclear Export (SINE) that specifically blocks XPO1 cargo interactions and is under clinical evaluation for adults with cancer (NCT02649790). In previous Pediatric Preclinical Testing Consortium (PPTC) studies, eltanexor showed potent in vivo activity against acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs). In an effort to understand whether eltanexor exhibited subtype-specific activity in pediatric ALL we carried out a single-mouse trial (SMT) against an intended 90 pediatric ALL PDXs. Methods: Pediatric ALL PDXs, an orthotopic model of the disease, were inoculated into NSG mice in an SMT format (a single mouse inoculated with a single PDX was treated with a single drug). Engraftment and drug responses were assessed by weekly enumeration of the % human leukemic blasts in the peripheral blood (%huCD45+/HLA-ABC+). Treatment commenced when the median %huCD45+/HLA-ABC+ exceeded 1%, and mice received eltanexor at 12.5 mg/kg per oral daily x 5 for 4 weeks. The baseline level of the %huCD45+/HLA-ABC+ in each mouse served as its own control. PDX responses to treatment were assessed by time to event, the maximum decrease in %huCD45+/ABC+ at any point after treatment initiation, and by stringent Objective Response Measures (ORMs) modeled after the clinical setting (Houghton et al, Pediatr Blood Cancer, 2007, 49:928-40). Results: Eltanexor was well tolerated with a mean maximum weight loss of 5.5% across all mice. SMT testing was successful in all 90 pediatric ALL PDXs representative of B-ALL (typical B-ALL, Philadelphia chromosome-positive ALL [Ph+-ALL] and Ph-like ALL), T-ALL (typical T-ALL and early T-cell precursor ALL [ETP-ALL]), and MLL-rearranged ALL (MLLr-ALL). Event-free survival (EFS) of mice ranged from 2.6-137 days, and 61 (68%) of mice experienced EFS that extended beyond the treatment window. Regressions of ≥50% from baseline were observed in 56 (62%) of mice, and these were most pronounced in T-ALL (14/18, 78%) and Ph-like ALL (11/19, 58%). ORMs classified as Complete Response (CR) or Maintained CR (MCR) were elicited in 43 (48%) of PDXs, and again these were more common in T-ALL (12/18, 67%). The ALL subtypes that exhibited the poorest responses to eltanexor were Ph+-ALL and ETP-ALL, although with relatively small sample size (n=3 and 6, respectively). ORMs in the SMT correlated highly with historical conventional drug testing (R=0.94, P<0.001, n=12). Conclusions: Eltanexor exhibits potent single-agent in vivo activity against PDXs derived from a broad range of ALL subtypes including T-ALL and Ph-like ALL and warrants further investigation in pediatric ALL. (Supported by NCI Grants CA199222 & CA199000) Citation Format: Richard B. Lock, Kathryn Evans, Connor D. Jones, Stephen W. Erickson, Beverly A. Teicher, TJ Unger, Yosef Landesman, Malcolm A. Smith. The XPO1 inhibitior, eltanexor, exhibits potent in vivo activity against a broad range of pediatric acute lymphoblastic leukemia subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4181.

Abstract 569: Rational combination approaches with CRM-1 inhibitor in ovarian cancer

