A phase Ia/b first-in-human, open-label, dose-escalation, safety, PK and PD study of TP-0903 in solid tumours

Abstract

Abstract Background TP-0903 is a novel, oral small molecule AXL kinase inhibitor impacting oncogenesis and resistance. AXL is upregulated in many solid tumors and influences the mesenchymal phenotype, which drives resistance to targeted cancer therapeutics, traditional chemotherapies, and immuno-oncology agents. Methods A dose escalation study was performed to examine the safety and clinical activity of TP-0903 in patients with advanced solid tumors. Patients received oral TP-0903 once daily for 21 of 28-day cycles. Nine dose levels were explored using modified 3\xa0+\xa03 dose escalation rules. The primary objective of the trial was to identify the maximum tolerated dose of TP-0903 prior to expanding into refractory colorectal, platinum refractory/resistant ovarian cancer and TP-0903 in combination with immunotherapy or EGFR tyrosine kinase inhibitor in immunotherapy-resistant tumors or non-small cell lung cancers. Potential biomarkers were evaluated using liquid biopsies and pre-and post-dose tumor biopsies will be reported. Results Thirty-six patients were enrolled between December 2016 and April 2019 receiving 1.5 to 37mg/m2 over 9 cohorts. The most frequently observed >Gr3 AEs were thrombocytopenia (3), anemia (2), nausea (2), syncope (2), and vomiting (2), all manageable with supportive care. Grade 4 thrombocytopenia was the dose limiting toxicity observed in one patient in cohort 8 (28\xa0mg/m2), reoccurring as grade 3 thrombocytopenia in 2 patients in cohort 9 (37mg/m2) without meeting DLT criteria. Patients are currently still ongoing in cohort 9. Eleven patients, (11/36, 30.6%), had stable disease with a median duration of 3.7 months (range 1.6 to 7.4+ months). Baseline serum soluble AXL of all enrolled patients was determined by immunoassay and indicated higher levels in patients with documented stable disease vs. progressive disease (p\xa0=\xa00.0332). Conclusions The oral small molecule AXL kinase inhibitor TP-0903 is well tolerated with a manageable safety profile. Hematologic toxicity was observed as a DLT. Future studies will evaluate the role of TP0903 in selected disease cohorts as monotherapy and in combination. Serum soluble AXL will be evaluated as a potential predictive biomarker of response. Clinical trial identification NCT: 02729298. Legal entity responsible for the study Tolero Pharmaceuticals, Inc. Funding Tolero Pharmaceuticals, Inc. Disclosure J. Sarantopoulos: Research grant / Funding (institution): Tolero. G. Fotopoulos: Research grant / Funding (institution): Tolero Pharmaceuticals. F.Y. Tsai: Advisory / Consultancy: Tempus Lab; Officer / Board of Directors, Co-Founder: Caremission LLC; Shareholder / Stockholder / Stock options: Salarius Pharmaceuticals. M.S. Beg: Research grant / Funding (institution): Tolero Pharmaceuticals. A.A. Adjei: Research grant / Funding (institution): Tolero Pharmaceuticals. Y. Lou: Research grant / Funding (institution): Tolero Pharmaceuticals; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Stem Centrx; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Vaccinex; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MacroGenics. M. Seetharam: Research grant / Funding (institution): Tolero Pharmaceuticals. M.A. Villalona-Calero: Research grant / Funding (institution): Tolero Pharmaceuticals; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol Meyers; Research grant / Funding (institution): Novocure; Research grant / Funding (institution): Guardant. J. Melear: Research grant / Funding (institution): Tolero Pharmaceuticals. M. Janat-Amsbury: Full / Part-time employment: Tolero Pharmaceuticals. H. Beever: Full / Part-time employment: Tolero Pharmaceuticals. L. Mouritsen: Full / Part-time employment: Tolero Pharmaceuticals. M. Wade: Full / Part-time employment: Tolero Pharmaceuticals. B.V. Bryan: Full / Part-time employment: Tolero Pharmaceuticals. D.J. Bearss: Leadership role, Full / Part-time employment: Tolero Pharmaceuticals.