About AML

AML is the most common type of acute leukemia in adults, representing 29% of all new leukemia cases in 2009. AML results in uncontrolled growth and accumulation of malignant cells, or “blasts,” which fail to function normally and inhibit the production of normal blood cells. According to the American Cancer Society, approximately 13,000 adults were newly diagnosed with AML in 2009 in the United States, with approximately 9,000 expected to die of the disease in that year. AML is generally a disease of older people and uncommon before the age of 40. The average age of patients with AML is 67 at diagnosis and median survival for these patients is less than six months.

Standard-of-care treatment for AML has not changed appreciably for decades. However, factors such as age, cytogenetics and other prognostic factors, including FLT3-ITD status, play a critical role in determining the appropriate course of treatment. Front-line therapy typically begins with induction chemotherapy followed by post-remission, or consolidation, chemotherapy. Currently approved therapies for AML include chemotherapy drugs such as cytarabine, daunorubicin and mitoxantrone. However, these therapies have low cure rates, usually lead to relatively short disease remissions and can have life-threatening side effects such as severe neutropenia, which are associated with infection, especially in older patients. Although most adult AML patients may respond to initial treatment, the majority will relapse within five years and those that are FLT3-ITD positive often relapse in less than one year. Due to the high relapse rate and poor long-term survival, the treatment goal for healthier AML patients is tumor eradication for a period of at least three months to permit time for the identification of a suitable donor and preparation of the patient for a bone marrow transplant (BMT). Although BMT may offer a higher probability of cure, it is not an option for many patients due to potential toxicity with the procedure or the absence of an appropriate donor. Accordingly, there is a significant need for well-tolerated, targeted therapies for patients who cannot tolerate or are unlikely to benefit from chemotherapy or BMT.

 

Role of the FLT3 Kinase in AML

FLT3 is a receptor tyrosine kinase involved in cell growth signaling. Signaling through FLT3 plays an important role in the survival, proliferation and differentiation of progenitor cells into mature, functioning dendritic cells and granulocytes. Mutations in FLT3 are believed to play an important role in the development of certain cancers such as AML. Internal tandem duplication (ITD) mutations in the FLT3 gene are the most common mutations associated with AML and are a prognostic for particularly poor disease outcomes.

 

Development of Quizartinib in AML

Quizartinib Phase 1/2 Clinical Trial:
Treatment with quizartinib was evaluated in an open-label Phase 1/2 dose-escalation trial where it was dosed as a monotherapy in 76 AML patients. The majority of these patients were relapsed/refractory and had undergone an average of four prior treatment regimens. They were not selected on the basis of FLT3 activating mutations, although FLT3 genotype status was determined in most patients.

The trial utilized a standard 3+3 dose escalation scheme with 50% dose increments. Dosing initially was on a 14-day-on, 14-day-off schedule, with a starting dose of 12 mg/day. During the course of the trial the protocol was amended to provide for continuous dosing due to observed tolerability, efficacy and evidence of disease progression during drug holidays. The maximum tolerated dose (MTD) with continuous, once-daily oral dosing was determined to be 200 mg/day. Investigators presented preliminary findings from this study at the American Society of Hematology meeting in December 2009. Final results of this study will be published in a peer-review journal.

 

Quizartinib Phase 2 Clinical Trial:
In November 2009, Ambit initiated a Phase 2 clinical trial of quizartinib as monotherapy in relapsed/refractory AML patients. This single-arm, open-label trial is designed to evaluate the efficacy and safety of quizartinib in relapsed/refractory AML patients with FLT3-ITD activating mutations, which we refer to as FLT3-ITD positive. We plan to enroll at least 300 patients worldwide in four different cohorts. The first cohort consists of patients 60 years of age or older who have relapsed or did not respond after one induction chemotherapy regimen. The second cohort consists of patients 18 years of age or older who relapsed after, or did not respond to, second line "salvage" therapy or relapsed after BMT. The two remaining cohorts consist of FLT3-ITD negative patients who are the equivalent of cohorts one and two. The trial is designed to measure the rate of complete response, or CR, complete response rate with incomplete platelet recovery, or CRp, complete response rate with incomplete neutrophil recovery, or CRi, and partial response, or PR. The co-primary endpoints of the trial are (1) composite complete response, or CR + CRp + CRi, and (2) CR measured over the first 84 days. Secondary endpoints include duration of remission, disease-free survival and overall survival. In addition, within this ongoing pivotal Phase 2 clinical trial we are also planning to evaluate quizartinib as monotherapy in AML patients without the FLT3-ITD mutation that have the same age and treatment history criteria as those that possess the FLT3-ITD mutation.

An interim analysis on clinical response and safety in a subset of patients from this ongoing trial was reported at the 16th Annual Congress of the European Hematology Association (EHA) in London on June 13, 2011 (see presentation).  Safety data was reported on 62 patients and clinical response data was reported on a group of 53 patients who met the efficacy evaluable (EE) criteria.  Patients included in the analysis were either >60 years old and relapsed or refractory to first-line chemotherapy (Cohort 1, N=25), or >18 years old and relapsed or refractory to second-line chemotherapy or HSCT (Cohort 2, N=37).

In the efficacy evaluable population, there was a composite complete response (CRc) rate of 45% for all patients, and 41% and 48% in Cohort 1 and Cohort 2, respectively, with the majority of CRc cases represented by CRi, with no CRs observed, in the first 84 days.  Notably, a CRc rate of 62% was achieved in patients who were refractory to the prior line of treatment (N=16).  Key secondary end points in the study include duration of remission, rates of partial response, and overall survival.  The median duration of response for patients achieving a CRc was 12.1 weeks and 10.6 weeks in all patients and Cohort 2, respectively, with patients censored at the time of the transplant.  Cohort 1 has yet to achieve a median duration of response. In addition to the observed CRc rate, an additional 25% of efficacy evaluable patients achieved a partial response (PR).  The median survival of efficacy evaluable patients was 24.7 weeks and 24.1 weeks for all patients and Cohort 1, respectively.  Cohort 2 has yet to achieve a median survival, with 22 out of 31 patients alive at the time of analysis.  More than one-third of the patients in the safety population for Cohort 2 who had previously failed both induction chemotherapy and salvage therapy transitioned to HSCT.

No treatment-related deaths have been reported at the time of the analysis. The most common treatment-related adverse events included nausea, vomiting, fatigue and febrile neutropenia. Several cases of asymptomatic QTc prolongation were reported early in the study, but most resolved following a dose adjustment, and no Grade 4 cases have been reported. Management of other adverse events is also being explored with dose modifications in the ongoing study.

 

Other Potential Opportunities for Quizartinib in AML
Ambit, with its partner Astellas, plans to explore the use of quizartinib in other AML populations including:

  • In combination with standard chemotherapy for newly diagnosed AML patients
  • As single-agent maintenance for newly diagnosed AML patients following chemotherapy
  • As single-agent maintenance for patients post bone marrow transplant
  • Pediatric leukemias where FLT3-ITD activating mutations play a role
  • AML patients without the FLT3-ITD activating mutation