The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Background: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity. In a phase I and II studies the composite response rate (CRR) was approximately 50% among patients with FLT3-ITD. There is in-vitro synergy between quizartinib and 5-AZA or LDAC. We hypothesize that adding quizartinib to a hypomethylating agent such as 5-azacitidine (AZA) or cytarabine may improve the response rate expected from the use of either agent alone.

Objectives: The primary objective of phase I part is to determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of the combination of quizartinib (AC220) with either AZA or low-dose cytarabine (LDAC); for phase II is to determine the clinical activity of both combinations. This planned interim analysis reports on the recommended phase II dose (RP2D) and first futility analysis.

Methods: For phase I, patients with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or AML were eligible irrespective of FLT3 mutation and salvage status. For phase II, presence of FLT3-ITD is a requisite. Phase II enrollment is limited to patients >60 years with untreated MDS/CMML/AML, or any age receiving first salvage treatment. Additional eligibilities include performance status ECOG ≤2, adequate organ function, normal electrolytes (potassium, calcium and magnesium). Important exclusions include QTcF> 450 mSec, concomitant drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers with the exception of antibiotics, antifungals, and antivirals that are used as standard of care.

Treatment cycle is defined as 28 days. Treatment comprises of AZA 75 mg/m² subcutaneously (SQ) or intravenously (IV) for 7 days of every cycle (Days 1-7), or cytarabine 20 mg SQ twice daily for 10 days of every cycle (Days 1-10) along with quizartinib at two planned dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2) uninterrupted. Patients are assigned to AZA or LDAC arm by physician choice or slot availability. Planned accrual for each arm in phase 2 is 26 pts each and an ORR of ≥50% will be considered favorable. Accrual of 26 pts will give a 95% credible interval for overall response rate of (0.32, 0.68). The study will be stopped for toxicity (>30%) and/or futility (ORR <50%) at interim analysis for each arm.

Results: Twenty-six (Phase I=12, phase II=14) pts have been enrolled: 18 to AZA arm and 8 to LDAC arm. Median age is 62 years (range, 25-79 years), 7 (27%) are female. Cytogenetics are diploid=14, +8=2, -7=2, miscellaneous=6, 11q and t(8;21)= 1 each. Median number of prior therapies is 2 (range, 0-7), 7 patients received prior FLT3 inhibitor. For both schedules quizartinib 60 mg daily was identified as the recommended phase II dose (RP2D) based on emerging results from separate dose-finding study.

Eighteen [5 in LDAC arm (63%) and 13 (72%) in AZA arm; all with FLT3-ITD mutation without D835 mutation] of 26 total pts (69%) have responded (CR=1/ CRp=3/ CRi=2/ MLFS=10/PR=1/HI=1). Among patients with FLT3-ITD (N=22), ORR is 82%. Four of 7 (57%) patients with prior FLT3 inhibitor exposure responded. Median number of days to respond is 57 days (range, 25-102 days). Among responders two patients died (MLFS=1, PR=1): one with gastro-intestinal bleeding and other with progressive pneumonia. Three additional responders have discontinued therapy for stem cell transplant (1), withdrawal of consent (1), and loss of response with emergence of D835 mutation (1). Nine responders (CR=1, CRi=1, CRp=1, PR=1, MLS=5) had >50% reduction of FLT3-ITD allelic burden and 2 additional pts (CR=1, CRi=1) had no detectable FLT3-ITD at response. Number of pts with treatment emergent grade 3/4 toxicities irrespective of attribution include hypokalemia (15), hypophosphatemia (5), hyponatremia (4), hypocalcemia (4), hyperbilirubinemia (3), increase in ALT (1), hypernatremia (1hyperglycemia (1), hypotension (1), QTcF prolongation (1, grade 3).

Conclusion: Combination of quizartinib and AZA or LDAC is highly active among patients with AML/MDS/CMML with FLT3-ITD . Response rates appear higher than expected with either agent alone. Clinically significant QTcF prolongation is infrequent. Accrual to both arms of the current trial continues.