TP-0903 (AXL inhibitor)
TP-0903 is an investigational AXL receptor tyrosine kinase (RTK) inhibitor, which is known to be involved in acquiring resistance to chemotherapeutics and developing metastatic capacity in cancer cells.1,2
AXL AS A POTENTIAL TARGET IN CANCER TREATMENT
AXL and other TAM family (Tyro-3, AXL, and Mer) RTKs are known to be involved in maintaining a mesenchymal phenotype in cancer cells.2 Mesenchymal cells have increased invasion and migratory properties, enhanced cell survival in stressed environments, and increased resistance to targeted therapies compared to epithelial cells. AXL overexpression has been observed in multiple tumor types that have acquired resistance to various agents.1
In vitro, treatment of cancer cells with TP-0903 reverses the mesenchymal phenotype and sensitizes them to treatment with other targeted agents, eg, erlotinib in EGFR-mutant lung cancer and cetuximab in head and neck cancer models. In preclinical tumor models, TP-0903 restored sensitivity to erlotinib by reversing the mesenchymal phenotype driving resistance.3
Tolero is exploring parallel clinical development paths for TP-0903 in both solid and liquid tumors. A phase 1, first-in-human trial of oral TP-0903 is currently being conducted in patients with advanced solid tumors.
Phase 1: First-in-human clinical trial of oral TP-0903 (a novel inhibitor of AXL) in patients with advanced solid tumors
A phase 1a/1b, first-in-human, open-label, dose-escalation, PK, PD, and safety study designed to determine the dose limiting toxicity of TP-0903 in patients with advanced solid tumors.
- Open-label, dose-escalation study
- Phase 1a: Once-daily dose of TP-0903 by oral administration on days 1-21 of each 28-day cycle
- Phase 1b: Upon confirmation of maximum tolerated dose (MTD), additional cohorts will receive oral daily doses of a flat dose of TP-0903 based on the average of the dose administration in the MTD expansion safety cohort on days 1-21 of each 28-day cycle
Key Inclusion Criteria
- Age ≥18 years
- ECOG PS 0 or 1
- Life expectancy ≥3 months
- Histologically confirmed diagnosis of advanced metastatic or progressive solid tumor
- Refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition
- One or more tumors measurable or evaluable as outlined by modified RECIST v1.1 criteria
See ClinicalTrials.gov (NCT02729298) for comprehensive eligibility criteria.
For sites in the US that are actively recruiting, visit ClinicalTrials.gov (NCT02729298).
ECOG PS=Eastern Cooperative Oncology Group Performance Status; RECIST=Response Evaluation Criteria in Solid Tumors
TP-0903 is an investigational agent and is not approved by the US FDA or any other regulatory authorities.
- Park IK, Mundy-Bosse B, Whitman SP, et al. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia. 2015;29(12):2382-2389.
- Soh KK, Bahr BL, Bearss JJ, et al. Inhibition of Axl kinase reverses the mesenchymal phenotype in leukemic cells through the disruption of retinoic signaling [Abstract]. Blood. 2015;126:3253.
- Soh KK, Kim W, Lee YS, et al. Abstract 235: AXL inhibition leads to a reversal of a mesenchymal phenotype sensitizing cancer cells to targeted agents and immune-oncology therapies. Exp Mol Ther. 2016;76(14 suppl).