Selinexor is a first-in-class oral selective inhibitor of nuclear export that is approved in the US for treatment of patients with relapsed multiple myeloma, and has demonstrated anti-cancer activity in patients with other haematological and solid tumor malignancies. Diagnostic, demographic and baseline laboratory data from 1,936 cancer patients treated with selinexor on 13 clinical trials were used to predict tolerability (measured by days on selinexor) and best overall response. An integrated machine learning model averaging neural networks, random forests, logistic regression, and gradient boosting was used. To distinguish between predictive markers for selinexor and general prognostic markers, patients enrolled on the BOSTON study treated with selinexor, dexamethasone, and bortezomib (SVd), were compared to patients on the control arm (Vd). A combined machine learning model for predicting response that tested over 70 variables among selinexor treated patients achieved an area under the receiver operating characteristic curve of 0.674. Lower lactate dehydrogenase (LDH), higher hematocrit (HCT) and higher hemoglobin (HGB) were found to have the strongest associations with positive response. In a separate analysis of selinexor tolerability, higher HGB, lower LDH and higher HCT were also the three strongest predictors of longer time on study. When applying these models to the BOSTON study, variable correlations with treatment duration were stronger and more consistent with data from other trials for patients on the SVd arm compared to those on the Vd arm, indicating specificity for predicting tolerance to selinexor (Table).Table89P Comparison of single variable correlations with time on study between two arms of the BOSTON studyVariable (measured at baseline)SVd armVd armOverall correlation in selinexor-treated patients from all trialshemoglobin0.140.090.18lactate dehydrogenase-0.12-0.01-0.18hematocrit0.160.130.17red blood cell count0.160.100.16albumin0.250.100.15neutrophil/lymphocyte ratio-0.04-0.19-0.12creatine kinase0.170.140.11ECOG performance status-0.060.09-0.11pulse-0.12-0.22-0.11neutrophil count-0.10-0.18-0.10 Open table in a new tab Lower LDH and higher HCT/HGB may be useful for predicting patients who will respond safely and favorably to selinexor. Our combined models using common lab values that can easily be assessed may help in identifying patients most likely to derive clinical benefit from selinexor treatment.

SEL, an oral, first-in-class selective inhibitor of XPO1-mediated nuclear export (SINE), induces nuclear retention and activation of tumour suppressor proteins including p53, BRCA1/2, CDKN2A and pRB. SEL has anti-cancer activity in preclinical models of cervical cancer (CC) & ovarian cancer (OC) and in a phase I clinical study. In an effort to identify markers predictive of disease control with SEL, circulating tumour cells (CTCs) were enumerated during the phase 2 trial from patients (pts) with heavily pretreated OC, CC & endometrial cancer (EC). NCT02025985. Patients with ≥ 2 lines of prior therapy, ECOG PS 0-1, were treated with single agent SEL. At predose C1D1, 7.5 mL of blood was collected in CellSave tubes and CTCs were identified using the Janssen Diagnostics CellSearch System. Intact cells that measured at least 4 microns in size and stained positive for DAPI, EpCAM, and cytokeratin while negative for CD45 were counted as CTCs. CTC were enumerated at predose C1D1 in 47 (33 OC, 8 EC, 6 CC) of 114 patients. To date, 31 pts had <2 CTCs at predose C1D1 with a median days on study of 108 days while 16 pts had >2 CTCs with a median days on study of 56 days (p = 0.01). Ten patients with <2 CTCs at predose showed stable disease for at least 12 weeks and 4 demonstrated partial response by RECIST 1.1. This study demonstrates that the presence of CTCs in pts prior to SEL treatment may correlate with a shorter TTP. Detection of CTC in the peripheral blood of cancer patients has proven feasible and of prognostic value in different neoplasms, including in patients with OC. These results suggest that low CTC count (<2) may also be used to identify pts with heavily pre-treated OC, CC & EC that may benefit from prolonged disease control with single agent oral single agent SEL. Additional studies are planned.

