P591: PRELIMINARY RESULTS OF A PHASE I STUDY OF CLIFUTINIB, A HIGHLY SELECTIVE, POTENT ORAL FLT-3 INHIBITOR, IN PATINETS WITH FLT3-MUTATED RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA

Background: An internal tandem duplication (ITD) in the juxtamembrane domain of FLT3 on chromosome 13q12, which accounts for 30% of patients with Acute Myeloid Leukemia (AML), is associated with poor prognosis, including a lower complete remission (CR) rate, a reduced duration of remission (DOR), a higher relapse rate, and a decreased overall survival. Clifutinib, a highly selective oral FLT-3 inhibitor, demonstrated potent activity against FLT3-ITD mutated human cell lines, both in vitro and in vivo. Aims: This present study (NCT04827069) is a first-in-human study of Clifutinib, including dose-escalation and dose-expansion phases, with a purpose to evaluate the safety, tolerability, pharmacokinetics (PK) and antitumor activity in Chinese patients with relapsed/ refractory (R/R) FLT3-mutated AML. Here we report the preliminary results of the study. Methods: AML patients aged≥18 years with refractory to ≥ 2 cycles of standard induction chemotherapy, or relapsed after achieved remission from prior treatments were enrolled. Previous use of FLT3 inhibitors was allowed. The primary endpoints included safety and tolerability, including dose limiting toxicity (DLT), adverse event (AE). Secondary endpoints were PK and anti-leukemic effect [CR/ CRh (Complete Remission with Partial Hematologic Recovery) rate, Composite Complete Remission (CRc) rate, DOR, and overall survival (OS)]. Clifutinib was administered orally on an empty stomach at 10~70 mg daily, 28 consecutive days as a treatment cycle. Resumption of Clifutinib was not allowed after hematopoietic stem cell transplantation (HSCT). Modified 3 + 3 and accelerated titration design was utilized. Results: As of December, 2021, fifty-seven patients were enrolled, including one at 10 mg, one at 20 mg, 6 at 55 mg, 34 at 40 mg, 15 at 70mg dose groups. The median age was 52 years, and one third of the subjects received prior FLT-3 inhibitors treatments. Two subjects discontinued from the study due to AEs. Eighteen subjects were evaluable for DLT determination. Only one subject in the 55 mg group experienced DLT (Grade 3 QT prolongation), and MTD had not been reached. Fifty-three subjects were evaluable for safety analysis. The most common treatment-related AEs of any grade included platelet count decreased (69.8%), decreased white cell count (69.8%), neutrophil count decreased (60.4%), anemia (43.3%), lymphocyte count decreased (32.1%). Plasma concentrations of Clifutinib increased with increasing dose, with tmax between 2 and 6 hours. Accumulation was observed following repeat dosing, with estimated t1/2 values of 68.3 to 114.2 hours based on accumulation index. Approximately dose-linear PK parameters were observed over the dose range for both single and repeat dosing. Of 53 FLT3-ITD positive, evaluable subjects, CR/CRh rate was 17.0% (9/53), and CRc rate was 45.3% (24/53). Among subjects administered with Clifutinib 40 mg daily, the CR/CRh rate was 18.2% (6/33) with 3 patients achieved CR, median DOR of CR/CRh was 5.7 months, the CRc rate was 48.5% (16/33), and median OS was 7.4 months. Among patients experienced only one prior regimen, the CR/CRh rate of 40 mg dose group was 25% (4/16), the CRc rate was 50% (8/16), and the median OS was 13.0 months. Summary/Conclusion: Preliminary results of this phase 1 study demonstrated that Clifutinib has an acceptable safety profile and promising antitumor activity, especially at the dose of 40 mg daily. A confirmatory phase 3 study is planned to further evaluate the efficacy and safety of Clifutinib at 40 mg daily in FLT3-mutated R/R AML.