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Trial registered on ANZCTR


Registration number
ACTRN12611001112954
Ethics application status
Approved
Date submitted
26/08/2011
Date registered
25/10/2011
Date last updated
11/06/2019
Date data sharing statement initially provided
11/06/2019
Date results information initially provided
11/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the role of targeted therapy Sorafenib - the Fms-like tyrosine kinase 3 (FLT3) inhibitor, in combination with intensive chemotherapy, for previously untreated adult patients with Acute Myeloid Leukaemia (AML) with FLT3 mutations. A Phase II randomised placebo-controlled multi-centre study
Scientific title
Sorafenib in combination with intensive chemotherapy for previously untreated adult FLT3-Internal Tandem Duplication (FLT3-ITD) - positive AML: A Phase II randomised placebo-controlled multi-centre study evaluating two year progression-free survival
Secondary ID [1] 262183 0
Nil
Universal Trial Number (UTN)
U1111-1122-6056
Trial acronym
ALLG AML M16
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Previously untreated adult acute myeloid leukaemia (AML) with FLT3-ITD mutation. 265866 0
Condition category
Condition code
Cancer 266022 266022 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will screen newly diagnosed AML patients aged 15-65 for the presence of the FLT3-ITD mutation. Based on power calculations, 99 patients with FLT3-ITD will be randomized 2:1 to receive Sorafenib or placebo on days 4-10 of induction (1-2 x 28 day cycles), days 4-10 of consolidation (2 x 28 day cycles) and then for 12 months as maintenance therapy.

Patients with suspected AML (WHO 2008 classification) will be consented for standard preliminary study procedures, including centralized cytogenetics review, molecular testing, tissue banking and the commencement of standard induction chemotherapy.

Patients with acute promyelocytic leukaemia (APML) will be excluded.

All patients will receive the following INDUCTION chemotherapy regimens:

Age 15-55 (HiDAC-3)

CYTARABNE 3 g/m2 IV over 2-4 hours twice daily (bd) days 1,3,5,7. Patients with a serum creatinine greater than ULN prior to therapy should receive cytarabine at 1 g/m2 IV over 2-4 hours bd days 1,3,5,7.
IDARUBICIN 12 mg/m2 IV days 1-3

Age 56-65 (7+3)

CYTARABINE 100mg/m2 IV continuous infusion on days 1-7
IDARUBICIN 12 mg/m2 IV days 1-3

FLT3-ITD identification

Patients will be assessed for molecular eligibility prior to commencement of Sorafenib via a network of molecular centres located throughout Australia and New Zealand. These centres will undergo a regular quality assessment program conducted in association with the Australian Leukaemia and Lymphoma Group (ALLG) laboratory sciences committee.

On day 4 of induction chemotherapy, patients with FLT3-ITD positive AML (allelic mutant: wild-type ratio = 0.05), will be randomized 2:1 by the ALLG biostatistical and coordinating centre (BaCT) to commence taking the FLT3 inhibitor Sorafenib or placebo.

Sorafenib administration

Patients allocated Sorafenib will be given 400 mg twice daily (bd) orally from day 4 to day 10, inclusive (14 doses), after starting induction chemotherapy. If the first dose of Sorafenib is given late in the afternoon on day 4, the final dose may be given on the morning of day 11.

A bone marrow assessment will occur on day 28 to assess response.

Those achieving CR/CRi/CRp will receive CONSOLIDATION chemotherapy.

Age 15-55 (IcE)

IDARUBICIN 9 mg/m2 IV days 1,2
CYTARABINE 100 mg/m2 days 1-5 IVI
ETOPOSIDE 75 mg/m2 IV days 1-5

Age 56-65 (HiDAC-2)

CYTARABINE 1000 mg/m2 IV over 2-4 hours bd days 1,3,5
IDARUBICIN 12 mg/m2 IV days 1,2

Those randomized to Sorafenib during induction will receive for consolidation:
Sorafenib 400 mg bd from day 4 to day 10, inclusive (14 doses)

Maintenance therapy

Patients with FLT3-ITD positive AML who received Sorafenib during induction and consolidation will also receive Sorafenib as maintenance therapy, commencing day 42 after day 1 of the last round of consolidation chemotherapy, or up to day 60 if recovery of neutrophils to 1.0 x 109/L and platelets to 75 x 109/L is delayed. Sorafenib will be given at a dose of 400 mg bd for a total maintenance period of 12 months. Patients allocated to receive placebo will continue to do so in a double-blinded manner.

The tablet cores contain Sorafenib tosylate (BAY 54-9085) and the excipients croscarmellose sodium, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium lauryl sulphate and magnesium stearate. The film-coat consists of hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and red iron oxide. The tablets have a red colour in appearance, a weight of 350mg, and a 10mm round shape.
Intervention code [1] 264591 0
Treatment: Drugs
Comparator / control treatment
The placebo tablets contain croscarmellose sodium, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium lauryl sulphate and magnesium stearate. The film-coat consists of hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and red iron oxide. The tablets have a red colour in appearance, a weight of 350mg, and a 10mm round shape.
Control group
Placebo

Outcomes
Primary outcome [1] 266766 0
To determine 2 year event-free survival (EFS) in untreated adult AML (age 15-65) with FLT3 ITD mutation administered the FLT3 inhibitor Sorafenib compared to a placebo control group not receiving Sorafenib.

