Results Of a Phase 2 Randomized, Open-Label, Study Of Lower Doses Of Quizartinib (AC220; ASP2689) In Subjects With FLT3-ITD Positive Relapsed Or Refractory Acute Myeloid Leukemia (AML)

FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown the highest level of single agent activity seen with a FLT3 targeted agent in FLT3+ relapsed AML to date. This Phase 2 study was conducted to assess the efficacy and safety of two lower doses of quizartinib monotherapy in FLT3-ITD positive (+) pts aged 18 yrs or older with AML relapsed or refractory to 2^nd-line, salvage chemotherapy or relapsed after hematopoietic stem cell transplantation (HSCT) to identify the optimal dose for future studies. The co-primary endpoints of the study were the composite complete remission (CRc) rate, which included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi) and the rate of grade ³2 QTc prolongation. The Phase 2 study enrolled a total of 76 pts who were randomized to either 30 mg or 60 mg daily.

Preliminary data from the entire study of 76 pts are included here; updated information will be provided for presentation. Thirty eight patients each were randomized to each arm and treated continuously during 28-day cycles. 58% of the randomized patients were male. The pts had a median age of 53 yrs (range 19 to 77).

For 30 mg pts the derived CRc rate was 50% (5% CR, and 45% CRi). For 60 mg pts the CRc rate was 50 % (3% CR, 3% CRp, and 45% CRi). 29% of pts at 30mg and 37% of pts at 60mg were successfully bridged to HSCT.

Efficacy Results in AML Pts Relapsed/Refractory to 2^nd-line Therapy or HSCT

The rate of grade 2 or higher QTc prolongation assessed by central reading was 11% and 17% in 30 mg and 60 mg arms respectively, grade 3 QT prolongation was 3% in both arms and there was no grade 4. The mean maximum prolongation from baseline was 31.5 ms and 39.7 ms in 30 mg and 60 mg arms respectively.

A majority of patients (78%) had a treatment related adverse event. The most common (10%) treatment-related adverse events (AEs) were anemia (18%), nausea (15%), fatigue (12%) and diarrhea (11%). Sixteen patients (22%) had a serious adverse event (SAE) possibly related to study drug. The most common (5%) treatment-related SAE was febrile neutropenia (5%). A total of 4 pts (5%) experienced a treatment-related AE resulting in discontinuation of quizartinib.

The data from this Phase 2 study confirm the high degree of activity of quizartinib monotherapy in FLT3-ITD(+) AML pts relapsed/refractory to 2^nd-line treatment or HSCT, previously shown in the larger Phase 2 ACE study of 333 patients treated at higher doses (90mg, 135mg or 200mg). Importantly, 25 of 76 pts (33%) were successfully bridged to a potentially curative HSCT, an almost identical rate to that seen with higher doses. The safety profile is improved specifically decreasing QT prolongation rate at lower doses. Other safety findings were manageable, and were primarily gastrointestinal adverse events and myelosuppression. The data from this Phase 2 study confirms an improved risk:benefit profile with lower doses of quizartinib and multiple randomized Phase 3 studies with quizartinib in both relapsed and newly diagnosed AML patients are planned.