Abstract Background: After the frontline treatment, the majority of patients diagnosed with ovarian cancer at an advanced stage will develop recurrence (80%); thus, there is an urgent need for novel therapeutic approaches. Purpose: Selinexor is a CRM1 inhibitor, which is a selective inhibitor of nuclear export and has demonstrated antitumor effects in ovarian cancer. Here, we examined the efficacy of selinexor alone and in combination with PARP inhibitors in ovarian cancer. As Selinexor reduces the expression of DNA damage repair proteins, we hypothesized that this combination should reduce the number of DNA damage repair proteins, resulting in synergistic tumor cell death. Methods: Western blot was performed to assess baseline CRM1 expression in eleven ovarian cancer cell lines. We tested the efficacy of selinexor alone and in combination with olaparib in ovarian cancer cells (A2780ip2, OVCAR5). Combination Indices (CI) were calculated with CompuSyn and were considered synergistic when CI less than 1 for classic MTT arrays. We used the annexin V-FITC/PI assay to assess apoptosis as a result of selinexor and olaparib alone or in combination. Results: Baseline CRM1 expression was positive in eight of eleven ovarian cancer cell lines tested. The average IC50 in A2780ip2 for selinexor and olaparib was 0.09uM and 0.97uM, respectively. The median combination index was 0.81 in A2780ip2 and 0.92 in OVCAR5 cells. Flow cytometry demonstrated an additive effect of selinexor and olaparib in A2780ip2 cell apoptosis (7.34% and 7.93%, respectively, v. 17.86%). Conclusions: Selinexor demonstrates synergistic activity with olaparib, and this combination warrants further investigation. Citation Format: Katelyn F. Handley, Cristian Rodriguez-Aguayo, Shaolin Ma, Mark S. Kim, Prahlad T. Ram, Anil K. Sood. Rational combination approaches with CRM-1 inhibitor in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 569.

NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors.

XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from in vivo mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SINE in vitro and in vivo Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. Karyopharm Therapeutics Inc.

Selective inhibitors of nuclear export in aggressive B-cell lymphomas

Selective inhibitors of nuclear export in aggressive B-cell lymphomas

Selinexor for advanced hematologic malignancies

Recent measures to classify novel molecular targets with therapeutic potential across multiple hematologic tumors have identified the eukaryotic nuclear exporter, exportin 1 (XPO1), as a promising candidate. Molecular agents termed ‘Selective Inhibitors of Nuclear Export’ (SINEs) have been developed to selectively inhibit the essential regulatory functions of XPO1 in the eukaryotic cell and have been extensively studied in pre-clinical and clinical tumor models. Recently, selinexor (XPOVIO™), a first-in-class oral SINE molecule, was granted accelerated approval by the United States FDA for penta-refractory multiple myeloma. To establish a complete profile of this emerging drug candidate, this article reviews evidence collected from recent clinical studies against both solid and liquid tumors, describing selinexor as a promising new anti-cancer pharmaceutic against late-stage and highly aggressive tumors. With management of well-defined and predictable adverse effects, selinexor can be a life-saving therapeutic option in cancer patients with few alternatives.

SIENDO/ENGOT-EN5: A randomized phase III trial of maintenance with selinexor/placebo after combination chemotherapy in patients with advanced or recurrent endometrial cancer.

TPS6105 Background: Endometrial cancer is one of the most common gynecologic malignancies with increasing incidence and mortality. Patients with advanced disease that has relapsed or received prior platinum-based therapy or radiotherapy have limited options and the prognosis remains poor. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone was recently approved for patients with multiple myeloma. In addition, single agent selinexor has demonstrated broad activity in other hematologic malignancies and solid tumors. In a phase II study, 50 mg/m2 (~80 mg) selinexor administered twice weekly demonstrated a disease control rate of 35% with 2 confirmed partial responses among 23 patients with heavily pretreated endometrial cancer (Vergote I et al. Gynecol Oncol 2020). In the absence of approved maintenance therapies, we conducted this study to evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent endometrial cancer. Methods: This is a multicenter, double-blind, placebo-controlled, randomized phase III study in patients in partial or complete remission after completing at least 12 weeks of taxane-platinum combination therapy for primary Stage IV disease and recurrent disease (i.e., relapse after primary therapy for early stage disease including surgery and/or adjuvant therapy). A total of 192 patients will be enrolled at 80 sites in Europe, North America, and Israel. Patients will be randomized in a 2:1 ratio to either maintenance therapy with 80 mg oral selinexor once weekly or placebo. Stratification factors include primary Stage IV versus first recurrent disease at the time of taxane-platinum therapy and disease status after chemotherapy (partial versus complete response). Treatment will continue until disease progression. The primary endpoint is progression free survival (PFS) per RECIST v1.1. Secondary endpoints include disease-specific survival, overall survival, time to first subsequent therapy, time to second subsequent therapy, PFS on subsequent therapy and safety and tolerability. The study is currently open and enrolling patients. Clinical trial information: NCT03555422.

