Clinical trial NCT00989261: Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)
Official title: Phase 2 Open-Label, AC220 Monotherapy Efficacy (ACE) Study in Patients With Acute Myeloid Leukemia (AML) With and Without FLT3-ITD Activating Mutations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: AML
AC220
acute
FLT3
inhibitor
kinase
leukemia
leukaemia
myeloid
relapsed
refractory
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2009-10-05
Enrollment: 333
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants)
timeFrame: Within the first 3 cycles of treatment (84 days)
measure: Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [-] Participants)
timeFrame: Within the first 3 cycles of treatment (84 days)
measure: Number of Participants With Composite Complete Remission (CRc), Categorised by FLT3-ITD Status
timeFrame: within 28 months
Secondary outcomes:
measure: Duration of Composite Complete Remission in FLT3-ITD (+) Participants Who Achieved CRc Based on All On-Treatment Data
timeFrame: From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment
measure: Duration of Composite Complete Remission in FLT3-ITD (-) Participants Who Achieved CRc Based on All On-Treatment Data
timeFrame: From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment
measure: Duration of Any Response in FLT3-ITD (+) Participants
timeFrame: From the time of any response until disease progression or death, up to approximately 3 years post treatment
measure: Duration of Any Response in FLT3-ITD (-) Participants
timeFrame: From the time of any response until disease progression or death, up to approximately 3 years post treatment
measure: Median Duration of Leukemia-free Survival in FLT3-ITD (+) Participants
timeFrame: From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment
measure: Median Duration of Leukemia-free Survival in FLT3-ITD (-) Participants
timeFrame: From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment
measure: Median Duration of Overall Survival in FLT3-ITD (+) Participants
timeFrame: Time from first dose to death from any cause, up to 3 years post treatment
measure: Median Duration of Overall Survival in FLT3-ITD (-) Participants
timeFrame: Time from first dose to death from any cause, up to approximately 3 years post treatment
measure: Early Treatment-related Death
timeFrame: Within first 3 cycles of treatment (84 days)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Abramson Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Clinical Trials Center
state: Tennessee
city: Nashville
country: United States
facility: The Vanderbuilt Clinic
state: Tennessee
city: Houston
country: United States
facility: M.D. Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Marseille
country: France
facility: Institut Paoli Calmettes Centre Regional de Lutte Contre le Cancer
state: Cedex 9
city: Toulouse
country: France
facility: Hematologie - CHU Purpan
state: Cedex
city: Bobigny
country: France
facility: Hopital Avicenne
city: d'Angers
country: France
facility: Centre Hospitalier Universitaire d'Angers
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire Grenoble
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles
city: Lille
country: France
facility: Hopital Claude Huriez
city: Limoges
country: France
facility: Centre Hospitalier Universitaire Limoges
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Paris
country: France
facility: Hopital Saint-Antoine
city: Paris
country: France
facility: Hopital Saint-Louis
city: Pessac
country: France
facility: Hopital Haut-Leveque
city: Rouen
country: France
facility: Centre Henry Becquerel, Service d'Hematologie
city: Strasbourg
country: France
facility: Centre Hospitalier Regional Universitaire, Hopital de Hautepierre
city: Vandoeuvre les Nancy
country: France
facility: Centre Hospitalier Universitaire Brabois
city: Berlin
country: Germany
facility: Charite Campus Virchow Klinikum
city: Berlin
country: Germany
facility: Charite, Campus Benjamin Franklin
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Dresden
country: Germany
facility: Unikliniksklinikum Carl Gustav Carus
city: Essen
country: Germany
facility: Uniklinik Essen, Westdeutsches Tumorzentrum
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann Wolfgang Goethe Universitat
city: Hamburg
country: Germany
facility: Asklepios Klinik St Georg
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Jena
country: Germany
facility: Universitatsklinikum Jena
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig Selbstandige Abteilung fur Hamatologie
city: Magdeburg
country: Germany
facility: Universitatsklinikum Magdeburg
city: Mannheim
country: Germany
facility: Universitatsklinikum Mannheim
city: Marburg
country: Germany
facility: Philipps-Universitat Marburg
city: Munchen
country: Germany
facility: Klinikum rechts der Isar, Technische Universitat Munchen
city: Munster
country: Germany
facility: Universitatsklinikum Munster
city: Regensburg
country: Germany
facility: Universitatsklinikum Regensburg Abteilung fur Hamatologie
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus GmbH
city: Tubingen
country: Germany
facility: Universitatsklinikum Tubingen
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Wurzburg
country: Germany
facility: Universitatsklinikum Wurzburg
city: Bologna
country: Italy
facility: Instituto Di Ematologia "L.Ea. Seragnoli"
city: Brescia
country: Italy
facility: Unita Trapianti di Midollo Osseo per Adulti
city: Cagliari
country: Italy
facility: Presidio Ospedaliero "A. Businco" - Centro di Riferimento Oncologico Regionale
city: Catania
country: Italy
facility: Azienda Ospedaliera-Universitaria Vittorio Emanuele-Ferrarotto
city: Genova
country: Italy
facility: Azienda Ospedaliera Universitaria San Martino
city: Orbassano
country: Italy
facility: Farmacia Ospidaliera
city: Ravenna
country: Italy
facility: Ospedale Civile S. Maria delle Croci
city: Roma
country: Italy
facility: Ospedale Sant Eugenio
city: Roma
country: Italy
facility: Universita Degli Studi di Roma Tor Vergata
city: Siena
country: Italy
facility: Azienda Ospedaliero Universitaria Senese
city: Udine
country: Italy
facility: Azienda Ospedaliero Universitaria S. Maria della Misericordia di Udine, Clinica Ematologica
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Utrecht
country: Netherlands
facility: Utrecht University Medical Centre, Dept. of Hematology
city: Wroclaw
country: Poland
facility: Dolnoslaskie Centrum Transplantacji Komorkowych z
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia del Hospital Universitari Germans
city: Girona
country: Spain
facility: Instituto Catalan de Oncologia-Hospital Universitari de Girona
city: Madrid
country: Spain
facility: Hospital de la Princesa, Servicio de Hematologia
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca, Hospital Clinico, Servicio de Hematologia
city: Valencia
country: Spain
facility: Hospital La Fe, Servicio de Hematologia
city: Cambridge
country: United Kingdom
facility: Addenbrook's Hospital
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital
city: Leeds
country: United Kingdom
facility: Saint James University Hospital, Institute of Oncology
city: London
country: United Kingdom
facility: Hanmmersmith Hospital, Dept. of Hematology
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
Study officials:
affiliation: Ambit Biosciences Corporation
name: Interim Chief Medical Officer
role: STUDY_DIRECTOR
References:
citation: 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.