A Phase I Safety And Tolerance Study Of Fn-1501, A Novel Flt3 Inhibitor, In Patients With Advanced Solid Tumors And Acute Myeloid Leukemia.

Abstract Background: FLT3 mutations are found in approximately 30% of adult patients with Acute Myeloid Leukemia (AML) and to a lesser degree, in certain solid tumors. FN-1501 is a potent inhibitor of FLT3 and other tyrosine kinases such as CDK4/6, KIT, PDGFR, ALK and RET proteins, with demonstrated anti-tumor activity in several leukemia and colon cancer xenograft models. An ongoing, open-label, Phase I study (NCT03690154) is evaluating FN-1501 as monotherapy in patients with various advanced solid tumors and relapsed, refractory (R/R) AML. The objectives of the trial are to assess safety and tolerability, establish a Recommended Phase 2 Dose (RP2D), and evaluate preliminary anti-tumor activity. Methods: Pts received FN-1501 by IV thrice weekly for 2 weeks followed by 1 week off treatment in 21-day cycles. The dose escalation phase follows a standard 3+3 design. Primary objectives include determinations of dose-limiting toxicity (DLT), maximum tolerated dose (MTD), safety, and RP2D. Secondary objectives include pharmacokinetics (PK) and anti-tumor activity. Exploratory objectives include the relationship between pharmacogenetic mutations (e.g. FLT3, TP53, KRAS, NRAS, etc) and safety/efficacy. Expansion cohorts have been added to the ongoing protocol amendment to confirm safety and evaluate preliminary efficacy at RP2D. Results: At the time of data cut-off (Nov 17, 2020), 40 pts (n=1 AML; n=39 solid tumors) were enrolled at doses ranging from 2.5 to 128 mg. Median number of prior lines of treatment was 5 (range 1-12). Thirty-four patients met the minimum exposure criterion for DLT assessment. No DLTs were reported and MTD was not reached. Treatment-related adverse events (TRAEs) were reported in 58% of pts. The most common TRAEs in ≥10% of patients included fatigue (20%), nausea (15%), infusion related reaction (10%), mostly reversible grade 1 or 2. Grade ≥3 TRAEs consisting of anemia, fatigue and serum creatinine increase were observed in 3 pts. TRAEs resulted in dose delay/interruption in 4 pts (10%) but no treatment discontinuations. No serious TRAEs were observed. The exposure of FN-1501 (AUC and Cmax) increased in a dose proportional manner. Mean t1/2 was estimated to be 12-19 hours. Among 25 response-reportable pts, 1 had a best overall response of PR (47% target lesion shrinkage), 10 had stable disease and 14 had progressive disease. The confirmed PR (duration > 4 months) occurred at the 40 mg dose level in a pt with endometrial carcinoma. Conclusion: FN-1501 has demonstrated reasonable safety/tolerability across all doses tested, with promising anti-tumor activity in pts with certain advanced, heavily pre-treated solid tumors. Enrollment of pts into the dose escalation part of the study is continuing and updated safety, PK and molecular biomarker results will be presented at the meeting. Citation Format: Gary Edward Richardson, Stephen K. Williamson, Misako Nagasaka, Viviana Bozon, Maria Margarita Corvez, Chao Li, Wei Li, Jiao Wei, Ai-Min Hui. A Phase I safety and tolerance study of FN-1501, a novel FLT3 inhibitor, in patients with advanced solid tumors and acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT131.