Study of Elacytarabine Versus Investigator's Choice in Patients With Late Stage Acute Myeloid Leukaemia (AML)

Acute Myeloid Leukemia (AML) Clinical Trial

— CLAVELA  

Official title:

A Randomised Phase III Study of Elacytarabine vs. Investigator's Choice in Patients With Late Stage Acute Myeloid Leukaemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01147939
• Other study ID #: CP4055-306
• Status: Completed
• Phase: Phase 3
• First received: April 14, 2010
• Last updated: September 20, 2013
• Start date: June 2010
• Est. completion date: June 2013

Study information

• Verified date: September 2013
• Source: Clavis Pharma
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 381
• Est. completion date: June 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Elacytarabine
Elacytarabine 2000 mg/m2/d administered as a continuous intravenous infusion (CIV) in a d 1-5 q3w cycle.
• Investigator's Choice
E.g. cytarabine single agent/combinations, hypomethylating agents, best supportive care (BSC)

Locations

Country	Name	City	State
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Box Hill Hospital	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Perth	Western Australia
Australia	Royal North Shore Hopsital	Sydney	New South Wales
Belgium	Algemeen Ziekenhuis Sint-Jan	Brugge
Belgium	UZ Brussel	Brussels
Belgium	Institut Jules Bordet	Bruxelles
Belgium	University Hospital Antwerp	Edegem
Belgium	CHU Liège	Liège
Belgium	UCL Mont-Godinne	Yvoir
Canada	Princess Margaret Hospital	Toronto	Ontario
France	CHU Limoges - Hôpital Dupuytren	Limoges
France	Hopital Edouard Herriot	Lyon
France	Institut J. Paoli and I. Calmettes	Marseilles
France	Centre Antoine Lacassagne	Nice
France	Hopital Saint Antoine	Paris
France	CHU de Bordeaux - Hopital Haut-Leveque	Pessac
France	CHU de Toulouse - Hôpital Purpan	Toulouse
Germany	Charité-Campus B. Franklin Med. Klinik Haematology	Berlin
Germany	Evangelische Kliniken Johanniter- und Waldkrankenhaus Bonn GmbH	Bonn
Germany	Heinrich-Heine Universität Düsseldorf, Klinik für Hämatologie/Onkolog. und Klin. Immunologie	Düsseldorf
Germany	III. Medizinische Klinik und Poliklinik;Hämatologie, Onkologie und Pneumologie	Mainz
Germany	Universitätsklinikum Münster, Medisinische Klinik & Poliklinik A	Münster
Germany	Universitätsklinikum Rostock	Rostock
Germany	Robert-Bosch-Krankenhaus, Abt.Hämatologie,Onkologie u.Palliativmedizin	Stuttgart
Germany	Universitätsklinikum Ulm, Klinik für Innere Medizin III, Comprehensive Cancer Center Ulm (CCCU)	Ulm
Ireland	St James's Hospital Dublin	Dublin
Ireland	University Hospital Galway	Galway
Italy	A.O.U Careggi	Firenze
Italy	A.O San Martino	Genova
Italy	Fondazione San Raffaele del Monte Tabor	Milano
Italy	A.O. Cardarelli	Napoli
Italy	Hospital S. Maria delle Croci	Ravenna
Italy	Fondazion Policlin T Vergata	Roma
Norway	Haukeland Universitetssykehus	Bergen
Norway	Oslo University Hospital	Oslo
Norway	St Olavs Hospital	Trondheim
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw
Romania	Fundeni Clinical Institute "Stefan Berceanu" Center for Hematology and Bone Marrow Transplant	Bucharest
Romania	Oncology Institute ,,Ion Chiricuta" Cluj Napoca , Hematology dept.	Cluj Napoca
Romania	St. Spiridon" University Hospital, Hematology Department	Iasi
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital Universitario La Princesa	Madrid
Spain	Hospital Universitari Son Dureta	Palma de Mallorca
Spain	Hospital de Navarra	Pamplona
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario La Fé, Servicio de Hematología	Valencia
United Kingdom	Bristol Haematology and Oncology Centre	Bristol
United Kingdom	Gartnavel General Hospital: Beatson WOS Cancer Centre	Glasgow	Scotland
United Kingdom	Christie Hospital, Haematology and Transplant Day Unit	Manchester
United States	The Blood and Marrow Transplant Group of GA	Atlanta	Georgia
United States	Winship Cancer Institute at Emory	Atlanta	Georgia
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	The Jewish Hospital	Cincinnati	Ohio
United States	Rocky Mountain Blood and Bone Marrow Transplant Program	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Shands at the University of Florida	Gainesville	Florida
United States	St. Francis Hospital	Greenville	South Carolina
United States	Northern New Jersey Cancer Associates	Hackensack	New Jersey
United States	St. Francis Hospital and Health Center	Indianapolis	Indiana
United States	University of Iowa Hopsitals	Iowa City	Iowa
United States	Scripps Cancer Center Clinical Research	La Jolla	California
United States	UCLA School of Medicine, Division of Hematology/Oncology	Los Angeles	California
United States	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California
United States	Froedtert Hospital, Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan-Kettering	New York	New York
United States	New York Presbyterian Hospital, Weill-Cornell Medical College	New York	New York
United States	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania
United States	LSU Health Sciences Center,	Shreveport	Louisiana
United States	New York Medical College	Valhalla	New York
United States	Wake Forest University, Health Sciences Section on Hematology and Oncology	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Clavis Pharma

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Ireland,  Italy,  Norway,  Poland,  Romania,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Time from date of randomisation until the date of death	Until 300 events occur	No
Secondary	Remission rate	Remission rate measured by overall response rate (ORR) (i.e. complete remission (CR) and complete remission with incomplete bone marrow recovery (CRi)); Remission rate measured by CR; Remission duration analysed using cumulative incidence of relapse (CIR) measured from date of CR or CRi	Until 300 events occur	No
Secondary	Compare number of patients with adverse events (AEs) per study arm as a measure of safety and tolerability	Summaries will include rates of occurrence of any AEs, rates of AEs by system organ classification (SOC),rates of discontinuation of study treatment due to AEs.	From first dose of study treatment, until 30 days after the last dose (for each patient)	Yes
Secondary	Characterize exposure-response relationships for measures of effectiveness and toxicity		During the first course of elacytarabine	No

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