Abstract 2555
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 + 3 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 mg/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 = 0.0332).
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.
Editorial acknowledgement
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.
Resources from the same session
1735 - mTOR inhibition in the treatment of resistant breast cancer
Presenter: María Rodriguez
Session: Poster Display session 1
Resources:
Abstract
6068 - Study of Photodynamic therapy in vitro
Presenter: Irene Jiménez Munguía
Session: Poster Display session 1
Resources:
Abstract
3011 - The potential of neratinib plus dasatinib in overcoming and preventing neratinib resistance in HER2-positive breast cancer models
Presenter: Neil Conlon
Session: Poster Display session 1
Resources:
Abstract
2644 - Novel HDACi, MHY446, induces apoptosis via regulation of mitochondria-endoplasmic reticulum interaction in HCT116 human colorectal cancer cells
Presenter: Nam Deuk Kim
Session: Poster Display session 1
Resources:
Abstract
3085 - Dual inhibition of TGF-β and AXL as a novel treatment for colorectal cancer
Presenter: Davide Ciardiello
Session: Poster Display session 1
Resources:
Abstract
1314 - PARP inhibition enhances cisplatin sensitivity in cervical cancer by modulating β-catenin signaling
Presenter: Minakshi Mann
Session: Poster Display session 1
Resources:
Abstract
2417 - Synergistic effect of DSF combined treatment with cisplatin in atypical teratoid/rhabdoid tumors (AT/RT)
Presenter: Seung Ah Choi
Session: Poster Display session 1
Resources:
Abstract
1149 - Reactive oxygen species induced by OSU-A9 inhibit the growth of duodenal cancer and gastric cancer cells through dephosphorylating intranuclear pyruvate kinase muscle isozyme M2
Presenter: Li-Yuan Bai
Session: Poster Display session 1
Resources:
Abstract
1862 - New therapy for intrahepatic cholangiocarcinoma targeted to cancer associated fibroblasts
Presenter: Takahiro Yamanaka
Session: Poster Display session 1
Resources:
Abstract
782 - Macrophage-cancer cell fusion is mediated by Phosphatidylserine-CD36 receptor interaction and induced by ionizing radiation
Presenter: Ivan Shabo
Session: Poster Display session 1
Resources:
Abstract