Phase 1 AML Study of AC220, a Potent and Selective Second Generation FLT3 Receptor Tyrosine Kinase Inhibitor

Abstract

Activating mutations in the receptor tyrosine kinase FLT3 are present in approximately 30% of patients (pts) with acute myeloid leukemia (AML), and they have a significantly worse prognosis than pts with wild type (WT) FLT3, suggesting that the activated kinase is a driver of the disease and a potential target for kinase inhibitor therapy. AC220 is a novel 2nd generation class III receptor tyrosine kinase (RTK) inhibitor with potent in vitro and in vivo activity in FLT3-dependent tumors. It is highly selective for WT and mutant FLT3 and several other class III RTKs, including KIT, CSF1R, RET and PDGFR. AC220 is in a first-in-human phase 1 study for relapsed or refractory AML pts, unselected for FLT3 mutations. The study has a standard 3+3 dose escalation design with 50% dose increments. AC220 is administered once daily as an oral solution for 14 days followed by a 14 day rest period (1 cycle) with a starting dose of 12 mg. Concurrently, pts are being dosed on a continuous dosing regimen starting at 200 mg/day for 28 days (1 cycle). Pts with clinical benefit may continue to receive further cycles. Currently, 52 pts have been dosed with AC220 up to 450 mg/day (10 dose cohorts). Median age was 60 yrs (range, 23 to 86 yrs), median number of prior therapies was 3 (range, 0 to 8) and 2 pts had prior allogeneic hematopoietic stem cell transplant (HSCT). Two elderly patients (age ≥ 78 yrs) unfit for induction chemotherapy were previously untreated. Fifteen patients have FLT3 mutations (12 ITD and 3 TKD), 25 are WT, and 12 are undetermined. Pts are also evaluated for PK, pFLT3, pSTAT5, FLT3 genotyping and ex vivo plasma inhibitory activity. AC220 is well tolerated and MTD has not yet been observed with either schedule. One pt had a possibly drug-related DLT in the 18 mg cohort (grade 3 CHF, although pt had a pre-existing heart condition) leading to cohort expansion, but no other cases of drug-related CHF or other DLT have been seen. Other possibly drug-related AEs (most frequently gastrointestinal events) were mild (grade ≤ 2). Response data based on investigator’s assessment are available on the first 45 pts. Responses were observed in 11 (24%) pts. Four pts achieved a complete response (CR) – 2 with incomplete platelet recovery (CRp) and 2 with incomplete platelet and neutrophil recovery (CRi), one of these pts also had complete resolution of leukemia cutis. In addition, 7 pts had partial responses (PR, defined as a decrease of ≥ 50% blasts to levels of 5%–25% in the bone marrow). Most responses (8/11, 73%) occurred after cycle 1 and one was observed after cycle 3. Median duration of response is 18 weeks (range, 4 to 26+ weeks). Three responders are FLT3 mutants (2 ITD and 1TKD), 5 are WT, 3 are undetermined. Six of the 9 non-responding pts with ITD mutations had initial rapid clearing of peripheral blasts with intermittent AC220 dosing, but subsequently progressed or had disease-related mortality. All these pts had aggressive disease and received a median of 6 prior treatment regimens (range, 3 to 8). AC220 plasma exposure is sustained between dose intervals and continues to increase in a dose-proportional manner from 12 mg to 300 mg. FLT3 phosphorylation is strongly suppressed when plasma obtained from study pts is tested ex vivo in FLT3-ITD and WT cell lines at 12 mg and 60 mg doses, respectively. Assessments of pFLT3 and pSTAT5 from treated pts’ peripheral blood are ongoing and will be presented. Encouraging preliminary efficacy results and an acceptable safety profile warrants continued evaluation of AC220 as a single agent and in combination with other therapeutics for the treatment of AML.

Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor

“…Compound 7 has demonstrated an acceptable toxicology profile in GLP studies and was tested in AML patients in a phase I study . The acceptable tolerability and excellent PK profile in humans combined with signs of beneficial effect in AML patients have justified the progression of 7 into phase II clinical trials …”

Discovery of the Novel Potent and Selective FLT3 Inhibitor 1-{5-[7-(3- Morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and Its Anti-Acute Myeloid Leukemia (AML) Activities in Vitro and in Vivo

“…Because of the therapeutic values in AML, the discovery of FLT3 inhibitors has increasingly attracted much attention in recent years. To date, several FLT3 inhibitors including SU-5416, 12 SU-11248, 13 CHIR-258, 14 PKC-412, 15 CEP-701, 16 MLN-518, 17 BAY-43-9006, 18 KW-2449, 19 and AC220 20 have been advanced to clinical trials. However, except for very few of them, such as AC220, the clinical efficacy of most of these FLT3 inhibitors in patients with AML seems unimpressive, mainly because of their potency and/or adverse events that stem from their poor target selectivity.…”