Abstract 564P
Background
XPO-1 is a key nuclear exporter of multiple tumour suppressor and growth factor proteins, including p53, p27, survivin and cyclin D1. Felezonexor (SL-801; Stemline Therapeutics), a novel, oral, reversible XPO-1 inhibitor, demonstrated potent in vitro and in vivo anti-tumor activity against diverse malignancies and is currently being assessed in a phase I study (NCT02667873).
Methods
STML-801-0115 is a first-in-human, multicenter 3x3 dose escalation study in patients with relapsed/refractory locally advanced or metastatic solid tumours. The principal objectives are to evaluate safety, activity, tolerability, identify the MTD, and assess PK and PD. Felezonexor was initially administered orally on days 1-4 and 8-11 of a 21-day cycle. To further improve tolerability while maintaining dose intensity the dosing schedule was amended with felezonexor administered once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle. 75 mg is the current dose level.
Results
As of April, 2020, 57 patients (53% female), with a median age of 62 years (range: 39-85 years), received felezonexor monotherapy; median prior systemic therapies = 3 [range: 2-6]. Dose-proportional increases in Cmax and AUC were observed. Most frequent treatment-emergent grade 1-2 adverse events (TEAEs) were nausea (73%), vomiting (62%), fatigue (51%), decreased appetite (33%), and diarrhea (27%). Grade 3 TEAEs included nausea (9%), anemia and fatigue (both 7%), and diarrhea, hypokalemia, hyponatremia and hypophosphatasemia (each 4%); with one grade 4 hypophosphatemia. A partial response lasting 7 months was achieved in a patient with heavily-retreated, K-RAS+ colorectal cancer. 14 patients had stable disease (SD) and remained on study for 2-11 months, including a basal cell carcinoma patient with SD for 11 months.
Conclusions
We demonstrated safety and activity of felezonexor in a heavily pre-treated cohort of patients with advanced, poor prognosis tumours. The ideal therapeutic dose has yet to be determined and dose escalation continues. Updated results will be presented. Next steps include evaluation in certain XPO1 mutant cancers and potential clinical trials in hematological malignancies, including multiple myeloma.
Clinical trial identification
NCT02667873.
Editorial acknowledgement
Legal entity responsible for the study
Stemline Therapeutics, Inc.
Funding
Stemline Therapeutics, Inc.
Disclosure
J.S. Wang: Research grant/Funding (institution): Stemline. E.G. Chiorean: Research grant/Funding (institution): Stemline Therapeutics, Inc.. K.D. Courtney: Research grant/Funding (institution): Stemline Therapeutics, Inc.. D. Qi: Shareholder/Stockholder/Stock options, Full/Part-time employment: Stemline Therapeutics, Inc.. J. Bullington: Shareholder/Stockholder/Stock options, Full/Part-time employment: Stemline Therapeutics, Inc.. M. Sardone: Shareholder/Stockholder/Stock options, Full/Part-time employment: Stemline Therapeutics, Inc.. J. Chen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Stemline Therapeutics, Inc.. C. Brooks: Shareholder/Stockholder/Stock options, Full/Part-time employment: Stemline Therapeutics, Inc.. M. Hoberman: Shareholder/Stockholder/Stock options, Full/Part-time employment: Stemline Therapeutics, Inc.. T.I. Mughal: Shareholder/Stockholder/Stock options, Full/Part-time employment: Stemline Therapeutics, Inc.. T.M. Bauer: Research grant/Funding (institution): Stemline Therapeutics, Inc.. All other authors have declared no conflicts of interest.