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

Phase 2

Completed

Conditions: Acute Myeloid Leukemia

Interventions: Drug: Compound AC220

Registration Number: NCT00989261

Lead Sponsor: Daiichi Sankyo

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 333

Inclusion Criteria

Males and females age ≥18 years in second relapse or refractory.
Males and females age ≥60 years in first relapse or refractory.
Must have baseline bone marrow sample taken.
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.
Able to swallow the liquid study drug.
Eastern Cooperative Oncology Group performance status of 0 to 2
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.
Persistent chronic clinically significant non-hematological toxicities from prior treatment must be ≤Grade 1.
Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC220.
Serum creatinine ≤1.5 × upper limit of normal (ULN) and glomerular filtration rate (GFR) > 30 mL/min
Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits.
Total serum bilirubin ≤1.5 × ULN
Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 × ULN
Females of childbearing potential must have a negative pregnancy test (urine β-hCG).
Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study.
Written informed consent must be provided.

Exclusion Criteria

Patients over the age of 85 years except at the discretion of the Investigator and with agreement of the Sponsor.
Diagnosis of acute promyelocytic leukemia
Diagnosis of chronic myelogenous leukemia (CML) in blast crisis
AML in relapse or refractory after 3 or more previous lines of chemotherapy (and/or HSCT) treatment
AML or antecedent MDS secondary to prior chemotherapy
Persistent clinically significant non-hematological toxicity that is Grade >1 by NCI CTCAE v4 from prior chemotherapy
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
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.
Patients who have previously received AC220
Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment)
Major surgery within 4 weeks prior to enrollment in the study
Radiation therapy within 4 weeks prior to, or concurrent with study
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.
Uncontrolled or significant cardiovascular disease
Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential
Men who are unwilling to use contraception if their partners are of childbearing potential
Active, uncontrolled infection
Human immunodeficiency virus positivity
Active hepatitis B or C or other active liver disease
History of cancer, except Stage 1 cervix or nonmelanotic skin cancer, with the possible exception of patients in complete remission

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1; ≥60 years of age	Compound AC220	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.
Cohort 2; ≥18 years of age	Compound AC220	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.

Primary Outcome Measures

Name	Time	Method
Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants)	Within the first 3 cycles of treatment (84 days)	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.
Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [-] Participants)	Within the first 3 cycles of treatment (84 days)	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.
Number of Participants With Composite Complete Remission (CRc), Categorised by FLT3-ITD Status	within 28 months	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.

Secondary Outcome Measures

Name	Time	Method
Median Duration of Leukemia-free Survival in FLT3-ITD (+) Participants	From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment	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).
Duration of Composite Complete Remission in FLT3-ITD (+) Participants Who Achieved CRc Based on All On-Treatment Data	From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment	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.
Duration of Composite Complete Remission in FLT3-ITD (-) Participants Who Achieved CRc Based on All On-Treatment Data	From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment	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.
Duration of Any Response in FLT3-ITD (+) Participants	From the time of any response until disease progression or death, up to approximately 3 years post treatment	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).
Duration of Any Response in FLT3-ITD (-) Participants	From the time of any response until disease progression or death, up to approximately 3 years post treatment	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).
Median Duration of Leukemia-free Survival in FLT3-ITD (-) Participants	From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment	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).
Median Duration of Overall Survival in FLT3-ITD (+) Participants	Time from first dose to death from any cause, up to 3 years post treatment	Kaplan-Meier analysis of overall survival (Safety Population)
Median Duration of Overall Survival in FLT3-ITD (-) Participants	Time from first dose to death from any cause, up to approximately 3 years post treatment	Kaplan-Meier analysis of overall survival (Safety Population)
Early Treatment-related Death	Within first 3 cycles of treatment (84 days)	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.

