(QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive

NCT ID: NCT02039726

Last Updated: 2021-02-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 367 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2020-09-08

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.

Conditions

AML

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Quizartinib

Participants who were randomized to receive 20 or 30 mg quizartinib tablets administered orally once daily.

Group Type: EXPERIMENTAL

Quizartinib

Intervention Type: DRUG

20 or 30 mg quizartinib tablets administered orally once daily

Salvage chemotherapy

Participants who were randomized to receive salvage chemotherapy, such as low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA), were administered during 28-day cycles.

Group Type: ACTIVE_COMPARATOR

Salvage Chemotherapy

Intervention Type: DRUG

Low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA) administered during 28-day cycles

Interventions

Quizartinib

20 or 30 mg quizartinib tablets administered orally once daily

Intervention Type: DRUG

Salvage Chemotherapy

Low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA) administered during 28-day cycles

Intervention Type: DRUG

Other Intervention Names

AC220; Standard of Care

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Daiichi Sankyo

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jorge E. Cortes, MD

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Global Clinical Leader

Role: STUDY_DIRECTOR

Daiichi Sankyo

Locations

City of Hope National Medical Center

Duarte, California, United States

University of Southern California, Norris Comprehensive Cancer Center

Los Angeles, California, United States

UCLA Medical Center

Los Angeles, California, United States

UC Davis Cancer Center

Sacramento, California, United States

Stanford University Medical Center Stanford Comprehensive Cancer Center

Stanford, California, United States

Yale University

New Haven, Connecticut, United States

Emory Winship Cancer Institute

Atlanta, Georgia, United States

University of Illinois at Chicago

Chicago, Illinois, United States

University of Chicago

Chicago, Illinois, United States

Franciscan Alliance

Indianapolis, Indiana, United States

University of Kansas Medical Center Research Institute Inc

Westwood, Kansas, United States

LSU Health Sciences Center Feist Weiller Cancer Center

Shreveport, Louisiana, United States

University of Maryland

Baltimore, Maryland, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan Health System

Ann Arbor, Michigan, United States

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Columbia University Medical Center

New York, New York, United States

University of Rochester

Rochester, New York, United States

NY Medical College

Valhalla, New York, United States

UNC Linebreger Comprehensive Cancer Center

Chapel Hill, North Carolina, United States

Duke Cancer Institute at Duke University Health System

Durham, North Carolina, United States

Wake Forest University Baptist Health

Winston-Salem, North Carolina, United States

University of Cincinnati

Cincinnati, Ohio, United States

Oregon Health and Science University Knight Cancer Institute

Portland, Oregon, United States

Geisinger Medical Center

Danville, Pennsylvania, United States

Penn State Milton S Hershey Medical Center

Hershey, Pennsylvania, United States

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States

Avera Cancer Institute

Sioux Falls, South Dakota, United States

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

MD Anderson Center, The University of Texas

Houston, Texas, United States

Swedish Cancer Institute

Seattle, Washington, United States

The Canbera Hospital

Garran, New South Wales, Australia

Westmead Hospital

Westmead, New South Wales, Australia

The Princess Alexandra Hospital

Brisbane, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

The Queen Elizabeth Hospital

Woodville, South Australia, Australia

Alfred Hospital

Melbourne, Victoria, Australia

ZNA Stuivenberg

Antwerp, BE, Belgium

UCL St Luc

Brussels, BE, Belgium

Leuven UZ Gasthuisberg

Leuven, BE, Belgium

University of Alberta Hospital

Edmonton, Alberta, Canada

Vancouver General Hospital

Vancouver, British Columbia, Canada

Princess Margaret Cancer Centre Princess Margaret Hospital

Toronto, Ontario, Canada

Klinička Bolinca Merkur

Zagreb, , Croatia

Kliničko Bolnički Centar Zagreb

Zagreb, , Croatia

Fakultni nemocnice Brno

Brno, , Czechia

Fakultni nemocnice Hradec Kralove

Hradec Králové, , Czechia

Fakultni nemocnice Olomouc

Olomouc, , Czechia

CHU de Caen

Caen, , France

Centre Hospitalier Universitaire Grenoble Hopital Michalon

Grenoble, , France

Centre Hospitalier de Versailles

Le Chesnay, , France

Hopital de la Conception

Marseille, , France

Centre Hospitalier Universitaire Nantes

Nantes, , France

Hôpital Saint Louis

Paris, , France

Hopital Saint-Antoine

Paris, , France

Hopital Haut Leveque Centre Francois Magendie

Pessac, , France

Centre Henri-Becquerel

Rouen, , France

Centre Hospitalier Universitaire Purpan

Toulouse, , France

Charité Universitätsmedizin Berlin

Berlin, , Germany

Charité Campus Virchow Klinikum

Berlin, , Germany

Klinikum Braunschweig

Braunschweig, , Germany

Universitatsklinikum Dresden

Dresden, , Germany

Klinikum der Johann Wolfgang-Goethe-Universität

Frankfurt, , Germany

Universitätsklinikum Halle

Halle, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Uniklinik Heidelberg Medizinische Klinik und Poliklinik V

