Abstract 3609
Background
SL-801 is a novel, oral, small molecule that reversibly inhibits Exportin-1 (XPO-1), a nuclear export protein, overexpressed in a variety of solid and hematologic malignancies. XPO-1 is a mediator of nuclear-cytoplasmic transport of over 200 nuclear proteins and has been associated with aggressive tumor behavior and poor prognosis. SL-801 has demonstrated potent in vitro and in vivo activity. Interim results from the dose-escalation stage are reported.
Methods
STML-801-0115 is a first-in-human, multicenter dose and schedule finding study in patients with localized unresectable, or metastatic solid tumors that are refractory to or are relapsed after treatment with standard therapy. Objectives are to identify the maximum tolerated dose or optimal dose/schedule, and assess pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity. SL-801 was initially orally administered on days 1-4 and 8-11 of a 21-day cycle (Schedule A). The dosing schedule has been amended to potentially allow a longer recovery time between dosing periods while maintaining dose intensity. Patients are now receiving SL-801 once daily on days 1-2, 8-9, 15-16 and 22-23 of a 28-day cycle (Schedule B). The starting dose in the study was 5 mg/day in Schedule A; current study dose level is 70 mg/day in Schedule B.
Results
45 patients received 5-65 mg/day of SL-801 in Schedule A (median age 63 YO [range: 39-83], 51% females, median number of prior systemic therapies, 4 [range: 2-10]; 57% received 3 or more. Common treatment-emergent adverse events (TEAEs) were nausea (62%), vomiting (64%), fatigue (44%), decreased appetite (33%), and diarrhea (29%). Grade 3 TEAEs included nausea (9%), anemia (7%), and fatigue, diarrhea, hyponatremia and hypophosphatasemia (each 4%). Most TEAEs were grade 1-2; no grade 4-5 toxicities reported. 12 patients (27%) had stable disease (SD) and remained on study for 2-11 months including 5 with SD for 4+ months. 1 patient with basal cell carcinoma had SD for 11 months. 3 patients had radiographic tumor shrinkage of 14-20% in target lesions.
Conclusions
SL-801 reversibly binds XPO1, a clinically validated target in oncology. To date 27% of heavily pre-treated patients have achieved SD as best response. Enrollment and dose escalation continue.
Clinical trial identification
NCT02667873.
Editorial acknowledgement
Legal entity responsible for the study
Stemline Therapeutics.
Funding
Stemline Therapeutics.
Disclosure
J. Wang: Speaker Bureau / Expert testimony: AstraZeneca. E. Chiorean: Research grant / Funding (institution): Boehringer-Ingelheim, Merck, BMS, Lilly, Stemline, Ignyta/Roche, Incyte, Halozyme; Advisory / Consultancy: AstraZeneca, Array, Ipsen, Eisai, Halozyme, Seattle Genetics, Vicus, Five Prime. P. LoRusso: Advisory / Consultancy: abbvie; Advisory / Consultancy, data safety monitoring board: agios; Advisory / Consultancy: alexion; Advisory / Consultancy: ariad; Advisory / Consultancy, data safety monitoring committee: Five prime; Advisory / Consultancy: GenMab; Advisory / Consultancy: Glenmark; Advisory / Consultancy, data safety monitoring: Halozyme; Advisory / Consultancy: Menarini; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: CytomX; Advisory / Consultancy: Omniox; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Takeda; Advisory / Consultancy: Sotio; Advisory / Consultancy, data safety monitoring committee: Tyme. K. Courtney: Advisory / Consultancy: Janssen; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Aragon; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (institution): PSMA Development; Research grant / Funding (institution): Stemline; Research grant / Funding (institution): Peloton; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Proacta; Spouse / Financial dependant, Receives patent royalties: Athena Diagnostics, Inc. D. Qi: Advisory / Consultancy: stemline. J. Bullington: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. M. Sardone: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. J. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. C. Brooks: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. S. Shemesh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. T.M. Bauer: Full / Part-time employment: Tennessee Oncology; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Loxo; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medpacto, Inc; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MabVax; Research grant / Funding (institution): Stemline Therapeutics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Amgen. All other authors have declared no conflicts of interest.
Resources from the same session
860 - Dose differential modulation of the autophagic behavior of estrogen expressing breast carcinoma cells
Presenter: Mariam Fouad
Session: Poster Display session 1
Resources:
Abstract
2304 - Synthetic peptide of tumor–associated antigen L6 formulated with polymer-based adjuvant enhances anti-tumor effects in mice
Presenter: Shih-jen Liu
Session: Poster Display session 1
Resources:
Abstract
4419 - Improving detection level of somatic mosaicism in neurofibromatosis type 1
Presenter: Kristina Karandasheva
Session: Poster Display session 1
Resources:
Abstract
5283 - Preclinical pharmacokinetic/pharmacodynamic (PK/PD) relationship of ABN401, a highly selective Met inhibitor, in gastric and non-small-cell lung cancer models
Presenter: JooSeok Kim
Session: Poster Display session 1
Resources:
Abstract
5488 - Transcription factors of Snail family in the regulation of resistance of breast cancer cells to hypoxic conditions
Presenter: Alvina Khamidullina
Session: Poster Display session 1
Resources:
Abstract
5417 - Metastasis is impaired by endothelial-specific Dll4 loss-of-function through inhibition of epithelial-to-mesenchymal transition and reduction of cancer stem cells and circulating tumour cells
Presenter: Liliana Mendonça
Session: Poster Display session 1
Resources:
Abstract
5494 - Identification of novel and known FGFR gene fusions in Chinese non-small cell lung cancer
Presenter: Weixin Zhao
Session: Poster Display session 1
Resources:
Abstract
3412 - WNT pathway mutations (APC/CTNNB1) and immune checkpoint inhibitors (ICI) response in metastatic non-small cell lung cancer (NSCLC) patients.
Presenter: Francisco Javier Ros Montana
Session: Poster Display session 1
Resources:
Abstract
1815 - Leukocytosis as a negative prognostic factor in patients with lung cancer: Which subpopulation of leukocytes is responsible?
Presenter: Filip Kohutek
Session: Poster Display session 1
Resources:
Abstract
5022 - Identification of MET gene amplifications using next-generation sequencing in non-small cell lung cancer patients
Presenter: Sergi Clavé
Session: Poster Display session 1
Resources:
Abstract