Results from a completed Phase II study with the investigational FLT3 inhibitor, quizartinib (AC220; Astellas Pharma/Ambit Biosciences) as an oral monotherapy treatment regimen in patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) were presented earlier today at the 54th Annual Meeting of the American Society of Hematology (ASH).

The Phase II ACE study recruited patients into two separate cohorts of patients with relapsed/refractory AML, and the results from each cohort of were presented in individual oral sessions.

Quizartinib (AC220) is a novel, potent, highly selective, orally bioavailable FMS-like tyrosine kinase-3 (FLT3) inhibitor. The trial drug is currently under evaluation in a Phase IIb clinical trial as monotherapy treatment for adult patients with relapsed or refractory AML, and in two Phase I studies in a combination treatment regimen with chemotherapy, and as a maintenance therapy following transplant, respectively.

Composite complete response
The combined key findings in FLT3-ITD positive patients showed that approximately 50% of FLT3-ITD positive patients achieved a CRc, or composite complete response (CRc: complete remission (CR) + complete remission with incomplete platelet recovery (CRp) + complete remission with incomplete hematologic recovery (CRi)). Approximately 50% of FLT3-ITD positive patients who were refractory (i.e. had no response to their prior AML therapy) achieved a CRc, and one-in-three FLT3-ITD positive patients who had relapsed or were refractory after two prior lines of treatment or after a prior hematopoietic stem cell transplant (HSCT) received a potentially curative HSCT following treatment with quizartinib. The trial data showed that, as of Sept. 28, 2012, 35 (18%) FLT3-ITD positive patients had survival of greater than 12 months.

A challenging hematological malignancy
“AML is amongst the most challenging hematological malignancies to treat, and patients with activating FLT3 mutations have a particularly poor prognosis and often relapse or are refractory to current treatment options,” noted Jorge E. Cortes, M.D., Internist and Professor, Deputy Chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

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“The findings from the Phase II ACE study with quizartinib in patients with relapsed and refractory AML are especially encouraging. In the patients with the FLT3-ITD mutation, quizartinib represents the most active single-agent we have observed with any class of investigational drugs in this challenging patient population. We look forward to further investigation of quizartinib in the expanding clinical program which includes multiple treatment strategies and subpopulations of AML patients”.

In addition to the clinical benefit observed in FLT3-ITD positive patients, there was substantial evidence of activity in FLT3-ITD negative patients, with approximately one-in-three of these patients achieving a CRc and a comparable percentage receiving HSCT as in the FLT3-ITD positive group.

Adverse Events
Safety findings in the study were primarily gastrointestinal, myelosuppression and QT prolongation, and these were generally mitigated with dose modifications. Twenty-two percent of patients experienced an adverse event (AE) that resulted in treatment discontinuation, with progressive disease being the most common AE.

“The results of this large Phase II ACE trial demonstrate the clinical benefit achieved with quizartinib in heavily pretreated AML patients with limited therapeutic options,” said Athena Countouriotis, M.D., Chief Medical Officer of Ambit. “A substantial portion of patients who relapsed or were refractory to two prior lines of treatment, or a prior HSCT, were successfully bridged to HSCT, which is considered the only potentially curative procedure for patients diagnosed with AML. For those patients who are not eligible for HSCT, prolonged quizartinib use may positively impact quality of life as an outpatient treatment. Further, these results showed a safety and tolerability profile comparable with what was observed in an early study, but with a lower rate of asymptomatic Grade 3 QT prolongation.”

Trial Design
The open-label Phase II trial included a total of 333 patients with relapsed or refractory AML. Data from 271 patients were reported here from the “confirmatory” phase of the study. Data from 62 patients from an “exploratory” phase had been reported earlier. In the “confirmatory” phase, quizartinib was investigated in two separate cohorts, and each of these cohorts was presented in separate oral sessions.

Cohort 1 included patients who were 60 years of age or older who are relapsed after one first-line chemotherapy regimen (with or without consolidation) and after first remission of less than 12 months duration or are primary refractory to first-line chemotherapy. Cohort 2 included patients who were 18 years of age or older, including patients 60 years of age or older, who are relapsed or refractory after one second-line (salvage) regimen or are relapsed or refractory after HSCT

Quizartinib was administered orally, once-a-day, at a starting dose of 90 mg/day (females) or 135 mg/day (males), in 28-day treatment cycles until disease progression, elective HSCT or unacceptable toxicity that could not be mitigated with dose adjustments. The co-primary endpoints were CRc (CR + CRp + CRi) and CR. Additionally, partial response (PR), overall survival (OS), HSCT rates, molecular pharmacodynamic (PD) biomarkers and standard safety assessments were evaluated.

For more information:

Clinical trials
NCT01565668 – An Open Label Study to Evaluate the Safety and Efficacy of Two Doses of Quizartinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia
NCT01468467 – A Study of AC220 Given After Transplant in Subjects With Acute Myeloid Leukemia (AML)
NCT01390337 – A Study to Assess AC220 Given in Combination With Induction and Consolidation Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML)

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