Heidelberg, , Germany

Universitätsklinikum Jena

Jena, , Germany

Universitätsklinikum Leipzig

Leipzig, , Germany

University Mainz

Mainz, , Germany

Universitätsklinikum Giessen und Marburg GmbH

Marburg, , Germany

LMU München Klinikum Großhadern

München, , Germany

Medizinische Klinik A Hämatologie Hämostaseologie Internistische Onkologie und Pneumologie

Münster, , Germany

The Chinese University of Hong Kong, Prince of Wales Hospital

Hong Kong, , Hong Kong

The University of Hong Kong, Queen Mary Hospital

Hong Kong, , Hong Kong

Szegedi Tudomanyegyetem Altalanos Orvostudomanyi Kar Szent Gyorgyi Albert Klinikai Kozpont

Szeged, Csongrád megye, Hungary

Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Intezet

Debrecen, Hajdú-Bihar, Hungary

Semmelweis Egyetem Altalanos Orvostudomanyi Kar I. Belgyogyaszati Klinika

Budapest, Pest County, Hungary

AOU Policlinico Consorziale di Bari

Bari, , Italy

Università di Bologna

Bologna, , Italy

Unità Operativa di Ematologia e Unità Operativa CTMO

Cagliari, , Italy

Arcispedale S Anna

Ferrara, , Italy

AOU Careggi

Florence, , Italy

IRCCS Azienda Ospedaliera Universitaria San Martino

Genova, , Italy

Opsedale San Martino di Genova

Genova, , Italy

Ospedale San Raffaele

Milan, , Italy

Azienda Ospedaliera Universitaria Federico II

Napoli, , Italy

Azienda Ospedaliero Universitaria San Luigi Gonzaga

Orbassano, , Italy

L'UOC di Ematologia del Policlinico Tor Vergata

Rome, , Italy

Policlinico Universitario Agostino Gemelli

Rome, , Italy

Azienda Ospedaliero Universitaria Senese, Policlinico S. Maria alle Scotte

Siena, , Italy

Ospedale di Circolo-a Fondazione Macchi

Varese, , Italy

VU Medisch Centrum

Amsterdam, , Netherlands

Universitair Medisch Centrum Groningen

Groningen, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Uniwersytecki Szpital Kliniczny w Biatymstoku, Klinika Hematologii z Pododzialem Chorob Naczyn

Bialystok, , Poland

Samodzielny Publiczny Szpital Kliniczny im. Andrzeja Mieleckiego Slaskiego Uniwersytetu Medycznego w Katowicach Oddzial Hematologii i Transplantacji Szpiku

Katowice, , Poland

Samodzielny Publiczny Szpital Kliniczny Nr 1, Klinika Hematoonkologii i Transplantacji Szpiku

Lublin, , Poland

Klinicki Centar Srbije

Belgrade, , Serbia

Klinicki Centar Vojvodine

Novi Sad, , Serbia

National University of Singapore

Singapore, , Singapore

Singapore General Hospital

Singapore, , Singapore

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, South Korea

Kyungpook National University Hospital

Daegu, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

The Catholic University of Korea Seoul St. Mary's Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Hospital Son Espases

Palma, De Mallorca, Spain

Hospital La Fe

Valencia, SP, Spain

Hospital Clinic I Provincial de Barcelona

Barcelona, , Spain

Hospital Universitari Germans Trias i Pujol

Barcelona, , Spain

Hospital General Universitario Gregorio Marañon

Madrid, , Spain

Complejo Hospitalario de Navarra

Pamplona, , Spain

Hospital Clínico Universitario de Salamanca

Salamanca, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

China Medical University Hospital

Taichung, , Taiwan

National Cheng Kung University Hospital

Tainan City, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Taipei Veterans General Hospital

Taipei, , Taiwan

Bristol Haematology and Oncology Centre

Bristol, England, United Kingdom

Saint James University Hospital

Leeds, England, United Kingdom

King's College Hospital

London, England, United Kingdom

Nottingham City Hospital NHS Trust

Nottingham, England, United Kingdom

Royal Marsden Hospital Sutton

Sutton, England, United Kingdom

Aberdeen Royal Infirmary

Aberdeen, Scotland, United Kingdom

University Hospital of Wales

Cardiff, South Glamorgan, United Kingdom

Countries

United States; Australia; Belgium; Canada; Croatia; Czechia; France; Germany; Hong Kong; Hungary; Italy; Netherlands; Poland; Serbia; Singapore; South Korea; Spain; Taiwan; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 33415416 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31175001 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29859851 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

EudraCT Number 2013-004890-28

Identifier Type: OTHER

Identifier Source: secondary_id

AC220-007

Identifier Type: -

Identifier Source: org_study_id