73P Selinexor in combination with carboplatin and pemetrexed (CP) in patients with advanced or metastatic solid tumors: Results of an open label, single-center, multi-arm phase Ib study

Abstract

Exportin 1(XPO-1) is overexpressed in various tumors and selinexor is a first-in-class oral potent selective inhibitor of XPO-1, leading to intranuclear accumulation of tumor suppressor proteins. In vivo studies have suggested that selinexor in combination with various chemotherapeutics exerts antitumor activity in multiple cancers. This was an open label, single-center, multi-arm phase Ib study utilizing a “3 + 3” design and a “basket type” expansion. CP + selinexor was employed as one of the 13 parallel arms. While carboplatin was dosed at AUC6 along with pemetrexed at 500 mg/m2 IV Q3W, selinexor was dosed at 60 mg twice weekly (BIW) or 40-60 mg once weekly (QW). Patients with advanced or metastatic solid tumors whose disease was refractory, had relapsed following prior systemic therapy or where the addition of selinexor to standard chemotherapy deemed appropriate and acceptable, were eligible. Six patients with the median age of 51 (range, 37–69 years) were treated, and 4 were evaluable for response. The cancer types were ovarian (n=2), and 1 each with thymoma, cervical, rectal, and non-small cell lung cancers. All patients had at least one treatment-emergent adverse events (TEAE) and the common TEAE were thrombocytopenia (6/6), neutropenia (5/6), fatigue (5/6), anemia (4/6), leukopenia (4/6), elevated AST or ALT (3/6), nausea (3/6), and vomiting (3/6). The most prevalent grade ≥3 TEAE were thrombocytopenia (4/6), anemia (3/6), neutropenia (3/6), leukopenia (2/6), and fatigue (2/6). A patient dosed at selinexor 40mg QW experienced DLT with grade 3 fatigue despite medical supportive care ≥5 days. The patient with lung adenocarcinoma who had 2 prior therapies including prior carbo-taxol achieved partial response (PR) whereas 2 patients with ovarian cancer and cervical cancer had stable disease (SD), contributing the clinical benefit rate (CR+PR+SD ≥4 months) of 50%. Albeit the number of patients in this study arm was small, once weekly oral selinexor in combination with CP was plausible and conferred some clinical activity and disease stabilization. The RP2D of selinexor was 40 mg QW in combination with CP.