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673 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemia - Therapy, excluding Transplantation: New drugs in acute myeloid leukemia
Monday, December 10, 2012: 4:30 PM
A101, Level 1, Building A (Georgia World Congress Center)

Mark J. Levis, MD, PhD1, Alexander E Perl, MD2, Hervé Dombret, MD3, Hartmut Döhner, MD4*, Björn Steffen, MD5*, Philippe Rousselot, MD, PhD6*, Giovanni Martinelli, MD, PhD7*, Elihu H. Estey, MD8, Alan K Burnett, MD9, Guy Gammon, MD10*, Denise Trone10*, Eugen Leo, MD, PhD, MBA10* and Jorge E Cortes, MD11*

1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
2Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3Hématologie Adultes, Hôpital Saint-Louis, AP-HP, Université Paris 7, Paris, France
4Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
5Dept. of Medicine, Hematology/Oncology, Goethe University of Frankfurt, Frankfurt, Germany
6Service d’Hématologie et Oncologie, Hopital de Versailles, Université Versailles Saint Quentin en Yvelines, Le Chesnay, France
7Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
8Department of Medicine/Division of Hematology, University of Washington, Seattle, WA
9Department of Medical Genetics, Haematology and Pathology, Cardiff University School of Medicine, Cardiff, United Kingdom
10Ambit Biosciences Corporation, San Diego, CA
11Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX

FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival.  Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that is active against both ITD mutant and wild type FLT3, and has shown promising activity in a Phase 1 study of patients (pts) with AML.  This Phase 2 study was conducted to assess the efficacy and safety of quizartinib monotherapy in FLT3-ITD positive (+) and FLT3-ITD negative (-) pts with a total of 333 pts included in two cohorts. Cohort 2 included pts aged ≥ 18 yrs with AML relapsed or refractory to 2nd-line, salvage chemotherapy or relapsed after hematopoietic stem cell transplantation (HSCT).  A total of 137 pts were included in this cohort and constitute the basis for this analysis.

Data through 31 January 2012 from 137 pts in this cohort were analyzed. These pts included 99 (72%) who were FLT3-ITD(+) and 38 (28%) who were FLT3-ITD(-). A total of 50% of the 99 FLT3‑ITD(+) pts and 61% of the 38 FLT3-ITD(-) pts were male. The FLT3-ITD(+) pts had a median age of 50 yrs (range 19 to 77 yrs), and the FLT3-ITD(-) pts had a median age of 55 yrs (range 30 to 73 yrs).  Pts received quizartinib at a starting dose of 90 mg/day (females) or 135 mg/day (males), and were treated continuously during 28-day cycles.

The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi).  For FLT3-ITD(+) pts the CRc rate was 44% (4% CR, 0 CRp, and 40% CRi), with a median duration of response of 11.3 weeks and median overall survival of 23.1 weeks. Of those refractory to their last AML therapy, 47% achieved a CRc with quizartinib.  For FLT3-ITD(-) pts the CRc rate was 34% (3% CR, 3% CRp, and 29% CRi), with a median duration of response of 5.0 weeks and median overall survival of 25.6 weeks. Of those refractory to their last AML therapy, 31% achieved a CRc with quizartinib.

Efficacy Results in AML Pts Relapsed/Refractory to 2nd-line Therapy or HSCT



N = 99


N = 38

   Cumulative CRc, n (%)

44 (44)

13 (34)

   CRc + PR, n (%)

67 (68)

18 (47)

   Prior nonresponders achieving CRc to quizartinib, n (%)

27/57 (47)

9/29 (31)

   Subjects discontinuing quizartinib because of HSCT, n (%)

34 (34)

13 (34)

   Median CRc duration, weeks



   Median overall survival, weeks



CRc = composite complete remission; HSCT = hematopoietic stem cell transplantation; NR = not reached; PR = partial remission.

The most common (≥20%) treatment-related adverse events (AEs) were nausea (38%), anemia (29%), QT interval prolongation (26%), vomiting (26%), febrile neutropenia (25%), diarrhea (20%), and fatigue (20%). The most common (≥10%) Grade 3 or 4 treatment-related AEs were anemia (26%), febrile neutropenia (25%), thrombocytopenia (15%), neutropenia (12%), and QT interval prolongation (10%).  An AE of QT interval prolongation occurred in 36/137 pts (26%) and was Grade 3 in 13 pts (10%). No Grade 4 QT interval prolongation occurred. A total of 14 pts (10%) experienced a treatment-related AE resulting in discontinuation of quizartinib.

The final data from this Phase 2 study confirm the high degree of activity of quizartinib monotherapy in FLT3‑ITD(+) and FLT3-ITD(-) AML pts relapsed/refractory to 2nd-line treatment or HSCT. These data represent the highest level of single agent activity observed to date for FLT3-targeted therapy in FLT3-ITD(+) relapsed/refractory AML.  Of clinical significance in this heavily pretreated population, approximately 1/3 of pts were successfully bridged to potentially curative HSCT, and many pts who were refractory to prior therapy responded to quizartinib. Safety findings were manageable, and were primarily myelosuppression and QT prolongation that was mitigated with dose modifications. Further Phase 1 and 2 studies with lower doses of quizartinib as monotherapy and in combination with other agents in FLT3-ITD(+) and FLT3-ITD(-) AML are being planned/ongoing.

Disclosures: Levis: Ambit Biosciences: Consultancy. Perl: Ambit Biosciences: Consultancy. Dombret: Celgene: Consultancy. Döhner: Celgene, Amgen, Lilly, Genzyme: Consultancy. Steffen: Novartis: Travel/accommodations/meeting expenses Other. Rousselot: Ambit Biosciences: Consultancy. Martinelli: BMS, Novartis; Pfizer, Roche: Consultancy. Estey: Ambit Biosciences: Consultancy. Burnett: Ambit Biosciences: Consultancy. Gammon: Ambit Biosciences: Employment. Trone: Ambit Biosciences: Employment. Leo: Ambit Biosciences: Employment. Cortes: Novartis: Consultancy.

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