Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML) (ACE)

Phase 2 Open-Label, AC220 Monotherapy Efficacy (ACE) Study in Patients With Acute Myeloid Leukemia (AML) With and Without FLT3-ITD Activating Mutations

AC220 will be administered as a once daily oral solution given continuously as 28-day treatment cycles, without any rest periods, until disease progression, relapse, intolerance to the drug, or elective allogeneic hematopoietic stem cell transplantation (HSCT).

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Compound AC220

• Study Type: Interventional
• Enrollment (Actual): 333
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
• France
  • Bobigny, France
    • Hopital Avicenne
  • Grenoble, France
    • Centre Hospitalier Universitaire Grenoble
  • Le Chesnay, France
    • Centre Hospitalier De Versailles
  • Lille, France
    • Hôpital Claude Huriez
  • Limoges, France
    • Centre Hospitalier Universitaire Limoges
  • Lyon, France
    • Hôpital Edouard Herriot
  • Paris, France
    • Hôpital Saint-Antoine
  • Paris, France
    • Hôpital Saint-Louis
  • Pessac, France
    • Hopital Haut-Leveque
  • Rouen, France
    • Centre Henry Becquerel, Service d'Hematologie
  • Strasbourg, France
    • Centre Hospitalier Régional Universitaire, Hôpital de Hautepierre
  • Vandoeuvre les Nancy, France
    • Centre Hospitalier Universitaire Brabois
  • d'Angers, France
    • Centre Hospitalier Universitaire d'Angers
  • Cedex
    • Toulouse, Cedex, France
      • Hematologie - CHU Purpan
  • Cedex 9
    • Marseille, Cedex 9, France
      • Institut Paoli Calmettes Centre Régional de Lutte Contre le Cancer
• Germany
  • Berlin, Germany
    • Charite, Campus Benjamin Franklin
  • Berlin, Germany
    • Charite Campus Virchow Klinikum
  • Bonn, Germany, 5311
    • Universitätsklinikum Bonn
  • Dresden, Germany
    • Unikliniksklinikum Carl Gustav Carus
  • Essen, Germany
    • Uniklinik Essen, Westdeutsches Tumorzentrum
  • Frankfurt am Main, Germany
    • Klinikum Der Johann Wolfgang Goethe Universitat
  • Hamburg, Germany
    • Asklepios Klinik St Georg
  • Hannover, Germany
    • Medizinische Hochschule Hannover
  • Heidelberg, Germany
    • Universitätsklinikum Heidelberg
  • Jena, Germany
    • Universitatsklinikum Jena
  • Leipzig, Germany
    • Universitatsklinikum Leipzig Selbstandige Abteilung fur Hamatologie
  • Magdeburg, Germany
    • Universitätsklinikum Magdeburg
  • Mannheim, Germany
    • Universitätsklinikum Mannheim
  • Marburg, Germany
    • Philipps-Universität Marburg
  • Munchen, Germany
    • Klinikum rechts der Isar, Technische Universität München
  • Munster, Germany
    • Universitätsklinikum Münster
  • Regensburg, Germany
    • Universitatsklinikum Regensburg Abteilung fur Hamatologie
  • Stuttgart, Germany
    • Robert-Bosch-Krankenhaus GmbH
  • Tubingen, Germany
    • Universitätsklinikum Tübingen
  • Ulm, Germany
    • Universitätsklinikum Ulm
  • Wurzburg, Germany
    • Universitätsklinikum Würzburg
• Italy
  • Bologna, Italy
    • Instituto Di Ematologia "L.Ea. Seragnoli"
  • Brescia, Italy
    • Unita Trapianti di Midollo Osseo per Adulti
  • Cagliari, Italy
    • Presidio Ospedaliero "A. Businco" - Centro di Riferimento Oncologico Regionale
  • Catania, Italy
    • Azienda Ospedaliera-Universitaria Vittorio Emanuele-Ferrarotto
  • Genova, Italy
    • Azienda Ospedaliera Universitaria San Martino
  • Orbassano, Italy
    • Farmacia Ospidaliera
  • Ravenna, Italy, 48100
    • Ospedale Civile S. Maria delle Croci
  • Roma, Italy, 00144
    • Ospedale Sant Eugenio
  • Roma, Italy
    • Universita Degli Studi di Roma Tor Vergata
  • Siena, Italy
    • Azienda Ospedaliero Universitaria Senese
  • Udine, Italy
    • Azienda Ospedaliero Universitaria S. Maria della Misericordia di Udine, Clinica Ematologica
• Netherlands
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Utrecht, Netherlands
    • Utrecht University Medical Centre, Dept. of Hematology
• Poland
  • Wroclaw, Poland
    • Dolnoslaskie Centrum Transplantacji Komorkowych z
• Spain
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Hospital Clinic i Provincial de Barcelona
  • Barcelona, Spain
    • Institut Catala d'Oncologia del Hospital Universitari Germans
  • Girona, Spain
    • Instituto Catalan de Oncologia-Hospital Universitari de Girona
  • Madrid, Spain
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain
    • Hospital de la Princesa, Servicio de Hematologia
  • Salamanca, Spain
    • Hospital Universitario de Salamanca, Hospital Clinico, Servicio de Hematologia
  • Valencia, Spain
    • Hospital La Fe, Servicio de Hematologia
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universidad de Navarra
• United Kingdom
  • Cambridge, United Kingdom
    • Addenbrook's Hospital
  • Cottingham, United Kingdom, HU 16 5JQ
    • Castle Hill Hospital
  • Leeds, United Kingdom, LS9 7TF
    • Saint James University Hospital, Institute of Oncology
  • London, United Kingdom
    • Hanmmersmith Hospital, Dept. of Hematology
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham University Hospitals NHS Trust
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10032
      • Columbia University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Clinical Trials Center
    • Nashville, Tennessee, United States, 37232
      • The Vanderbuilt Clinic
  • Texas
    • Houston, Texas, United States, 77030
      • M.D. Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Current enrollment is open only to FLT3-ITD positive, Cohort 1.

