Clinical trial NCT02039726: (QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive
Official title: A Phase 3 Open-label Randomized Study of Quizartinib (AC220) Monotherapy Versus Salvage Chemotherapy in Subjects With Tyrosine Kinase 3 - Internal Tandem Duplication (FLT3-ITD) Positive Acute Myeloid Leukemia (AML) Refractory to or Relapsed After First-line Treatment With or Without Hematopoietic Stem Cell Transplantation (HSCT) Consolidation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: AML
Keywords: Acute Myeloid Leukemia
AML
FMS-like tyrosine kinase 3
FLT3-ITD
Quizartinib
Leukemia
Tablets
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2014-01-20
Enrollment: 367
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to determine whether quizartinib monotherapy prolongs overall survival (OS) compared to salvage chemotherapy in subjects with FMS-like tyrosine kinase 3 - Internal Tandem Duplication (FLT3-ITD) positive AML who are refractory to or have relapsed within 6 months, after first-line AML therapy.


Eligibility criteria: Inclusion Criteria:

1. Provision of written informed consent approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) with privacy language in accordance with national regulations (e.g., Health Insurance Portability and Accountability Act \[HIPAA\] authorization for United States \[US\] sites) prior to any study related procedures, including withdrawal of prohibited medications if applicable.
2. Age ≥ 18 years or the minimum legal adult age (whichever is greater) at the time of Informed consent.
3. Morphologically documented primary Acute Myeloid Leukemia (AML) or AML secondary to Myelodysplastic Syndrome (MDS), as defined by World Health Organization (WHO) criteria, as determined by pathology review at the study site.
4. In first relapse (with duration of remission of 6 months or less) or refractory after prior therapy, with or without HSCT. Induction therapy must have included at least 1 cycle of an anthracycline/mitoxantrone-containing induction block at a standard dose.
5. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood (allelic ratio as determined by a central laboratory with a cutoff of ≥3% FLT3-ITD/total FLT3). If a specimen has been sent for FLT3-ITD testing at the central laboratory but the subject requires treatment for AML before the central FLT3-ITD test result is available, a local test result may be acceptable for randomization after consultation with the Medical Monitor.
6. Eligibility for pre-selected salvage chemotherapy, according to the Investigator's assessment.
7. Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
8. Discontinuation of prior AML treatment before the start of study treatment (except hydroxyurea or other treatment to control leukocytosis) for at least 2 weeks for cytotoxic agents, or for at least 5 half-lives for non cytotoxic agents.
9. Serum creatinine ≤1.5×upper limit of normal (ULN), or glomerular filtration rate \>25 mL/min, as calculated with the Cockcroft-Gault formula.
10. Serum potassium, magnesium, and calcium (serum calcium corrected for hypoalbuminemia) within institutional normal limits. Subjects with electrolytes outside the normal range will be eligible if these values are corrected upon retesting following any necessary supplementation.
11. Total serum bilirubin ≤1.5×ULN.
12. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5×ULN.

Exclusion Criteria:

1. Acute Promyelocytic Leukemia (AML subtype M3).
2. AML secondary to prior chemotherapy for other neoplasms, except AML secondary to prior Myelodysplastic Syndrome (MDS).
3. History of another malignancy, unless the candidate has been disease-free for at least 5 years.
4. Persistent, clinically significant \> Grade 1 non-hematologic toxicity from prior AML therapy.
5. Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation of treatment or treatment escalation within 21 days, and/or \> Grade 1 persistent or clinically significant non hematologic toxicity related to HSCT.
6. History of or current, central nervous system involvement with AML.
7. Clinically significant coagulation abnormality, such as disseminated intravascular coagulation.
8. Prior treatment with quizartinib or participated in a prior quizartinib study.
9. Prior treatment with a FLT3 targeted therapy including sorafenib or investigational FLT3 inhibitors (not including the multi-kinase inhibitor, midostaurin).
10. Major surgery within 4 weeks prior to screening.
11. Radiation therapy within 4 weeks prior to screening.
12. Uncontrolled or significant cardiovascular disease
13. Active infection not well controlled by antibacterial or antiviral therapy.
14. Known infection with human immunodeficiency virus, or active hepatitis B or C, or other active clinically relevant liver disease.
15. Unwillingness to receive infusion of blood products according to the protocol.
16. In a man whose sexual partner is a woman of childbearing potential, unwillingness or inability of the man or woman to use a highly effective contraceptive method for the entire study treatment period for at least 3 months after study completion. Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and 105 days after the final study drug administration.
17. In a heterosexually active woman of childbearing potential, unwillingness or inability to use a highly effective contraceptive method for the entire study treatment period and for at least 3 months after study treatment completion. Additionally, for women randomized to chemotherapy, unwillingness to adhere to the restrictions in the respective locally established guidelines and local approved label (prescribing information, Summary of Product Characteristics, or US product insert) from the manufacturer and the Patient Information Leaflet (package insert) as instructed by the Investigator.
18. Pregnancy.
19. Female Subjects must agree to not breastfeed from the time of Screening and throughout the study period, and for 25 days after the final study drug administration.
20. Medical condition, serious intercurrent illness, or other circumstance that, in the Investigator's judgment, could jeopardize the candidate's safety as a study subject, or that could interfere with study objectives.
21. For subjects in the United Kingdom only: Refusal of permission to allow the subject's General Practitioner to be notified of their participation in the study.