Trial Locations

Locations (85): Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Northwestern Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
University of California, San Francisco
🇺🇸
San Francisco, California, United States
Farmacia Ospidaliera
🇮🇹
Orbassano, Italy
Centre Hospitalier Universitaire Brabois
🇫🇷
Vandoeuvre les Nancy, France
Centre Henry Becquerel, Service d'Hematologie
🇫🇷
Rouen, France
Philipps-Universitat Marburg
🇩🇪
Marburg, Germany
Seattle Cancer Care Alliance
🇺🇸
Seattle, Washington, United States
University of Michigan Medical Center
🇺🇸
Ann Arbor, Michigan, United States
Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Milton S. Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Clinical Trials Center
🇺🇸
Nashville, Tennessee, United States
Columbia University
🇺🇸
New York, New York, United States
The Vanderbuilt Clinic
🇺🇸
Nashville, Tennessee, United States
Abramson Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
Hematologie - CHU Purpan
🇫🇷
Toulouse, Cedex, France
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
Hopital Avicenne
🇫🇷
Bobigny, France
Institut Paoli Calmettes Centre Regional de Lutte Contre le Cancer
🇫🇷
Marseille, Cedex 9, France
Centre Hospitalier Universitaire d'Angers
🇫🇷
d'Angers, France
Hopital Claude Huriez
🇫🇷
Lille, France
Centre Hospitalier de Versailles
🇫🇷
Le Chesnay, France
Hopital Edouard Herriot
🇫🇷
Lyon, France
Hopital Saint-Louis
🇫🇷
Paris, France
Centre Hospitalier Universitaire Limoges
🇫🇷
Limoges, France
Hopital Saint-Antoine
🇫🇷
Paris, France
Charite, Campus Benjamin Franklin
🇩🇪
Berlin, Germany
Hopital Haut-Leveque
🇫🇷
Pessac, France
Centre Hospitalier Regional Universitaire, Hopital de Hautepierre
🇫🇷
Strasbourg, France
Charite Campus Virchow Klinikum
🇩🇪
Berlin, Germany
Unikliniksklinikum Carl Gustav Carus
🇩🇪
Dresden, Germany
Asklepios Klinik St Georg
🇩🇪
Hamburg, Germany
Universitatsklinikum Jena
🇩🇪
Jena, Germany
Universitatsklinikum Leipzig Selbstandige Abteilung fur Hamatologie
🇩🇪
Leipzig, Germany
Universitatsklinikum Regensburg Abteilung fur Hamatologie
🇩🇪
Regensburg, Germany
Klinikum rechts der Isar, Technische Universitat Munchen
🇩🇪
Munchen, Germany
Universitatsklinikum Munster
🇩🇪
Munster, Germany
Universitatsklinikum Ulm
🇩🇪
Ulm, Germany
Robert-Bosch-Krankenhaus GmbH
🇩🇪
Stuttgart, Germany
Universitatsklinikum Tubingen
🇩🇪
Tubingen, Germany
Universitatsklinikum Wurzburg
🇩🇪
Wurzburg, Germany
Unita Trapianti di Midollo Osseo per Adulti
🇮🇹
Brescia, Italy
Presidio Ospedaliero "A. Businco" - Centro di Riferimento Oncologico Regionale
🇮🇹
Cagliari, Italy
Ospedale Sant Eugenio
🇮🇹
Roma, Italy
Azienda Ospedaliera-Universitaria Vittorio Emanuele-Ferrarotto
🇮🇹
Catania, Italy
Azienda Ospedaliera Universitaria San Martino
🇮🇹
Genova, Italy
Azienda Ospedaliero Universitaria Senese
🇮🇹
Siena, Italy
Utrecht University Medical Centre, Dept. of Hematology
🇳🇱
Utrecht, Netherlands
Clinica Universidad de Navarra
🇪🇸
Pamplona, Navarra, Spain
Instituto Catalan de Oncologia-Hospital Universitari de Girona
🇪🇸
Girona, Spain
Hospital Clinic i Provincial de Barcelona
🇪🇸
Barcelona, Spain
Hospital de la Santa Creu i Sant Pau
🇪🇸
Barcelona, Spain
Hospital de la Princesa, Servicio de Hematologia
🇪🇸
Madrid, Spain
Nottingham University Hospitals NHS Trust
🇬🇧
Nottingham, United Kingdom
Hospital La Fe, Servicio de Hematologia
🇪🇸
Valencia, Spain
Addenbrook's Hospital
🇬🇧
Cambridge, United Kingdom
Hanmmersmith Hospital, Dept. of Hematology
🇬🇧
London, United Kingdom
Saint James University Hospital, Institute of Oncology
🇬🇧
Leeds, United Kingdom
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Institut Catala d'Oncologia del Hospital Universitari Germans
🇪🇸
Barcelona, Spain
University of Iowa Hospitals and Clinics
🇺🇸
Iowa City, Iowa, United States
Indiana University
🇺🇸
Indianapolis, Indiana, United States
University of Maryland
🇺🇸
Baltimore, Maryland, United States
Johns Hopkins Hospital
🇺🇸
Baltimore, Maryland, United States
M.D. Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Universitatsklinikum Bonn
🇩🇪
Bonn, Germany
Centre Hospitalier Universitaire Grenoble
🇫🇷
Grenoble, France
Klinikum der Johann Wolfgang Goethe Universitat
🇩🇪
Frankfurt am Main, Germany
Medizinische Hochschule Hannover
🇩🇪
Hannover, Germany
Uniklinik Essen, Westdeutsches Tumorzentrum
🇩🇪
Essen, Germany
Universitatsklinikum Heidelberg
🇩🇪
Heidelberg, Germany
Universitatsklinikum Magdeburg
🇩🇪
Magdeburg, Germany
Instituto Di Ematologia "L.Ea. Seragnoli"
🇮🇹
Bologna, Italy
University Medical Center Groningen
🇳🇱
Groningen, Netherlands
Ospedale Civile S. Maria delle Croci
🇮🇹
Ravenna, Italy
Azienda Ospedaliero Universitaria S. Maria della Misericordia di Udine, Clinica Ematologica
🇮🇹
Udine, Italy
Universita Degli Studi di Roma Tor Vergata
🇮🇹
Roma, Italy
Dolnoslaskie Centrum Transplantacji Komorkowych z
🇵🇱
Wroclaw, Poland
Hospital General Universitario Gregorio Maranon
🇪🇸
Madrid, Spain
Hospital Universitario de Salamanca, Hospital Clinico, Servicio de Hematologia
🇪🇸
Salamanca, Spain
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Universitatsklinikum Mannheim
🇩🇪
Mannheim, Germany
Castle Hill Hospital
🇬🇧
Cottingham, United Kingdom