Selinexor, daratumumab, and dexamethasone in patients with relapsed/refractory multiple myeloma (MM).

8510 Background: Selinexor is a first-in-class oral Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates exportin 1 (XPO1). Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with relapsed/refractory MM (RRMM). Single agent daratumumab has demonstrated an ORR of 29% in MM reftactory to proteasome inhibitors (PIs)/immunomodulatory drug (IMiDs). We evaluated the safety, tolerability and preliminary efficacy of the combination of Sel-dex and daratumumab (SDd) in pts with MM refractory to PIs/IMiDs. Methods: This is a multicenter, open-label, phase 1b/2 dose escalation and expansion study. Pts were eligible if they had received ≥ 3 prior lines of therapy, including a PI and an IMiD, or whose MM was refractory to a PI and an IMiD. In the expansion phase, pts were required to be anti-CD38 monoclonal antibody-naïve. One dose level was tested at each schedule: selinexor once-weekly (QW at 100 mg) or twice-weekly (BIW at 60 mg) with dexamethasone 40 mg. Daratumumab 16 mg/kg IV was administered per label. Primary objective was to determine the maximum tolerated dose and recommended phase 2 dose (RP2D), and assess safety, tolerability and efficacy of SDd in pts with RRMM. Results: A total of 34 pts were enrolled; 3 in the 60 mg BIW and 31 in the 100 mg QW cohorts. Median age was 69 and median number of prior treatment regimens was 3 (range, 1–10). Out of 34 pts, 62% and 65% were refractory to bortezomib and lenalidomide respectively. Common treatment related adverse events (all grades, grades 3/4) included: thrombocytopenia (71%, 47%), fatigue (62%, 18%), nausea (71%, 9%), anemia (62%, 32%) and neutropenia (50%, 26%). 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. 32 patients were evaluable for efficacy. The ORR was 73% (11 VGPR, 11 PR) for 30 daratumumab-naïve pts. Median progression-free survival was 12.5 months in both groups. Conclusions: Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dexamethasone 40 mg, administered QW. In pts with PI and IMiD refractory MM, weekly SDd demonstrated promising activity with an ORR of 73% in daratumumab-naïve pts and a median PFS of 12.5 months. This supports further development of a novel non-PI, non-IMiD backbone in earlier lines of therapy. Clinical trial information: NCT02343042 .

Once weekly selinexor, carfilzomib, and dexamethasone (SKd) in patients with relapsed/refractory multiple myeloma (MM).

8530 Background: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with refractory MM. We hypothesize that once weekly (QW) SKd may be an active well tolerated regimen and evaluated this combination in a dose escalation/expansion study. Methods: STOMP is a phase 1b/2 study evaluating various doses and enrolled pts with carfilzomib naive relapsed MM. Oral selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (on days 1, 8 and 15 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), as well as explore the efficacy and safety of SKd. Results: As of January 2020, 18 pts were enrolled. Median age was 71 years (range: 50-76). Median number of prior regimens was 4 (range: 1-8). All pts (n = 18) were previously treated with bortezomib and lenalidomide, and 50% and 56% pts were refractory to bortezomib and lenalidomide respectively. Nine (50%) pts received prior pomalidomide treatment and 8 (44%) pts were refractory. Eleven (61%) pts received prior daratumumab treatment and 9 (50%) were refractory. The MTD was selinexor 80 mg QW, carfilzomib 56 mg/m2 QW and dexamethasone 40 mg QW. The ORR and CBR were 72% and 79% respectively with 4 complete responses, 7 very good partial responses, 2 partial responses, and 1 minimal response. Stable disease was observed in 3 pts. With a median follow-up period of 4.7 (1.8-16.3) months, median progression-free survival has not been reached. Common treatment-related adverse events (total, Grade ≥3) were thrombocytopenia (83.3%, 66.7%), nausea (66.7%, 0%), anemia (55.6%, 11.1%), fatigue (50%, 11.1%), anorexia (44%, 5.6%), weight loss (44%, 0%), and neutropenia (33.3%, 11.1%). Conclusions: Once weekly SKd demonstrated an encouraging ORR of 72% in pts with a median of 4 lines of prior therapy. The majority of responses are deep and predominantly CR and VGPR. The combination is well tolerated with no new safety signal, no Grade ≥3 nausea, vomiting, diarrhea, weight loss or anorexia. The side effects are a function of the dose and schedule and can be managed with dose modification and supportive care. Enrolment is ongoing and supports a phase 3 study of SKd. Clinical trial information: NCT02343042 .

