OS07.5 Interim analysis data from Phase 2 study on efficacy, safety &amp; intratumoral pharmacokinetics of oral Selinexor (KPT-330) in patients with recurrent glioblastoma (GBM)
Authors: A. B. Lassman, M. J. V. D. Bent, P. Y. Wen, A. Walenkamp, S. Plotkin, A. Kung, H. Gardner, S. Shacham, A. Chudnovsky, P. M. Mau-Sorensen
Journal: Neuro-Oncology (2017)

Background: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers. XPO1 overexpression in glioma correlates with higher grade and decreased overall survival. Selinexor (SEL) is an oral selective inhibitor of XPO1 which crosses the blood-brain barrier. SEL forces the nuclear retention & activation of tumor suppressor proteins such as p53, IκB, & p27. Methods: We conducted an open label, 4-Arm Phase II trial enrolling adults with recurrent, bevacizumab naïve, measurable GBM. In arms A and B patients (pts) received Selinexor at 50 mg/m2 (~ 80 mg) twice weekly (BIW); arm C, 60 mg BIW; and arm D, 80 mg once weekly. Arm A incorporated <=3 doses of SEL 50 mg/m2 prior to resection of recurrent disease to explore intra-tumoral pharmacokinetics and pharmacodynamics; the other arms were non-surgical. Enrolment in arms C and D was based on Simon’s two-stage design. In arms B-D, the primary endpoint was defined by 6-months progression-free survival rate (6mPFS). Secondary endpoints were response rate according to the Response Assessment in Neuro-Oncology (RANO) criteria, median overall survival (OS), and median progression-free survival (PFS). Results: 61 pts were enrolled in 6 centers in US, Denmark and Netherlands. 8 pts (7/1 M/F, median age 57, 1–2 prior tx regimens (PTR)) were treated on Arm A, 24 (19/5, M/F, median age 51; 1–3 PTR) on Arm B, 14 (10/4 M/F, median age 49; 1–3 PTR) on Arm C, and 15 (9/6 M/F, median age 57; 1–3 PTR) on Arm D. Arm B was closed due to poor tolerability of the dosing regimen. Overall the most commonly reported hematologic (hem) and non-hematologic (non-hem) AE Grade >=3 were neutropenia (13%), thrombocytopenia (8%) and fatigue (21%), hypophosphatemia (8%) respectively. Most common all grade hem and non-hem AEs in the 3 dosing regimens were: in Arm B, thrombocytopenia (62%), fatigue (77%), nausea (46%); in Arm C, thrombocytopenia (14%), fatigue (21), vomiting (21%), anorexia (14%), nausea (14%); and in Arm D, neutropenia (13%), nausea (33%), fatigue 20%. Mean tumor SEL concentration in Arm A was 122 nM which approached the average in vitro IC50 (133 nM). RANO (investigator assessed) defined ORR in arms B, C and D were: 13%, 0%, and 8%, respectively. 6mPFS in arms B, C and D were 17%, 8%, and >= 20% respectively (in Arm D there is 1 patient without PD at 149 days, which would result in 6mPFS of 27% if doesn’t progress for 6 months). Molecular correlative analyses are ongoing. Conclusions: SEL achieved reasonable intra-tumor penetration. Toxicities were expected, reasonable and manageable with standard supportive care except in Arm B where frequencies of fatigue, nausea, anorexia and vomiting were significantly higher than expected. Responses were observed, 6mPFS in Arm D appears encouraging on preliminary analysis, and accrual will resume. Updated results will be presented at the meeting.