Clinical trial NCT01147939: Study of Elacytarabine Versus Investigator's Choice in Patients With Late Stage Acute Myeloid Leukaemia (AML)
Official title: A Randomised Phase III Study of Elacytarabine vs. Investigator's Choice in Patients With Late Stage Acute Myeloid Leukaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia (AML)
Keywords: Acute Myeloid Leukaemia
AML
Haematology
Investigator's Choice
Elacytarabine
Refractory or relapsed AML
Phase III
Randomized
CLAVELA
CP4055-306
Elacyt
Lead sponsor: Clavis Pharma
Sponsor class: INDUSTRY
First posted: 2010-06-22
Enrollment: 381
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 purpose of the study is to assess the efficacy and safety of elacytarabine versus investigator's choice treatment in patients with relapsed or refractory acute myeloid leukemia (AML).

Detailed description: The study investigates the new nucleoside analogue derivative, elacytarabine, as treatment for patients with relapsed or refractory Acute Myeloid Leukemia (AML). To be included in the study, patients must have failed to respond to two or three different therapies for AML, or have obtained remission but then relapsed within a relatively short period of time. Patients of age ≥ 65 with adverse cytogenetics can be included in the study after having received one and up to three previous induction/re-induction therapies.

Elacytarabine is an investigational drug which is not commercially available. It is the elaidic acid ester derivative of cytarabine. Cytarabine is routinely used in the treatment of patients with AML. A substantial portion of AML patients have a deficient uptake of cytarabine, often explained by lack of a transport protein (hENT1) in the leukemic cell membrane. Due to the elaidic acid (a naturally occurring fatty acid), cellular uptake of elacytarabine is independent of this transport protein.

Patients included in the study will be randomized to elacytarabine or control treatment. Since there is no standard therapy for relapsed or refractory AML, there is a list of 7 control treatments and the investigator has to choose one that is locked before randomization.

Elacytarabine is given as a continuous infusion over five days, followed by a rest period of minimum two weeks. Investigator's choice treatment is given according to the specific routine.

After each course response evaluation and a decision on further treatment will be made.

Repeated courses of elacytarabine and control treatment might be needed to attain and/or maintain complete remission or clinical benefit.

After the end of study treatment, all patients will be followed for relapse and survival.

Eligibility criteria: Inclusion Criteria:

* 18 years of age or older
* Confirmed diagnosis of AML according to WHO classification (excluding acute promyelocytic leukaemia) who have received two or three previous induction/re-induction regimens or patients of age ≥ 65 with adverse cytogenetics who have received 1-3 previous induction/re-induction regimens. One of the (re-)induction regimens could be stem cell transplantation (SCT) for achievement of remission. Maintenance and consolidation (including SCT) may have been given, but are not counted as previous regimens.
* Bone marrow aspirates and/or biopsies must contain \> 5 % leukaemic blast cells or patient must have biopsy-proven extramedullary AML, or patient's peripheral blood shows occurrence of leukaemic blast cells
* Patients must

  * have never attained CR or CRi (primary refractory), or
  * have failed initial induction therapy, and have attained CR or CRi after salvage therapy(ies), and then relapsed within \< 6 months, or
  * have attained CR or CRi after initial induction therapy and relapsed within \<12 months, and failed to respond to salvage therapy(ies), or
  * have relapsed after the latest CR or CRi within \< 6 months
* Patients younger than 65 years should have received previous treatment with cytarabine
* Patients must have recovered from previous bone marrow and/or stem cell transplantation to a stage that the patient can tolerate the study treatment. There is no restriction on number of regimens or type of treatment administered for maintenance or consolidation during previous stages of the disease
* ECOG performance status (PS) of 0 - 2
* Women of child-bearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to treatment start
* Male and female patients must use acceptable contraceptive methods for the duration of time on study, and males also for 3 months after the last elacytarabine dose
* Capable of understanding and complying with protocol requirements, and must be able and willing to sign a written informed consent form

Exclusion Criteria:

* A history of allergic reactions to egg. A history of allergic reactions of CTCAE grade 3 or 4 to cytarabine
* Persistent clinically significant toxicities from previous chemotherapy
* A cancer history that, according to the investigator, might confound the assessment of the study endpoints
* Known positive status for human immunodeficiency virus (HIV)
* Pregnant and nursing patients
* Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements
* Impairment of hepatic or renal function to such an extent that the patient, in the opinion of the investigator, will be exposed to an excessive risk if entered into this clinical study
* Active heart disease including myocardial infarction within previous 3 months, symptomatic coronary artery disease, arrhythmias not controlled by medication, or uncontrolled congestive heart failure. Any New York Heart Association (NYHA) functional classification grade 3 or 4
* Applicable only for patients for whom an anthracycline is part of the selected control treatment: Left ventricular ejection fraction (LVEF) must be ≥ 45 % as measured by MUGA scan or 2D ECHO within 14 days prior to start of therapy. Either method is acceptable for measuring LVEF
* Applicable only for patients for whom an anthracycline is part of the selected control treatment: The patient should tolerate minimum one course of combination therapy
* Any anti-leukaemic agents within the last 3 weeks. Hydroxyurea,however, is allowed for up to 12 hours prior to study treatment
* Any investigational treatment within the last 14 days
* Any medical condition which in the opinion of the investigator places the patient at an unacceptably high risk for toxicities

