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Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Purpose 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. Patients and Methods Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m2, 50 mg/m2, 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. Results 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. Conclusion 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.

2044 Background: Patients (pts) with recurrent GBM have few treatment options and a poor prognosis. Selinexor is an oral inhibitor of XPO1 mediated nuclear export resulting in nuclear retention of ...

10569 Background: Sarcomas are a heterogeneous group of malignancies with diverse genetic abnormalities. Selinexor is a first-in-class, oral, inhibitor of XPO1, (nuclear exportin protein 1) with potent anti-tumor activity in multiple sarcoma cell lines and in murine liposarcoma xenografts. Here we report results from a Phase 1b dose expansion trial of selinexor in sarcoma patients (NCT01896505). Methods: Patients (pts) with advanced, refractory sarcomas with radiographic progression received oral selinexor at 50 mg/m2 twice weekly per 28 day cycle. Pharmacokinetics (PK, n = 12) was assessed in the fasted and fed state. Pharmacodynamic studies were performed on fresh tumor biopsies. Response was evaluated every 2 cycles (RECIST 1.1). Results: 36 pts (14 M / 22 F, ECOG 0/1: 19/17, median age 57.5 years [range 18–86], median lines of previous treatments: 3 [range 1–9]). Disease subtypes include liposarcoma (LPS; N = 12), leiomyosarcoma (LMS; N = 8) and other sarcomas (N = 16). Grade 3 drug related adverse ev...

5522 Background: Increased XPO1 expression has been linked to progression of OvCa and is an independent poor prognostic for survival. Most tumor suppressor proteins (TSP) are transported out of the...

2505 Background: In cancers, the majority of tumor suppressor proteins (TSP) are transported out of the nucleus exclusively by Exportin 1 (XPO1/CRM1), rendering these TSPs non-functional. KPT-330 is a potent inhibitor of XPO1, and forces the nuclear retention and activation of > 10 TSPs resulting in tumor cell death in vitro, in murine preclinical models and in dogs with spontaneous lymphomas. Methods: KPT-330 was administered orally for 10 doses in a 28-day cycle. Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and serial tumor biopsies were performed. Response evaluation was done every 2 cycles (RECIST 1.1). All pts entering the study had documented progressive disease. Results: 23 pts (10 males; median age 62 yrs; ECOG PS 0/1: 5/18) received KPT-330 across 6 dose levels (3 to 30 mg/m2). There has been no dose limiting toxicity. Nine drug related grade 3/4 adverse events (AEs) post cycle 1 were reported in 6 pts (neutropenia, thrombocytopenia, hyponatremia, increased ALT, fatigue, vomiting [n=2], nausea [n=2]). The most common grade 1/2 AEs were nausea (78%), fatigue (74%) and anorexia (74%). PK analysis demonstrated a fairly proportional increase in Cmax and AUC with increasing dose, with no accumulation and without affecting half-life or clearance of KPT-330. At 30 mg/m2, AUC0-last. (4375 ng*h/mL) was comparable to the anti tumor exposure observed in mice and dogs. Tmax (~3 hrs) and T1/2 (6-7 hrs) were consistent across doses. Significant increase (2-20x) in XPO1 mRNA levels (PDn marker) in circulating leukocytes was observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA induction. Analysis of tumor biopsies confirmed nuclear localization of TSPs (e.g. p53, FOXO3A, IκB) and apoptosis of cancer cells following KPT-330 administration. RECIST response was evaluable in 13 pts. Stable disease (SD) was noted in 9 pts, with 3 (colon, endocervical & endometrial stromal tumors) remaining with SD at 6+ months (dose levels 3 & 6 mg/m2), as well as one minor response (colon). Conclusions: KPT-330 treatment is generally well tolerated, with favorable PK and PDn properties. Preliminary signals of clinical antitumor activity were observed. Clinical trial information: NCT01607905.

e13549 Background: Inhibition of nuclear export can promote re-activation of tumor suppressor pathways. CRM1 (chromosomal regional maintenance 1) or XPO1 (exportin 1) is the major protein that mediates nuclear export. We hypothesized that CRM1 mediated nuclear export represents a novel therapeutic target that can be manipulated to inhibit melanoma cell survival. Methods: The growth inhibitory and pro-apoptotic effects of KPT-185, KPT-276 and KPT-330, small molecules selective inhibitor of nuclear export (SINE) were evaluated in human melanoma cell lines using an MTT assay and Annexin V/PI staining, respectively. Fluorescence microscopy and immunoblots were used to assess nuclear accumulation of tumor suppressor proteins. The trans-isomer of KPT-185 and DMSO (vehicle) were used as a negative controls in all assays. The pharmacokinetic (PK) profile of all compounds was evaluated in mice. Results: CRM1 protein was highly expressed in human melanoma cell lines with diverse molecular profiles (i.e., B-Raf, NRAS, p53). KPT-SINE inhibited melanoma cell growth in a concentration-dependent manner and induced apoptosis at nanomolar concentrations. Importantly, there was no evidence that B-Raf V600 mutational status influenced melanoma cell response to these agents. Nuclear accumulation and/or induction of p53, p21, FOXO3a, STAT1 and BAD, and reduction of MCL-1 occurred in melanoma cells at time points prior to apoptosis as shown by increase in cleaved PARP and caspase 3 levels. PK studies were conducted in mice following oral administration of 10 mg/kg, to guide drug selection for our ongoing efficacy studies in murine melanoma models. KPT-185 showed limited bioavailability and systemic exposure, while KPT-276 and KPT-330 showed >50% bioavailability reaching Cmax >5µM. Conclusions: This study represents the first report of CRM1 inhibition in melanoma. These data indicate that the novel SINE compounds can effectively inhibit CRM1-mediated nuclear export and induce apoptosis in melanoma cells. KPT-330 is currently under development as orally bioavailable, small molecule inhibitors for a human clinical trial.