Bioinformatic analysis of selinexor-induced gene expression in patient-derived-chordomas to reveal mechanisms of action leading to tumor growth inhibition.

e23502 Background: Selinexor is a selective inhibitor of nuclear export that inhibits XPO1 from shuttling its cargo from the nucleus to the cytoplasm. This leads to accumulation of tumor suppressor proteins in the nucleus, activation of cell cycle checkpoints, cell cycle arrest and apoptosis in cancer cells. Chordomas are rare cancers emanating from the skull base and spine that originate from remnants of the notochord. Patients with chordomas have poor prognosis with limited treatment options. To investigate the in vivo efficacy and assess molecular effects of selinexor treatment in chordoma, two patient-derived xenograft (PDX) mouse models were tested. Methods: Murine chordoma PDX models of recurrent clival chordoma (SF8894) and metastatic sacral chordoma (CF466) were treated with selinexor (5mg/kg PO, 4x weekly). Tumor volume was monitored for 6 weeks of treatment, then excised tumors were used for immunohistochemistry (IHC) analysis and RNA sequencing. Results: Selinexor treatment significantly reduced the tumor volume of mice bearing CF466-derived tumors (5 mice/group; 57.6% reduction in volume compared to control; P = 0.031), and SF8894-derived tumors (4 mice/group; 76.2% reduction; P < 0.001). Differential gene expression between selinexor and vehicle treated samples showed significant differences in 428 genes and 156 genes in the CF466 and SF8894 tumors, respectively (adjusted P-value [Padj] < 0.01). In both models, XPO1 protein levels were markedly decreased and expression of the tumor suppressors TP53 (CF466: Padj = 1.4x10−17; SF8894: Padj = 0.002) and ARRDC3 (CF466: Padj = 2.2x10−72; SF8894: Padj = 2.9x10−12) were increased. In the CF466 chordoma model, selinexor reduced SOX9 (Padj = 1.6x10−18), SMAD4 (Padj = 0.019), and SHH (Padj = 0.028), which were confirmed to be reduced at the protein level by IHC. The SF8894 model showed reduction in EZH2 expression (Padj = 0.0012). Pathway analysis of both models showed activated TP53 signaling (CF466: z-score = 0.82; SF8894: z-score = 2.16) and apoptosis (CF466: P = 5.2x10−8; SF8894: P = 1.2x10−8). G2/M checkpoint regulators were upregulated in the CF466 model (z-score = 2.83). Conclusions: Selinexor treatment led to reduction in tumor growth in two PDX models of chordoma. Both models showed upregulation of TP53 signaling and apoptosis upon treatment, with downregulation of distinct oncogenic pathways. Further investigation of selinexor as a treatment option for chordoma is warranted.