Inclusion Criteria:

1. Males and females age ≥18 years in second relapse or refractory.
2. Males and females age ≥60 years in first relapse or refractory.
3. Must have baseline bone marrow sample taken.
4. Morphologically documented primary AML or AML secondary to myelodysplastic syndrome (MDS with ≥20% bone marrow or peripheral blasts), as defined by the World Health Organization (WHO) criteria, confirmed by pathology review at treating institution.
5. Able to swallow the liquid study drug.
6. Eastern Cooperative Oncology Group performance status of 0 to 2
7. In the absence of rapidly progressing disease, the interval from prior treatment to time of AC220 administration will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents. The use of chemotherapeutic or antileukemic agents other than hydroxyurea is not permitted during the study with the possible exception of intrathecal (IT) therapy at the discretion of the Investigator and with the agreement of the Sponsor.
8. Persistent chronic clinically significant non-hematological toxicities from prior treatment must be ≤Grade 1.
9. Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC220.
10. Serum creatinine ≤1.5 × upper limit of normal (ULN) and glomerular filtration rate (GFR) > 30 mL/min
11. Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits.
12. Total serum bilirubin ≤1.5 × ULN
13. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 × ULN
14. Females of childbearing potential must have a negative pregnancy test (urine β-hCG).
15. Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study.
16. Written informed consent must be provided.

Exclusion Criteria:

1. Patients over the age of 85 years except at the discretion of the Investigator and with agreement of the Sponsor.
2. Diagnosis of acute promyelocytic leukemia
3. Diagnosis of chronic myelogenous leukemia (CML) in blast crisis
4. AML in relapse or refractory after 3 or more previous lines of chemotherapy (and/or HSCT) treatment
5. AML or antecedent MDS secondary to prior chemotherapy
6. Persistent clinically significant non-hematological toxicity that is Grade >1 by NCI CTCAE v4 from prior chemotherapy
7. Patients who have had HSCT and are within 100 days of transplant and/or are still taking immunosuppressive drugs and/or have clinically significant graft-versus-host disease requiring treatment and/or have >Grade 1 persistent non hematological toxicity related to the transplant
8. Clinically active central nervous system (CNS) leukemia. Patients with CNS leukemia, which is controlled, but who are still receiving IT therapy at study entry may be considered eligible and continue receive IT therapy at the discretion of the Investigator and with agreement of the Sponsor.
9. Patients who have previously received AC220
10. Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment)
11. Major surgery within 4 weeks prior to enrollment in the study
12. Radiation therapy within 4 weeks prior to, or concurrent with study
13. Use of concomitant drugs that prolong the time between the start of the Q wave and the end of the T wave (QT)/corrected interval between the Q wave and T wave (QTc) interval and/or are CYP3A4 inhibitors are prohibited with the exception of antibiotics, antifungals, and other antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient.
14. Uncontrolled or significant cardiovascular disease
15. Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential
16. Men who are unwilling to use contraception if their partners are of childbearing potential
17. Active, uncontrolled infection
18. Human immunodeficiency virus positivity
19. Active hepatitis B or C or other active liver disease
20. History of cancer, except Stage 1 cervix or nonmelanotic skin cancer, with the possible exception of patients in complete remission