Primary outcomes:
measure: Overall survival
timeFrame: Until 300 events occur
Secondary outcomes:
measure: Remission rate
timeFrame: Until 300 events occur
measure: Compare number of patients with adverse events (AEs) per study arm as a measure of safety and tolerability
timeFrame: From first dose of study treatment, until 30 days after the last dose (for each patient)
measure: Characterize exposure-response relationships for measures of effectiveness and toxicity
timeFrame: During the first course of elacytarabine
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Scripps Cancer Center Clinical Research
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Los Angeles
country: United States
facility: UCLA School of Medicine, Division of Hematology/Oncology
state: California
city: Denver
country: United States
facility: Rocky Mountain Blood and Bone Marrow Transplant Program
state: Colorado
city: Gainesville
country: United States
facility: Shands at the University of Florida
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute at Emory
state: Georgia
city: Atlanta
country: United States
facility: The Blood and Marrow Transplant Group of GA
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: St. Francis Hospital and Health Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hopsitals
state: Iowa
city: Shreveport
country: United States
facility: LSU Health Sciences Center,
state: Louisiana
city: Hackensack
country: United States
facility: Northern New Jersey Cancer Associates
state: New Jersey
city: New York
country: United States
facility: New York Presbyterian Hospital, Weill-Cornell Medical College
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University, Health Sciences Section on Hematology and Oncology
state: North Carolina
city: Cincinnati
country: United States
facility: The Jewish Hospital
state: Ohio
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital
state: Pennsylvania
city: Greenville
country: United States
facility: St. Francis Hospital
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Milwaukee
country: United States
facility: Froedtert Hospital, Medical College of Wisconsin
state: Wisconsin
city: Sydney
country: Australia
facility: Royal North Shore Hopsital
state: New South Wales
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan
city: Brussels
country: Belgium
facility: UZ Brussel
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet
city: Edegem
country: Belgium
facility: University Hospital Antwerp
city: Liège
country: Belgium
facility: CHU Liège
city: Yvoir
country: Belgium
facility: UCL Mont-Godinne
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Limoges
country: France
facility: CHU Limoges - Hôpital Dupuytren
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Marseilles
country: France
facility: Institut J. Paoli and I. Calmettes
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hopital Saint Antoine
city: Pessac
country: France
facility: CHU de Bordeaux - Hopital Haut-Leveque
city: Toulouse
country: France
facility: CHU de Toulouse - Hôpital Purpan
city: Berlin
country: Germany
facility: Charité-Campus B. Franklin Med. Klinik Haematology
city: Bonn
country: Germany
facility: Evangelische Kliniken Johanniter- und Waldkrankenhaus Bonn GmbH
city: Düsseldorf
country: Germany
facility: Heinrich-Heine Universität Düsseldorf, Klinik für Hämatologie/Onkolog. und Klin. Immunologie
city: Mainz
country: Germany
facility: III. Medizinische Klinik und Poliklinik;Hämatologie, Onkologie und Pneumologie
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Medisinische Klinik & Poliklinik A
city: Rostock
country: Germany
facility: Universitätsklinikum Rostock
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus, Abt.Hämatologie,Onkologie u.Palliativmedizin
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Klinik für Innere Medizin III, Comprehensive Cancer Center Ulm (CCCU)
city: Dublin
country: Ireland
facility: St James's Hospital Dublin
city: Galway
country: Ireland
facility: University Hospital Galway
city: Firenze
country: Italy
facility: A.O.U Careggi
city: Genova
country: Italy
facility: A.O San Martino
city: Milano
country: Italy
facility: Fondazione San Raffaele del Monte Tabor
city: Napoli
country: Italy
facility: A.O. Cardarelli
city: Ravenna
country: Italy
facility: Hospital S. Maria delle Croci
city: Roma
country: Italy
facility: Fondazion Policlin T Vergata
city: Bergen
country: Norway
facility: Haukeland Universitetssykehus
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Trondheim
country: Norway
facility: St Olavs Hospital
city: Wroclaw
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu
city: Bucharest
country: Romania
facility: Fundeni Clinical Institute "Stefan Berceanu" Center for Hematology and Bone Marrow Transplant
city: Cluj Napoca
country: Romania
facility: Oncology Institute ,,Ion Chiricuta" Cluj Napoca , Hematology dept.
city: Iasi
country: Romania
facility: St. Spiridon" University Hospital, Hematology Department
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Palma de Mallorca
country: Spain
facility: Hospital Universitari Son Dureta
city: Pamplona
country: Spain
facility: Hospital de Navarra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitario La Fé, Servicio de Hematología
city: Glasgow
country: United Kingdom
facility: Gartnavel General Hospital: Beatson WOS Cancer Centre
state: Scotland
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Manchester
country: United Kingdom
facility: Christie Hospital, Haematology and Transplant Day Unit
Study officials:
affiliation: Duke University Medical Center, Durham, NC, USA
name: David Rizzieri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cancer Therapy & Reseach Center at the University of Texas Health Science Center San Antonio, TX, USA
name: Francis J Giles, MD, PhD
role: STUDY_CHAIR
References:
citation: Roboz GJ, Rosenblat T, Arellano M, Gobbi M, Altman JK, Montesinos P, O'Connell C, Solomon SR, Pigneux A, Vey N, Hills R, Jacobsen TF, Gianella-Borradori A, Foss O, Vetrhusand S, Giles FJ. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2014 Jun 20;32(18):1919-26. doi: 10.1200/JCO.2013.52.8562. Epub 2014 May 19.