Quality-of-life (QOL) analyses in patients with multiple myeloma: Results from the selinexor (KPT-330) treatment of refractory myeloma (STORM) phase IIb study.

e20522 Background: Selinexor, a novel oral selective inhibitor of nuclear export, was recently approved for use in relapsed/refractory multiple myeloma (MM). The efficacy and safety of selinexor and dexamethasone was evaluated in a phase 2b, single-arm, open-label, multicenter trial in patients with penta-exposed, triple-class refractory MM. Patient-reported outcomes were measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM) assessment. While minimal clinically important differences (MCID) have been established for other FACT scales, there is no known, validated definition of MCID for the FACT-MM. This study reports results of QoL analyses in patients with MM enrolled in the STORM phase 2b trial and examines two approaches to calculate MCID for the FACT-MM. Methods: FACT-MM data were collected at baseline, on day 1 of each 4-week cycle, and at end of treatment (EOT) during the STORM phase 2b trial. Change from baseline was analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain. Two approaches for evaluating MCID were explored: the first based on patient-reported assessment of meaningful change, defined as 10% of the instrument range (Ringash 2007), and the second based on mean baseline differences between ECOG groups (0 vs 1 to 2) based on patient level data. Additional analyses were performed to identify trends among treatment responders and non-responders, including a difference-in-difference (DID) analysis to compare changes between baseline and EOT. Results: Eighty patients had sufficient data to be included in longitudinal QOL analyses. MCID analyses demonstrated that most patients did not experience decline during the first six cycles of treatment; this pattern was consistent with MCID defined either as 10% of the instrument range (range 54% to 75% of patients), or as an ECOG-based anchor (range: 54% to 73% of patients). The DID analysis found that the mean change in QoL of non-responders decreased significantly between baseline and EOT, while responders had no significant change. This difference between responders and non-responders was significant for the FACT-G. Conclusions: Most patients did not experience QoL decline during the early cycles of selinexor treatment during the STORM 2b trial. The MCID decline, evaluated by two approaches, was greater among treatment non-responders than responders. A DID approach demonstrated greater decline between baseline and EOT for non-responders. Clinical trial information: NCT02336815.

Preclinical evaluation of XPO1 inhibition in Wilms tumors.

3580 Background: XPO1 is a nuclear export protein that selectively transports tumor and growth regulatory proteins out of the nucleus, thereby effectively inhibiting their function. We previously utilized the Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) algorithm to discover that malignant rhabdoid tumors were dependent upon XPO1 inhibition and then evaluated a preclinical cohort using selinexor (KPT-330), the first-in-class selective inhibitor of nuclear export, to demonstrate that XPO1 inhibition was sufficient to cause cell cycle arrest, apoptosis, and disease control in multiple cell line and patient derived xenograft (PDXs) models. Our subsequent analysis revealed that the most common childhood kidney tumor, Wilms tumor, has even high higher inferred activity of XPO1 than rhabdoid tumors leading to our hypothesis that XPO1 inhibition is an effective therapeutic strategy to treat Wilms tumors. Methods: A panel of 9 Wilms tumor cell lines and 3 Wilms tumor PDXs were genomically characterized and tested to evaluate the pre-clinical efficacy of XPO1 inhibition in Wilms tumors. Results: Proliferation rate, increased XPO1 protein expression, and loss of function mutations in TP53 correlated with in vitro Wilms tumor cell line sensitivity to selinexor. Evaluation of co-segregation of all single nucleotide variant changes using with inferred activity of XPO1 on VIPER in all TGCA tumors demonstrates a strong association with TP53 alterations. XPO1 inhibition was effective in all Wilms tumor models tested, most significantly in MSKREN-57196, a favorable histology Wilms tumor PDX with somatic 1q gain as well as WTX and MYCN mutations, as well as in MSKREN-31827, a diffusely anaplastic TP53 mutant Wilms tumor PDX. Eltanexor (KPT-8602) is an XPO1 inhibitor with decreased CNS penetration and an improved toxicity profile; this drug was tested in these in vivo models and found to be at least as effective as selinexor. Conclusions: Somatic 1q gain in favorable histology Wilms tumors and TP53 mutations in diffusely anaplastic Wilms tumors have a particularly poor prognosis in the relapsed setting. Our study demonstrates that XPO1 inhibition may provide a rational therapeutic option to treat such high-risk Wilms tumors. Future clinical trials evaluating XPO1 inhibitors should evaluate its efficacy in children with relapsed Wilms tumors.