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; ≥60 years of age; Participants ≥60 years of age who were relapsed after one first-line chemotherapy regimen (with or without consolidation) and after first complete remission <12 months or are primary refractory to first-line chemotherapy received a starting dose of 200 mg/day quizartinib. Exploratory: FLT3-ITD (+) and FLT3-ITD (-) Confirmatory: FLT3-ITD (+) and FLT3-ITD (-) After an amendment, male participants received a starting dose of 135 mg/day quizartinib and all females received a starting dose of 90 mg/day.	Drug: Compound AC220; Precomplexed powder in bottle formulation supplied as 200 mg in a 60 cc polyethylene terephthalate (PET) plastic bottle. Requires reconstitution by a pharmacist, must be stored securely, and protected from light.; Other Names: AC010220 × 2HCl, oral powder for reconstitution
Experimental: Cohort 2; ≥18 years of age; Participants ≥18 years of age (including participants ≥60 years of age) who were relapsed or refractory after one second-line (salvage) regimen or after hematopoietic stem cell transplant (HSCT) received a starting dose of 200 mg/day quizartinib. Exploratory: FLT3-ITD (+) and FLT3-ITD (-) Confirmatory: FLT3-ITD (+) and FLT3-ITD (-) After an amendment, male participants received a starting dose of 135 mg/day quizartinib and all females received a starting dose of 90 mg/day.	Drug: Compound AC220; Precomplexed powder in bottle formulation supplied as 200 mg in a 60 cc polyethylene terephthalate (PET) plastic bottle. Requires reconstitution by a pharmacist, must be stored securely, and protected from light.; Other Names: AC010220 × 2HCl, oral powder for reconstitution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants)	Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD[+] Participants) Modified from Cheson et al, abbreviations include the following: CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia=all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia <1 x 10^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib=All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp=complete remission with incomplete platelet recovery; NR=no response; PR=partial remission.	Within the first 3 cycles of treatment (84 days)
Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [-] Participants)	Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD[-] Participants) Modified from Cheson et al, abbreviations include the following: CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia=all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia <1 x 10^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib=All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp=complete remission with incomplete platelet recovery; NR=no response; PR=partial remission.	Within the first 3 cycles of treatment (84 days)
Number of Participants With Composite Complete Remission (CRc), Categorised by FLT3-ITD Status	CRc is defined as composite complete remission (CR+CRp+CRi) - CR = complete remission; CRp = complete remission with incomplete platelet recovery; CRi = complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia = all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia <1 x 10^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib = all criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion.	within 28 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Composite Complete Remission in FLT3-ITD (+) Participants Who Achieved CRc Based on All On-Treatment Data	Kaplan-Meier analysis of duration of composite complete remission derived based on local morphology including all on-treatment data (Safety Population). The definition of relapse at CRc includes an evaluation of blasts in the peripheral blood of >1%.Though not specified in the protocol, the addition of these criteria was deemed necessary for consistency with the Cheson criteria.	From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment
Duration of Composite Complete Remission in FLT3-ITD (-) Participants Who Achieved CRc Based on All On-Treatment Data	Kaplan-Meier analysis of duration of composite complete remission derived based on local morphology including all on-treatment data (Safety Population). The definition of relapse at CRc includes an evaluation of blasts in the peripheral blood of >1%.Though not specified in the protocol, the addition of these criteria was deemed necessary for consistency with the Cheson criteria.	From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment
Duration of Any Response in FLT3-ITD (+) Participants	Kaplan-Meier analysis of duration of any response (CR, CRp, CRi, or PR), derived based on local morphology for participants who achieved a response during the first 3 cycles of treatment (Safety Population).	From the time of any response until disease progression or death, up to approximately 3 years post treatment
Duration of Any Response in FLT3-ITD (-) Participants	Kaplan-Meier analysis of duration of any response (CR, CRp, CRi, or PR), derived based on local morphology for participants who achieved a response during the first 3 cycles of treatment (Safety Population).	From the time of any response until disease progression or death, up to approximately 3 years post treatment
Median Duration of Leukemia-free Survival in FLT3-ITD (+) Participants	Kaplan-Meier analysis of leukemia-free survival in participants who achieved a CRc in the first three cycles of treatment derived based on local morphology (Safety Population).	From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment
Median Duration of Leukemia-free Survival in FLT3-ITD (-) Participants	Kaplan-Meier analysis of leukemia-free survival in participants who achieved a CRc in the first three cycles of treatment derived based on local morphology (Safety Population).	From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment
Median Duration of Overall Survival in FLT3-ITD (+) Participants	Kaplan-Meier analysis of overall survival (Safety Population)	Time from first dose to death from any cause, up to 3 years post treatment
Median Duration of Overall Survival in FLT3-ITD (-) Participants	Kaplan-Meier analysis of overall survival (Safety Population)	Time from first dose to death from any cause, up to approximately 3 years post treatment
Early Treatment-related Death	Early treatment-related deaths included all treatment-related deaths prior to the end of Cycle 3 with a 3-day window (Cycle 3 end date + 3 days), unless the death was following a CRc response assessed by the Investigator.	Within first 3 cycles of treatment (84 days)

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Investigators: Study Director: Interim Chief Medical Officer, Ambit Biosciences Corporation

Publications and helpful links

General Publications

• Cortes J, Perl AE, Dohner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Kramer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, Levis M. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):889-903. doi: 10.1016/S1470-2045(18)30240-7. Epub 2018 May 31.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): September 28, 2012
• Study Completion (Actual): December 31, 2014

Study Registration Dates

• First Submitted: October 1, 2009
• First Submitted That Met QC Criteria: October 1, 2009
• First Posted (Estimate): October 5, 2009

Study Record Updates

• Last Update Posted (Actual): December 11, 2019
• Last Update Submitted That Met QC Criteria: December 3, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: acute; AML; relapsed; refractory; inhibitor; leukemia; kinase; leukaemia; FLT3; myeloid; AC220
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: AC220-002; 2009-013093-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR