Preliminary Analysis Results of a Phase I Study of the FLT3 Inhibitor SKLB1028 in Patients with Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia

Background: Mutations of FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) are associated with poor prognosis. SKLB1028, a novel multikinase inhibitor, has shown exceptional antileukemic activity in mouse xenograft models of FLT3-driven AML. Preclinical data has demonstrated that SKLB1028 has anti-proliferation and pro-apoptosis effects on tumor cells in vitro and in vivo, and prolonged survival in SKLB1028-treated mice has been observed in a dose-dependent manner (Cao et al., Leukemia, 2012). The present study is to assess the safety, tolerability and pharmacokinetics (PK) of SKLB1028 in patients with relapsed/refractory (R/R) FLT3-mutated AML. Here we report the preliminary analysis results of the study.

Methods: An open label, 3+3 cohort dose escalation, single arm, phase I study was conducted in adult patients with FLT3-mutated AML who were refractory to or relapsed after ≥ 1 cycle of induction chemotherapy and had an Eastern Cooperative Oncology Group performance status of ≤ 3. Dose cohorts of at least 3 patients received study drug following a sequential dose-escalation design with 20 mg/day as the lowest dose level. For each dose level, patients were firstly given 1 dose of SKLB1028 as an oral capsule followed by 72-hour observation in the single-dose PK period. Then the patients entered the repeated-dose period from day 1, cycle 1, and received oral SKLB1028 once per day in a 28-day cycle. Observations of dose limiting toxicities (DLTs) were recorded through cycle 1. For a specific dose level, if a DLT was observed during the first cycle in 1 patient, 3 additional patients were enrolled at that level. If a second DLT was observed within the same dose cohort, escalation was discontinued, and maximum tolerated dose (MTD) was defined as the immediately lower dose level. Patient who had completed cycle 1 and did not experience a DLT or disease progressionduring cycle 1 could continue receiving SKLB1028, at the discretion of the investigator, until disease progression or intolerable toxicity occurred. The primary endpoints were safety and tolerability. Secondary endpoints included PK and efficacy. Analyses of safety (e.g. DLT and adverse event (AE)) and efficacy parameters (e.g. complete response (CR) and partial response (PR))were performed using descriptive statistics on safety analysis set and full analysis set respectively. PK parameters were estimated using non-compartmental analysis on PK analysis set.

Results: Twenty-eight patients with a median age of 50 years (range 19-70 years) were enrolled. The median number of prior regimens was 3.5 (range 1-9). Patients received a median of 2.5 cycles (range 1-15)of therapyin 8 dose cohorts: 20, 40, 80, 120, 160, 200, 250, and 310 mg/day. Three patients discontinued from the study due to AEs. For a subject to be eligible for DLT evaluation, he/she should have received 100% of the planned (28) doses of SKLB1028 in cycle 1, unless the doses were omitted for DLT defining event. Two patients did not complete the first treatment cycle, 1 because of DLT and 1 because of withdrawal of consent. Twenty-seven patients were evaluable for DLT.One patient in the 200 mg cohort experienced DLT (Grade 3 hepatic function abnormal). Among 3 additional patients at this dose level, no DLTs occurred again. The most common treatment-emergent AEs of any grade (regardless of causality) were pyrexia (67.9%), diarrhoea (64.3%), asthenia (53.6%), dizziness (50.0%). There was no death attributed to the use of SKLB1028. The MTD had not been reached. Among the 28 patients treated, only 26 patients were evaluable for efficacy. Two patients were not enlisted due to premature discontinuation of study drug in cycle 1; 1 for DLT and the other for withdrawal of consent. Of 28 patients in the full analysis set, overall response rate (ORR) was 21.4% (6/28) with 1 CR, 5 PR, 20 stable disease and no progressive disease as the best response. One patient achieved CR at the does of 250 mg/day. Of the 5 patients with PR, 1 was in the 160mg cohort, 3 in the 200 mg cohort, and 1 in the 310 mg cohort. The ORR for the 160 mg, 200 mg, 250 mg, and 310 mg cohort of 16 patients was 37.5% (6/16).

Conclusions: The results of our preliminary analysis suggested that SKLB1028 is safe, well-tolerated and effective for R/R FLT3-mutated AML patients. Larger studies are needed to more comprehensively assess the safety and efficacy of SKLB1028 in this population. This trial is registered at Clinical Trials.gov, number NCT02859948.