Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R. METHODS: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. RESULTS: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events. CONCLUSIONS: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).

Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML.

This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.

Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite.

AIMS: Quizartinib is an oral, highly potent and selective next-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor under investigation in patients with FLT3-internal tandem duplication-mutated acute myeloid leukaemia. This drug-drug interaction study assessed the pharmacokinetics (PK) of quizartinib when coadministered with strong or moderate cytochrome P450 3A (CYP3A) inhibitors. METHODS: In this parallel-group study, subjects were randomised to receive: (i) quizartinib + ketoconazole; (ii) quizartinib + fluconazole; or (iii) quizartinib alone. On Days 1-28, subjects received ketoconazole 200 mg or fluconazole 200 mg twice daily, and on Day 8, all subjects received a single 30-mg quizartinib dose. Blood samples were collected for PK analyses, steady-state PK parameters were simulated by superpositioning, and safety was assessed. RESULTS: Ninety-three healthy subjects were randomised; 86 completed the study. When administered with ketoconazole, geometric mean ratios (90% confidence interval) for quizartinib maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity were 117% (105%, 130%) and 194% (169%, 223%), respectively, vs quizartinib alone. Steady-state PK simulation demonstrated ~2-fold increase of both steady-state Cmax and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib Cmax and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Overall, 5.4% of subjects experienced quizartinib-related adverse events; no serious adverse events or deaths occurred. CONCLUSIONS: These results suggest reducing the dose of quizartinib when coadministered with a strong CYP3A inhibitor, but not with a moderate or weak CYP3A inhibitor. This dose reduction was implemented in phase 3 evaluation of quizartinib.

Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. FINDINGS: Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2. INTERPRETATION: Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses. FUNDING: Ambit Biosciences/Daiichi Sankyo.

Safety and tolerability of quizartinib, a FLT3 inhibitor, in advanced solid tumors: a phase 1 dose-escalation trial.

BACKGROUND: Quizartinib, an inhibitor of class III receptor tyrosine kinases (RTKs), is currently in phase 3 development for the treatment of acute myeloid leukemia (AML) bearing internal tandem duplications in the FLT3 gene. Aberrant RTK signaling is implicated in the pathogenesis of a variety of solid tumors, suggesting that inhibiting quizartinib-sensitive RTKs may be beneficial in precision cancer therapy. METHODS: This was a phase 1, open-label, modified Fibonacci dose-escalation study of orally administered quizartinib in patients with advanced solid tumors whose disease progressed despite standard therapy or for which there was no available standard treatment. Patients received quizartinib dihydrochloride (henceforth referred to as quizartinib) once daily throughout a 28-day treatment cycle. The primary endpoint was evaluation of the maximum tolerated dose (MTD) of quizartinib. Secondary endpoints included preliminary evidence of antitumor activity and determination of the pharmacokinetic and pharmacodynamic parameters of quizartinib. RESULTS: Thirteen patients were enrolled. Five patients received a starting dose of quizartinib 135 mg/day; dose-limiting toxicities (DLTs) of grade 3 pancytopenia, asymptomatic grade 3 QTc prolongation, and febrile neutropenia were observed in 1 patient each at this dose. A lower dose of quizartinib (90 mg/day [n = 8]) was administered without DLTs. The most common treatment-related treatment-emergent adverse events (AEs) were fatigue (n = 7, 54%), dysgeusia (n = 5, 38%), neutropenia (n = 3, 23%), and QTc prolongation (n = 3, 23%). Overall, all patients experienced at least 1 AE, and 4 experienced serious AEs (2 patients each in the 135-mg and 90-mg dose groups) including hematologic AEs, infections, and gastrointestinal disorders. Six patients (including 3 patients with gastrointestinal stromal tumors [GIST]) had a best response of stable disease. CONCLUSION: The MTD of quizartinib in patients with advanced solid tumors was 90 mg/day. Overall, the safety and tolerability of quizartinib were manageable, with no unexpected AEs. Quizartinib monotherapy had limited evidence of activity in this small group of patients with advanced solid tumors. TRIAL REGISTRATION: Clinical Trials Registration Number: NCT01049893 ; First Posted: January 15, 2010.

Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant.

