Simple SummaryFms-like tyrosine kinase type III (FLT3) inhibitors have been shown to induce significant clinical responses in patients with acute myeloid leukemia (AML) harboring FLT3 mutations. Responses to monotherapy and combination regimens are typically incomplete and transient, prompting the exploration of novel FLT3 inhibitors in AML as well as solid tumors. The aim of this study was to explore the safety and preliminary efficacy of a novel, intravenous FLT3 inhibitor, FN-1501, in patients with advanced solid tumors. The safety profile was consistent with that of approved FLT3 inhibitors. Preliminary efficacy and safety data from this study support further study of FN-1501 as an alternative treatment for patients with solid tumors.AbstractBackground: FN-1501, a potent inhibitor of receptor FMS-like tyrosine kinase 3 (FLT3) andCDK4/6,KIT,PDGFR,VEGFR2,ALK,andRETtyrosine kinase proteins, has demonstrated significant in vivo activity in various solid tumor and leukemia human xenograft models. Anomalies inFLT3have an established role as a therapeutic target where the gene has been shown to play a critical role in the growth, differentiation, and survival of various cell types in hematopoietic cancer and have shown promise in various solid tumors. An open-label, Phase I/II study (NCT03690154) was designed to evaluate the safety and PK profile of FN-1501 as monotherapy in patients (pts) with advanced solid tumors and relapsed, refractory (R/R) AML. Methods: Pts received FN-1501 IV three times a week for 2 weeks, followed by 1 week off treatment in continuous 21-day cycles. Dose escalation followed a standard 3 + 3 design. Primary objectives include the determination of the maximum tolerated dose (MTD), safety, and recommended Phase 2 dose (RP2D). Secondary objectives include pharmacokinetics (PK) and preliminary anti-tumor activity. Exploratory objectives include the relationship between pharmacogenetic mutations (e.g.,FLT3,TP53,KRAS,NRAS, etc.), safety, and efficacy; as well as an evaluation of the pharmacodynamic effects of treatment with FN-1501. Dose expansion at RP2D further explored the safety and efficacy of FN-1501 in this treatment setting. Results: A total of 48 adult pts with advanced solid tumors (N = 47) and AML (N = 1) were enrolled at doses ranging from 2.5 to 226 mg IV three times a week for two weeks in 21-day cycles (2 weeks on and 1 week off treatment). The median age was 65 years (range 30–92); 57% were female and 43% were male. The median number of prior lines of treatment was 5 (range 1–12). Forty patients evaluable for dose-limiting toxicity (DLT) assessment had a median exposure of 9.5 cycles (range 1–18 cycles). Treatment-related adverse events (TRAEs) were reported for 64% of the pts. The most common treatment-emergent adverse events (TEAEs), defined as those occurring in ≥20% of pts, primarily consisted of reversible Grade 1–2 fatigue (34%), nausea (32%), and diarrhea (26%). The most common Grade ≥3 events occurring in ≥5% of pts consisted of diarrhea and hyponatremia. Dose escalation was discontinued due to DLTs of Grade 3 thrombocytopenia (N = 1) and Grade 3 infusion-related reaction (N = 1) occurring in 2 pts. The maximum tolerated dose (MTD) was determined to be 170 mg. Conclusions: FN-1501 demonstrated reasonable safety, tolerability, and preliminary activity against solid tumors in doses up to 170 mg. Dose escalation was terminated based on 2 DLTs occurring at the 226 mg dose level.