Monday, December 10, 2012

Astellas and Ambit Bioscience present path breaking Phase 2 data on Quizartinib in AML

Astellas Pharma Inc. and Ambit Biosciences Corporation announced results from a completed Phase 2 study with the investigational FLT3 inhibitor, quizartinib (AC220), as an oral monotherapy treatment regimen in patients with relapsed or refractory acute myeloid leukemia (AML). In the study quizartinib demonstrated highest level of single agent activity observed to date for FLT3-targeted therapy in relapsed/refractory AML



Quizartinib which is designed to 'turn off' the mutated FLT3 enzyme, was evaluated in 333 patients divided into two cohorts. In the second cohort, involving 137 patients (99 with mutation and 38 without), a complete remission rate of 44% was observed in patients with the FLT3-ITD mutation with a median duration of response of 11.3 weeks and median overall survival of 23.1 weeks. Even in those patients without the mutation, researchers observed a 34% complete response.

Summary of the Phase 2 ACE Study Design

This open-label Phase 2 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

- Cohort 1: Patients who are 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: Patients who are 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.


Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients ≥ 60 Years of Age with FLT3-ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia

At 10 months of follow-up for overall survival, in cohort comprised of patients aged 60 years or older with AML relapsed in less than one year or refractory to 1st-line chemotherapy.
The cohort comprised a total of 133 patients - 90 (68 percent) FLT3-ITD positive, 42 (32 percent) FLT3-ITD negative and one patient whose FLT3 genotype status was unknown

Clinical Data in FLT3-ITD positive patients
o The CRc rate was 53 percent (3 percent CR+CRp and 50 percent CRi),
o The median duration of CRc was 10.4 weeks,
o An additional 21 percent of patients achieved a PR,
o Of those refractory to their prior AML therapy, 70 percent achieved at least a PR with
quizartinib,
o The rate of HSCT after quizartinib use was 9 percent, which was likely impacted by
patient age and other comorbid factors in this patient population,
o The median overall survival was 25.3 weeks,
o Those who were able to be bridged to a HSCT had an OS of 32.2 weeks vs. 24.9 weeks
for those who did not receive a HSCT,
o Twelve patients (13 percent) are considered “long-term survivors” given they remained
alive for more than 12 months

Data in  FLT3-ITD negative patients:
o The CRc rate was 36 percent (5 percent CR+CRp and 31 percent CRi),
o The median duration of CRc was 9.3 weeks,
o An additional 10 percent of patients achieved a PR,
o Of those refractory to their last prior AML therapy, 55 percent achieved at least a PR with
quizartinib
o The rate of HSCT after quizartinib use was 2 percent, which was likely impacted by
patient age and other comorbid factors in this patient population,
o The median overall survival was 19.0 weeks,
o Five patients (12 percent) are considered “long-term survivors” given they remained alive
for more than 12 months

 Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients with FLT3-ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia After Second-Line Chemotherapy or Hematopoietic Stem Cell Transplantation 

At 10 months of follow-up for overall survival, in the cohort comprised of patients aged 18 years or older with AML relapsed or refractory to second-line, salvage chemotherapy or relapsed after HSCT. A total of 138 patients – 100 (72 percent) FLT3-ITD positive and 38 (28 percent) FLT3-ITD negative were included in the cohort.

For FLT3-ITD positive patients:
o The CRc rate was 46 percent (6 percent CR+CRp and 40 percent CRi),
The median duration of CRc was 12.1 weeks, which was likely impacted by a high
percentage (37 percent) of patients who were bridged to HSCT,
o An additional 27 percent of patients achieved a PR,
o Of those refractory to last prior AML therapy, 75 percent achieved at least a PR with
quizartinib,
o The rate of HSCT after quizartinib use was 37 percent, which represents clinical benefit
in this heavily pretreated patient population,
o The median overall survival was 22.9 weeks, with the impact of bridge to HSCT shown by
a median overall survival of 33.3 weeks in those who received a subsequent HSCT after
quizartinib compared to median overall survival of 17.7 weeks in those patients who did
not undergo a subsequent HSCT,
o Twenty-three patients (23 percent) are considered “long-term survivors” given they
remained alive for more than 12 months

• For FLT3-ITD negative patients:
o The CRc rate was 32 percent (6 percent CR+ CRp and 26 percent CRi),
o The median duration of CRc was 7.0,weeks, which was likely impacted by a high
percentage (37 percent) of patients who were bridged to a HSCT,
o An additional 16 percent of patients achieved a PR,
o Of those refractory to their last AML therapy, 48 percent achieved at least a PR with
quizartinib,
o The rate of HSCT after quizartinib use was 37 percent, which represents clinical benefit
in this heavily pretreated patient population,
o The median overall survival was 25.6 weeks,
o Ten patients (26 percent) are considered “long-term survivors” given they remained alive
for more than 12 months

Conclusion

Quizartinib is designed to 'turn off' the mutated FLT3 enzyme, and researchers conducted the study among 333 patients divided into two cohorts. In the second cohort, involving 137 patients (99 with mutation and 38 without), a complete remission rate of 44% was observed in patients with the FLT3-ITD mutation with a median duration of response of 11.3 weeks and median overall survival of 23.1 weeks. Even in those patients without the mutation, researchers observed a 34% complete response.

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