FLT3-ITD-mutated acute myeloid leukemia (AML) has very high risk of relapse and is associated with poor outcome following allogeneic hematopoietic-cell transplant (allo-HCT). This two-part, phase 1, multicenter, open-label, sequential-group, dose-escalation study aimed to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and safety/tolerability of quizartinib, a selective and highly potent FLT3 inhibitor, when administered as maintenance therapy after allo-HCT. Thirteen subjects with documented FLT3-ITD-mutated AML in morphological remission following allo-HCT received one of two quizartinib dihydrochloride dose levels (DL): 40 mg/d (DL1; n = 7) and 60 mg/d (DL2; n = 6), administered orally in 28-day cycles for up to 24 cycles. Median age of participants was 43 years. All subjects received human leukocyte antigen (HLA)-matched allo-HCT. One subject treated at DL1 and 1 treated at DL2 had DLTs that required drug interruption (grade 3 gastric hemorrhage and grade 3 anemia, respectively). Ten subjects (77%) received quizartinib for >1 year; 5 (38%) completed 24 cycles. Four subjects (31%) discontinued quizartinib due to adverse events. One subject (8%) experienced relapse during cycle 1 and discontinued treatment. Most common grade 3/4 adverse events were neutropenia (23%), anemia (15%), leukopenia (15%), lymphopenia (15%), and thrombocytopenia (15%). This study demonstrated acceptable tolerability and early evidence of reduced relapse rate following allo-HCT with quizartinib maintenance compared to historical cohorts. No MTD was identified, but 60 mg daily was selected as highest dose for continuous daily administration based on randomized comparison of daily 30 and 60 mg doses in relapsed/refractory AML.

Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia.

Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n = 6), 60 mg/d for 14 days (DL2; n = 7), and 40 mg/d for 14 days (DL-1; n = 6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose-limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL-1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL-1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. The phase 3 QuANTUM-First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3-ITD mutated patients.

A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia.

Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B-cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open-label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty-seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression-free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.

Effect of Food on the Pharmacokinetics of Quizartinib.

Quizartinib is an oral, highly potent, and selective type II FMS-like tyrosine kinase 3 inhibitor in development for acute myeloid leukemia. This parallel-group study evaluated potential food effects on quizartinib absorption in healthy subjects who received a single 30-mg dose after overnight fasting (n = 34) or a high-fat, high-calorie meal (n = 30). Blood samples were collected through 504 hours after dosing, and pharmacokinetic parameters calculated were maximum observed concentration (Cmax ) and area under plasma concentration-time curve from time 0 to last quantifiable concentration (AUClast ) and from time 0 to infinity (AUCinf ). Mean quizartinib pharmacokinetic profiles were similar under fasted and fed conditions. The geometric least squares means ratios (%) for fed/fasted and associated 90% confidence intervals (CIs) for Cmax , AUClast , and AUCinf were 91.58 (82.15-102.08), 105.39 (90.79-122.35), and 108.39 (91.54-128.34), respectively. The 90%CI for the ratio fell within the 80% to 125% limits for Cmax and AUClast , with 90%CI for AUCinf slightly outside the limits (ie, 128%). Food delayed quizartinib time to Cmax by 2 hours. All adverse events were either mild or moderate; no discontinuations due to adverse events occurred. Based on these results, quizartinib can be administered without regard to food.

A drug-drug interaction study to assess the potential effect of acid-reducing agent, lansoprazole, on quizartinib pharmacokinetics.

PURPOSE: Quizartinib, a potent, selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, is currently in phase 3 development for patients with FLT3-internal tandem duplication-mutated acute myeloid leukemia (AML). Acid-reducing agents (ARAs; e.g., proton pump inhibitors) are frequently used during AML treatment. Since quizartinib demonstrates pH-dependent solubility, the effect of lansoprazole coadministration on pharmacokinetics (PK) of quizartinib tablet formulation was assessed. METHODS: An open-label, parallel-group study randomized 64 healthy adults to single-dose quizartinib 30 mg alone (reference) or lansoprazole (60 mg once daily, days 1-5) + single-dose quizartinib 30 mg (day 5) (test). Plasma concentrations of quizartinib and its active metabolite, AC886, were measured to 504 h postdose; the effect of lansoprazole on quizartinib PK was assessed by analysis of variance. RESULTS: Quizartinib geometric mean ratios (test/reference) and 90% confidence intervals for maximum observed plasma concentration (Cmax), area under the concentration-time curve to last measurable drug concentration (AUClast), and AUC to infinity were 86.11% (78.4%, 94.6%), 93.96% (79.6%, 110.9%), and 95.30% (80.2%, 113.3%), respectively. Comparisons showed a modest decrease in quizartinib absorption when co-administered with lansoprazole, with lower limits for Cmax and AUClast just below 80-125% limits. Treatment-emergent adverse events were mild or moderate; the most frequent in either treatment group were headache [quizartinib alone: (n = 3) 10%], upper respiratory tract infection [quizartinib alone: (n = 2) 6.7%; lansoprazole + quizartinib: (n = 3) 9.1%], and muscle tightness [quizartinib alone: (n = 2) 6.7%]. CONCLUSIONS: Concomitant lansoprazole had minimal effect on quizartinib PK as a formulated tablet, indicating that quizartinib can be administered with ARAs.

A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105.

RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.This article is highlighted in the In This Issue feature, p. 305.

Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status.

PURPOSE: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models. PATIENTS AND METHODS: Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML. RESULTS: Responses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17%) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53%; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14%; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41%; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10% incidence) were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤ grade 2. The maximum-tolerated dose was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay. CONCLUSION: Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.