ABSTRACT Aim: Exportin 1 (XPO1) is a nuclear export protein whose inhibition leads to the nuclear accumulation of tumor suppressor proteins (TSPs). XPO1 is overexpressed in many tumors including PrCa. Selinexor is an oral SINE that activates ≥10 TSPs with potent activity against various cancers including CRPC. Methods: Selinexor mediated nuclear localization of TSP & apoptosis induction was evaluated in CRPC cell lines & in pt derived tumors in vitro & xenografts (po 10 mg/kg QoDx3). Oral selinexor was given at 8 doses (twice weekly) 28-day cycle as part of an ongoing Phase 1 study in advanced solid tumors (KCP-330-002, NCT01607905). Response evaluation was every 2 cycles (CT & bone scans). Pts had progressing, chemotherapy refractory CRPC on study entry. Results: Selinexor induced nuclear accumulation of p53, p21, FOXO3a, & p27 in PrCa cells as well as nuclear retention of AR in androgen depleted PrCa cells. Oral selinexor showed strong (∼100%) inhibition of tumor growth in pt derived CRPC xenografts. 11 pts with CRPC (median 65 years; ECOG PS 0/1: 5/6; median prior regimens: 5.5 (range 2-10) received selinexor across 3 dose levels (35-65 mg/m2) & 8 were evaluable for response. All pts received taxanes & 5 pts either abiraterone and/or enzalutamide prior to selinexor. Grade 4 toxicities include leukopenia in 1 pt. The most common AEs (Grade 1/2/3) include: fatigue (18%/27%/18%), nausea (27%/18%/0%), anorexia (18%/27%/0%) & thrombocytopenia (9%/18%/9%). Supportive care with dexamethasone (9 pts, 8-24 mgs/weekly or equivalent), appetite stimulants & anti-emetics improved constitutional symptoms. Pharmacokinetics & pharmacodynamics showed dose-dependent increases in Cmax/AUC0-inf & in XPO1 mRNA. PSA & pain reductions were observed, 7 of 8 evaluable pts achieved prolonged SD (114-300+ days). 1 pt progressed during treatment. Conclusions: Selinexor shows potent activity in preclinical models of CRPC with activation of TSPs & retention of nuclear AR. Single agent oral selinexor induced long-term disease control in pts with chemotherapy-resistant CRPC. Future studies in pts with CRPC are planned in 2014. Disclosure: All authors have declared no conflicts of interest.

ABSTRACT Aim: Increased XPO1 expression has been linked to progression of OvCa. Nearly all tumor suppressor proteins (TSPs) are transported out of the nucleus exclusively by XPO1 and thereby inactivated. The XPO1 inhibitor, Selinexor, forces the nuclear retention and activation of >10 TSPs resulting in OvCa cell death. Methods: SINE induced TSP nuclear localization and induction of apoptosis were tested in OvCa cell lines and patient-derived cells. Combination with cisplatin was assessed in vitro & in patient-derived xenograft models (30 mg/m2 po, 3 times/week). An on-going Phase 1 (KCP-330-002, NCT01607905) in pts with solid tumors, oral selinexor (8 -10 doses/4-week cycle) was administered to pts with heavily pretreated OvCa that were progressing on study entry. Response was evaluated every 2 cycles (RECIST 1.1). Results: SINE potently induced cell death in platinum-sensitive and -resistant OvCa cell lines (IC50s Conclusions: Selinexor treatment provides synergistic activity with cisplatin in preclinical models. In pts, selinexor shows preliminary single agent antitumor activity against heavily pretreated platinum resistant/refractory OvCa. A single agent phase 2 study is ongoing (NCT02025985) & combination studies are planned. Disclosure: All authors have declared no conflicts of interest.

Aim: The nuclear export of most tumor suppressor proteins (TSPs) inactivates their anti-cancer functions. Exportin 1 (XPO1) is the exclusive nuclear exporter of nearly all TSPs. Multiple TSP pathways are altered in HN-SCC including p53, CDKN2A, pRB and others. Selinexor (KPT-330) is a novel, orally bioavailable, selective inhibitor of nuclear export (SINE) that blocks XPO1, leading to the nuclear accumulation and re-activation of TSPs. Selinexor has shown potent in vitro and in vivo activity in numerous models of solid tumors with squamous histology.

Aim: Increased XPO1 expression has been linked to progression of OvCa. Nearly all tumor suppressor proteins (TSPs) are transported out of the nucleus exclusively by XPO1 and thereby inactivated. The XPO1 inhibitor, Selinexor, forces the nuclear retention and activation of >10 TSPs resulting in OvCa cell death.

Aim: Exportin 1 (XPO1) is a nuclear export protein whose inhibition leads to the nuclear accumulation of tumor suppressor proteins (TSPs). XPO1 is overexpressed in many tumors including PrCa. Selinexor is an oral SINE that activates ≥10 TSPs with potent activity against various cancers including CRPC.