Primary outcomes:
measure: Overall Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy
timeFrame: At approximately 3 years 9 months
Secondary outcomes:
measure: Event-free Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy
timeFrame: At approximately 3 years 9 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California, Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center Stanford Comprehensive Cancer Center
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Atlanta
country: United States
facility: Emory Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan Alliance
state: Indiana
city: Westwood
country: United States
facility: University of Kansas Medical Center Research Institute Inc
state: Kansas
city: Shreveport
country: United States
facility: LSU Health Sciences Center Feist Weiller Cancer Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Valhalla
country: United States
facility: NY Medical College
state: New York
city: Chapel Hill
country: United States
facility: UNC Linebreger Comprehensive Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke Cancer Institute at Duke University Health System
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Health
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University Knight Cancer Institute
state: Oregon
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Center, The University of Texas
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Garran
country: Australia
facility: The Canbera Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: The Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Woodville
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
state: BE
city: Brussels
country: Belgium
facility: UCL St Luc
state: BE
city: Leuven
country: Belgium
facility: Leuven UZ Gasthuisberg
state: BE
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre Princess Margaret Hospital
state: Ontario
city: Zagreb
country: Croatia
facility: Klinička Bolinca Merkur
city: Zagreb
country: Croatia
facility: Kliničko Bolnički Centar Zagreb
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Hradec Králové
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Caen
country: France
facility: CHU de Caen
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire Grenoble Hopital Michalon
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles
city: Marseille
country: France
facility: Hopital de la Conception
city: Nantes
country: France
facility: Centre Hospitalier Universitaire Nantes
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hopital Saint-Antoine
city: Pessac
country: France
facility: Hopital Haut Leveque Centre Francois Magendie
city: Rouen
country: France
facility: Centre Henri-Becquerel
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire Purpan
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Berlin
country: Germany
facility: Charité Campus Virchow Klinikum
city: Braunschweig
country: Germany
facility: Klinikum Braunschweig
city: Dresden
country: Germany
facility: Universitatsklinikum Dresden
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang-Goethe-Universität
city: Halle
country: Germany
facility: Universitätsklinikum Halle
city: Hanover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Uniklinik Heidelberg Medizinische Klinik und Poliklinik V
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Mainz
country: Germany
facility: University Mainz
city: Marburg
country: Germany
facility: Universitätsklinikum Giessen und Marburg GmbH
city: Munchen
country: Germany
facility: LMU München Klinikum Großhadern
city: Münster
country: Germany
facility: Medizinische Klinik A Hämatologie Hämostaseologie Internistische Onkologie und Pneumologie
city: Hong Kong
country: Hong Kong
facility: The Chinese University of Hong Kong, Prince of Wales Hospital
city: Hong Kong
country: Hong Kong
facility: The University of Hong Kong, Queen Mary Hospital
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Altalanos Orvostudomanyi Kar Szent Gyorgyi Albert Klinikai Kozpont
state: Csongrad
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Intezet
state: Hajdu Bihar
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Altalanos Orvostudomanyi Kar I. Belgyogyaszati Klinika
state: Pest
city: Bari
country: Italy
facility: AOU Policlinico Consorziale di Bari
city: Bologna
country: Italy
facility: Università di Bologna
city: Cagliari
country: Italy
facility: Unità Operativa di Ematologia e Unità Operativa CTMO
city: Ferrara
country: Italy
facility: Arcispedale S Anna
city: Firenze
country: Italy
facility: AOU Careggi
city: Genova
country: Italy
facility: IRCCS Azienda Ospedaliera Universitaria San Martino
city: Genova
country: Italy
facility: Opsedale San Martino di Genova
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II
city: Orbassano
country: Italy
facility: Azienda Ospedaliero Universitaria San Luigi Gonzaga
city: Rome
country: Italy
facility: L'UOC di Ematologia del Policlinico Tor Vergata
city: Rome
country: Italy
facility: Policlinico Universitario Agostino Gemelli
city: Siena
country: Italy
facility: Azienda Ospedaliero Universitaria Senese, Policlinico S. Maria alle Scotte
city: Varese
country: Italy
facility: Ospedale di Circolo-a Fondazione Macchi
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Biatymstoku, Klinika Hematologii z Pododzialem Chorob Naczyn
city: Katowice
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny im. Andrzeja Mieleckiego Slaskiego Uniwersytetu Medycznego w Katowicach Oddzial Hematologii i Transplantacji Szpiku
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1, Klinika Hematoonkologii i Transplantacji Szpiku
city: Belgrade
country: Serbia
facility: Klinicki Centar Srbije
city: Novi Sad
country: Serbia
facility: Klinicki Centar Vojvodine
city: Singapore
country: Singapore
facility: National University of Singapore
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Palma
country: Spain
facility: Hospital Son Espases
state: De Mallorca
city: Valencia
country: Spain
facility: Hospital La Fe
state: SP
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Leeds
country: United Kingdom
facility: Saint James University Hospital
state: England
city: London
country: United Kingdom
facility: King's College Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital NHS Trust
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital Sutton
state: England
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: South Glamorgan
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Jorge E. Cortes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References:
citation: Kang D, Ludwig E, Jaworowicz D, Huang H, Fiedler-Kelly J, Cortes J, Ganguly S, Khaled S, Kramer A, Levis M, Martinelli G, Perl A, Russell N, Abutarif M, Choi Y, Yin O. Concentration-QTc analysis of quizartinib in patients with relapsed/refractory acute myeloid leukemia. Cancer Chemother Pharmacol. 2021 Apr;87(4):513-523. doi: 10.1007/s00280-020-04204-y. Epub 2021 Jan 8.
citation: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Kramer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. doi: 10.1016/S1470-2045(19)30150-0. Epub 2019 Jun 4.
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.