A phase I study of TR64, a VEGFR/CSF1R/c-KIT small molecule inhibitor, for the treatment of advanced malignant solid tumors.

Abstract

e15146 Background: Vascular endothelial growth factor receptors (VEGFRs) are highly expressed in many solid tumors and plays a key role in angiogenesis, while the CSF1R/CSF-1 axis is implicated in tumor progression and poorer prognosis. TR64, a small molecule inhibitor of VEGFR, CSF1R, and c-KIT, has demonstrated promising antitumor activity in preclinical studies. This Phase I study evaluates its safety, tolerability, pharmacokinetics, and preliminary efficacy in patients with advanced malignant solid tumors. Methods: Patients received TR64 orally once daily in 28-day cycles from 25mg to 200mg dose groups. The regimen in 300mg and 400mg cohorts consisted of a 14-day continuous dosing period, followed by a 7-day break, and then a 21-day treatment phase until disease progression, unacceptable toxicity, or withdrawal occurred. Adverse events were assessed per NCI-CTCAE v5.0, and tumor response was evaluated using RECIST v1.1. Results: By January 13, 2025, 31 patients were enrolled, including those with small-cell lung cancer (SCLC, n = 10), breast cancer (n = 9), pancreatic cancer (n = 4), gastrointestinal stromal tumor (GIST, n = 2), colon cancer (n = 2), rectal cancer (n = 1), duodenal cancer (n = 1), sacral osteosarcoma (n = 1), and spindle cell sarcoma (n = 1). The median age was 57 (range 33–74) with 58% males, and most were heavily pretreated with a median of 3 previous lines of therapy. The most common TRAEs (all grades/Grade ≥3) included lymphocytopenia (48.4%/12.9%), leukopenia (35.5%/12.9%), neutropenia （35.5%/12.9%）, elevated aspartate transferase (32.3%,3.2%), anemia (29%/0%), elevated hydroxybutyrate dehydrogenase (25.8%,0%), proteinuria (25.8%,0%)，elevated lactate dehydrogenase (25.8%,0%), elevated lipase (22.6%,0%), hypokalemia (22.6%,12.9%). In the subset of 5 evaluable SCLC patients, the overall response rate was 40% and the disease control rate 60%. Notably, an SCLC patient with brain metastases who previously underwent three lines of systemic and whole brain radiation therapies achieved a partial response with a 53.1% reduction in target lesion diameter on a 300 mg dose, remaining on treatment for nearly one year. Additionally, a GIST patient on 200 mg with four lines prior therapies and a HER2-positive breast cancer patient on 100 mg previously treated with five lines of therapies both achieved stable disease, continuing treatment for over 17 and 21 months, respectively. Pharmacokinetic analysis showed that both AUC₀₋₂₄ h and C max increased proportionally with dose, and the median T max was 4 hours. Conclusions: TR64 exhibits a favorable safety profile and promising efficacy, particularly in SCLC. These findings warrant further investigation in the ongoing dose-expansion study (NCT05649345). Clinical trial information: NCT05649345 .