Phase 1b study of weekly split-dose selinexor in soft tissue sarcoma (STS).

11563 Background: Selinexor has demonstrated clinical activity in a variety of tumors including STS. Selinexor dosing at 60mg twice a week or 80mg once a week in later phase trials was associated with gastrointestinal and hematologic toxicities requiring frequent dose interruption and reduction. Preclinical in vivo studies show that selinexor use in a split-dose regimen or sustained-release formula is associated with less toxicity. This phase 1b study aimed to evaluate the safety and tolerability of split-dose selinexor in patients (pts) with advanced STS. Methods: Eligible pts with advanced STS of any histologic subtype, and ECOG performance status (PS) ≤ 1 were treated with split-dose selinexor (40mg, 20mg, 20mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15 and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. Antiemetic prophylaxis (oral dexamethasone and ondansetron) was given to all pts. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAE) by CTCAE v5.0. The secondary endpoint was assessment of quality of life (QoL) using the EORTC QLQ-c30 tool v3. Descriptive analyses of Global Health Status (GHS) QoL scores at screening (baseline) and cycle 2 day 1 (C2D1) were performed. Radiologic tumor assessments (by RECIST v1.1) were performed every 8 weeks while on treatment. Results: Nineteen pts [12 female and 7 male; ECOG 0/1, 8/11; median age 61 years (range 41 – 83)] were enrolled. The most frequent of 12 STS subtypes was leiomyosarcoma (n = 7, 37%). Among 18 patients evaluable for toxicity, there were no grade ≥ 3 TRAE. The most common grade ≤ 2 TRAE were dysgeusia (n = 11, 61%), nausea (n = 11, 61%), fatigue (n = 10, 56%) and vomiting (n = 10, 56%). Grade ≤ 2 hematologic TRAE were thrombocytopenia (n = 6, 33%), neutropenia (n = 4, 22%) and anemia (n = 1, 6%). Dose reduction was required in 3 pts (17%) due to intolerable grade 2 TRAE (fatigue, nausea, thrombocytopenia). No serious adverse event due to selinexor was noted. QoL scores were evaluable for 15 pts. The mean (± SEM) change in GHS QoL score from baseline to C2D1 was -10.6 (± 4.8). Among 16 pts evaluable for radiologic response, the best response was stable disease (SD) in 10 pts (63%), and progressive disease (PD) in 6 pts (37%). Durable clinical benefit (SD for > 16 weeks) was seen in 5 pts (31%; 95%CI 11.0 – 58.7%) The median PFS was 3.6 months (95%CI 1.7 – 7.3). Conclusions: Split-dose selinexor was well tolerated in this heterogeneous group of pts with advanced STS and warrants further interrogation. Updated toxicity, safety, efficacy and QoL data will be presented at the meeting. Clinical trial information: NCT04811196.