Background: DCC-3014 is an orally administered kinase inhibitor targeting the switch pocket of colony-stimulating factor 1 receptor (CSF1R). DCC-3014 exhibits approximately 100-fold selectivity from kinases homologous to CSF1R, such as KIT, and greater selectivity against 300 other human kinases. Tumor-associated macrophages (TAMs) are dependent on CSF1R kinase activity for proliferation and maintenance of the immunosuppressive phenotype. TAMs are known to enable tumor cells escape from immune surveillance. DCC-3014 is designed to exhibit an antitumor effect by inhibition of immunosuppressive TAMs or other CSF1R signaling-dependent pro-tumor activities. In addition, tenosynovial giant cell tumor (TGCT) is a rare, monoarticular disease known to be caused by the translocation in the CSF1 gene leading to overexpression of CSF1. Anti-CSF1R therapies have shown clinical activity in diffuse TGCT. Methods: This study is a multicenter, first-in-human study of DCC-3014 to determine a recommended Phase 2 dose (RP2D) or maximally tolerated dose (MTD) with a 3+3 dose escalation design and evaluate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of DCC-3014 in advanced solid tumors, including diffuse-type TGCT [NCT03069469]. Results: As of June 2, 2019, the study is ongoing in the dose escalation phase and has enrolled 32 patients with advanced solid tumors in 7 cohorts. The first cohort was initiated at 10 mg daily. Based on preliminary PK analysis from the first cohort, subsequent cohorts utilized a loading dose followed by a maintenance dosing schedule to achieve steady-state exposures more rapidly. The median age of patients was 61 years old and 69% were female with the median of 4 lines of prior anti-cancer treatment. No dose limiting toxicities (DLTs) have been seen in the assessed cohorts. Most commonly seen treatment-emergent adverse events (TEAEs >20%) were constipation (38%), vomiting (34%), diarrhea (31%), nausea (31%), decreased appetite (25%), abdominal pain (22%), and dyspnea (22%) whereas diarrhea, nausea and fatigue were reported as treatment-related AEs seen in >10% of all patients (13%). TEAEs were mostly Grade 1 or 2. Serious AEs (SAEs) were seen in 16 patients, none of which were related to DCC-3014. Exposure was approximately dose proportional. PD effects were seen for dose levels at 10 mg and above, and induction of the CSF1R ligand, CSF-1, was seen up to 148-fold from baseline. The RP2D or MTD has not been selected or reached. Conclusion: DCC-3014 in this study was generally well tolerated in patients with advanced solid tumors and showed approximately dose-proportional exposure and PD changes as expected. Further evaluation is ongoing to determine the RP2D or MTD. Data from the TGCT cohort will be presented at a future meeting.

Citation Format: Matthew H Taylor, Stephen Leong, Ying Su, Cynthia B Leary, Xiaoyan Li, Keisuke Kuida, Rodrigo Ruiz-Soto, Todd Bauer. Phase 1 study of DCC-3014, an oral inhibitor of CSF1R, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors, including diffuse-type tenosynovial giant cell tumor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C087. doi:10.1158/1535-7163.TARG-19-C087