AC220 (Quizartinib) Can Be Safely Combined With Conventional Chemotherapy In Older Patients With Newly Diagnosed Acute Myeloid Leukaemia: Experience From The AML18 Pilot Trial

Introduction AC220 (Quizartinib) is a novel FLT3 inhibitor that has shown a high level of activity as monotherapy in patients with advanced FLT3 +ve disease, and more modest activity in FLT3 -ve patients across Phase 1 and 2 studies. This is the first presentation of quizartinib use in combination with chemotherapy in newly diagnosed (FLT3 +ve and FLT3 -ve) older AML patients. Study Aim In preparation for a prospective Phase 3 trial (NCRI AML 18) in older patients with newly diagnosed AML, we tested the feasibility and dose of AC220 which could be sequentially given two days after each of two courses of ADE (Ara-C/ Daunorubicin/ Etoposide) followed by one course of DA (2+5) in patients over age 60 with FLT3 +ve or FLT3 –ve newly diagnosed AML. Six cohorts with escalating doses (60mg, 90mg or 135mg based on doses used in the Phase 2 ACE study with quizartinib) for 7 or 14 days were planned. If 60mg was not tolerated there was provision to de-escalate to 40mg for 7 or 14 days. The study was based on a 3+3 design whereby if 1 of 3 developed a DLT a cohort expansion was required but if >2 of 6 had a DLT, the cohort failed. A DLT was defined as any grade 4 non-haematological toxicity or failure of count recovery by day 42 in the absence of marrow blasts, or a grade 3 toxicity that did not recover to at least grade 2 within 7 days. Because of the increased sensitivity in females to QTc prolongation, each cohort required a minimum of 3 females. The day of safety evaluation was on completion of the chemotherapy in course 2. Results 55 patients with a median age of 69 years (62-87) entered of whom 48 were evaluable. 4 patients were FLT3 ITD +ve. 13 patients (4 males, 9 females) entered cohort 1 (AC220 60mg for 7days). No DLTs were seen in males but 3 DLTs occurred in females (all grade 4:1 cardiac (MI), 1 hypokalaemia; 1 mucositis) so this cohort exceeded tolerability for females. 8 patients (all males) entered cohort 2 (AC220 60mg for 14 days) where 4 DLTs (all grade 3; 3 QTC, 1 appetite loss) were seen, so this cohort exceeded tolerability for males. The de-escalation cohort (cohort 3) was activated (AC220 40mg for 7 days). 2 DLTs (1 grade 4 lung; 1 lung infection grade 3 >7days) in 7 evaluable females and 0 DLTs in 9 evaluable males were seen, so both males and females progressed to Cohort 4 (AC220 40mg for 14 days). There was 1 DLT (haematological) of 5 evaluable males and 0 of 8 evaluable females had a DLT. The DLTs were similarly distributed between males (5/25) and females (5/23). Induction death (death with 30 days) occurred in 3/46 (6.5%) evaluable patients. CR was achieved in 33/42 (79%; including all 4 FLT3 ITD +ve) of patients evaluable for CR or 60% of all 55 patients. Overall median time to neutrophil and platelet count recovery (neutrophils to 1.0x109/l; platelets to 100x109/l) was prompt (28 and 22 days post course 1; 22 and 19 days post course 2 respectively). No patients received SCT. The median OS is currently 15 months. Conclusion AC220 at 40mg for 14 days can safely be given sequentially after chemotherapy in older patients with newly diagnosed AML. The Phase 3 AML 18 study is planned to start in early 2014 and will incorporate AC220 into multiple courses of DA therapy as well as maintenance therapy. On behalf of the UK NCRI AML Working Group. We acknowledge the support from Ambit Biosciences for this study. Disclosures: Burnett: Ambit: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: AC220 for newly diagnosed AML. Hills:Ambit: Consultancy.