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

AML Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02039726
• Other study ID #: AC220-007
• Secondary ID: EudraCT Number 2
• Status: Completed
• Phase: Phase 3
• Start date: May 2014
• Est. completion date: September 8, 2020

Study information

• Verified date: February 2021
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 367
• Est. completion date: September 8, 2020
• Est. primary completion date: February 22, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• AML
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Quizartinib
20 or 30 mg quizartinib tablets administered orally once daily
• 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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	The Princess Alexandra Hospital	Brisbane	Queensland
Australia	The Canbera Hospital	Garran	New South Wales
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Westmead Hospital	Westmead	New South Wales
Australia	The Queen Elizabeth Hospital	Woodville	South Australia
Belgium	ZNA Stuivenberg	Antwerpen	BE
Belgium	UCL St Luc	Brussels	BE
Belgium	Leuven UZ Gasthuisberg	Leuven	BE
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Princess Margaret Cancer Centre Princess Margaret Hospital	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Croatia	Klinicka Bolinca Merkur	Zagreb
Croatia	Klinicko Bolnicki Centar Zagreb	Zagreb
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Králové
Czechia	Fakultni nemocnice Olomouc	Olomouc
France	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
Germany	Charité Campus Virchow Klinikum	Berlin
Germany	Charité Universitätsmedizin Berlin	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	Munchen
Germany	Medizinische Klinik A Hämatologie Hämostaseologie Internistische Onkologie und Pneumologie	Münster
Hong Kong	The Chinese University of Hong Kong, Prince of Wales Hospital	Hong Kong
Hong Kong	The University of Hong Kong, Queen Mary Hospital	Hong Kong
Hungary	Semmelweis Egyetem Altalanos Orvostudomanyi Kar I. Belgyogyaszati Klinika	Budapest	Pest
Hungary	Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Intezet	Debrecen	Hajdu Bihar
Hungary	Szegedi Tudomanyegyetem Altalanos Orvostudomanyi Kar Szent Gyorgyi Albert Klinikai Kozpont	Szeged	Csongrad
Italy	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	Firenze
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
Korea, Republic of	Kyungpook National University Hospital	Daegu
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Erasmus Medical Center	Rotterdam
Poland	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
Serbia	Klinicki Centar Srbije	Belgrade
Serbia	Klinicki Centar Vojvodine	Novi Sad
Singapore	National University of Singapore	Singapore
Singapore	Singapore General Hospital	Singapore
Spain	Hospital Clinic I Provincial de Barcelona	Barcelona
Spain	Hospital Universitari Germans Trias i Pujol	Barcelona
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Son Espases	Palma	De Mallorca
Spain	Complejo Hospitalario de Navarra	Pamplona
Spain	Hospital Clínico Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital La Fe	Valencia	SP
Taiwan	China Medical University Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
United Kingdom	Aberdeen Royal Infirmary	Aberdeen	Scotland
United Kingdom	Bristol Haematology and Oncology Centre	Bristol	England
United Kingdom	University Hospital of Wales	Cardiff	South Glamorgan
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 States	University of Michigan Health System	Ann Arbor	Michigan
United States	Emory Winship Cancer Institute	Atlanta	Georgia
United States	University of Maryland	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Linebreger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	University of Chicago	Chicago	Illinois
United States	University of Illinois at Chicago	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	Duke Cancer Institute at Duke University Health System	Durham	North Carolina
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	MD Anderson Center, The University of Texas	Houston	Texas
United States	Franciscan Alliance	Indianapolis	Indiana
United States	UCLA Medical Center	Los Angeles	California
United States	University of Southern California, Norris Comprehensive Cancer Center	Los Angeles	California
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Pennsylvania Health System	Philadelphia	Pennsylvania
United States	Oregon Health and Science University Knight Cancer Institute	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	UC Davis Cancer Center	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Swedish Cancer Institute	Seattle	Washington
United States	LSU Health Sciences Center Feist Weiller Cancer Center	Shreveport	Louisiana
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Stanford University Medical Center Stanford Comprehensive Cancer Center	Stanford	California
United States	NY Medical College	Valhalla	New York
United States	University of Kansas Medical Center Research Institute Inc	Westwood	Kansas
United States	Wake Forest University Baptist Health	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy	Overall Survival is defined as the time (in weeks) from the date of randomization to the date of death due to any cause. Median and quartiles are calculated using the Kaplan-Meier method.	At approximately 3 years 9 months
Secondary	Event-free Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy	Event-free survival is defined as the time (in weeks) from randomization until documented refractory disease, relapse after complete composite remission (CRc), or death from any cause, whichever is observed first.	At approximately 3 years 9 months