The primary endpoint will be the Event-free survival (EFS), measured from the date of randomisation until the date of death from any cause, AML relapse or treatment failure. If the patient does not achieve a CR, EFS is defined as the point of progression or death, whichever comes first. Patients with none of these events at the close-out date will have their EFS censored at the close-out date. The atients with none of these events and who were also deemed to be lost to follow-up before the close-out date, will have their EFS censored at the date they were last known to be alive.
Timepoint [1] 266766 0
Event-free survival after 2 years from registration.
Secondary outcome [1] 276345 0
To confirm the safety of Sorafenib given in combination with HiDAC based induction chemotherapy.

Secondary endpoints are: response rate (CR, CRi), RFS (relapse-free survival) from CR, time-to-relapse (TTR) and overall survival (OS) from randomisation, as well as toxicity and biomarkers of response. The percentage of patients achieving CR with this treatment will be calculated as well as the 2-sided 95% CI for these rates using the Blyth-Still-Casella method. Logistic and Cox regression will be used for additional analyses involving the evaluation of additional prognostic factors.
Timepoint [1] 276345 0
Completion of the study
Secondary outcome [2] 276346 0
To determine other measures of efficacy in untreated adult AML with FLT3 ITD mutation administered the FLT3 inhibitor Sorafenib compared to a control group: CR, CRi, CRp, CRc, 2y-EFS, 2y-PFS and 2y-OS.
Timepoint [2] 276346 0
Completion of Study
Secondary outcome [3] 276347 0
To investigate exploratory markers of clinical benefit: MRD by flow cytometry and WT1.
Timepoint [3] 276347 0
Completion of Study
Secondary outcome [4] 276348 0
To identify biomarkers of response e.g. plasma FLT3 ligand levels, FLT3 mRNA transcript levels, quantitative FLT3 mutant allelic load, the presence of non-juxtamembrane FLT3-ITD lesions, the ability of plasma Sorafenib to inhibit FLT3 phosphorylation ex vivo, pharmacokinetic aspects of administered Sorafenib and modifying effects of other AML mutations e.g. NPM, CEBPA, IDH, Ras and others as they become available.
Timepoint [4] 276348 0
Completion of Study

Eligibility
Key inclusion criteria
A morphological diagnosis of AML by WHO 2008 criteria, confirmed by special stains, immunophenotyping and, if available, cytogenetics. All clinico-pathological subtypes will be eligible, except for AML with t(15;17) or variants.

Patients with secondary and therapy related AML are eligible

FLT3-ITD mutation with an allelic mutant:wild-type ratio of = 0.05

Age 15 to 65 years inclusive.

ECOG performance status 0 to 2 inclusive

Absence of serious cardiac, pulmonary, hepatic or renal disease. A serum creatinine <1.5 times the upper limit of normal (ULN) and serum bilirubin < 2.5 times the upper limit of normal, is required for eligibility

Normal left ventricular ejection fraction, according to institutional criteria.

No previous treatment for AML or history of cancer (other than basal cell skin cancer or carcinoma of the cervix in situ, or other localised cancer treated by surgical excision only more than 5 years earlier without evidence of recurrence in the intervening period)

No contraindication to the use of the study drugs

Treatment must be given at an affiliated ALLG centre, with approval of the protocol by the institution’s Human Research Ethics Committee, or equivalent body

Written informed consent must be obtained from each patient prior to registration and start of treatment
Minimum age
15 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Clinically active CNS leukaemia

Prior chemotherapy for AML (other than hydroxyurea ceased at least 24 hrs prior)

Known HIV positive

Known active hepatitis B or C, or any other active liver disease

Patients with parenchymal abnormality on screening chest x-ray must have no evidence of pulmonary infection on chest tomography (CT) prior to starting remission induction therapy

Any major surgery or radiation therapy within 4 weeks prior to study entry

Serious concomitant illnesses (for example, pulmonary infiltrate, unstable angina or myocardial infarction or stroke within 3 months prior to study entry, congestive heart failure AHA class 2 or greater, uncontrolled hypertension, uncontrolled diabetes, actively bleeding gastric ulcer, etc.), which in the investigator’s opinion would not make the patient a good candidate for the trial

Pregnant or breastfeeding

Any other known condition (e.g., familial, sociological, or geographical) or behaviour (including substance dependence or abuse, psychological or psychiatric illness), which in the investigator’s opinion would make the patient a poor candidate for the trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The patients will be screened and enrolled by their treating physician. The patients will be randomized according to their fulfilment of the inclusion criteria.

The patients must be registered on the AML Registry prior to induction chemotherapy. In order to do so, the patient must meet all eligibility criteria. In addition, the patient must be informed about the requirement to have blood and bone marrow samples taken, and about the initial screening tests prior to induction therapy, and the requirement to have blood samples taken after the first cycles of both induction and consolidation chemotherapy. A signed and dated AML Registry PICF must be obtained from the patient before commencing screening procedures for trial registration prior to induction chemotherapy. In addition, the patient should be offered the optional ALLG Tissue Banking PICF for samples submitted to the ALLG tissue bank. If applicable, consent must be taken for this prior to registration.

A patient will only be eligible for M16 if identified to have FLT3-ITD mutant allelic burden grater than or equal to 0.05, and continues to meet the AML Registry eligibility criteria.

If patient is eligible the patient must be randomised on day 3 to M16.

Each randomised pateint will be allocated a unique 5 digit study ID, e.g. ALF01, and a unique drug box number from the drug box numbers provided to the site prior to activation. As this is a double-blind study, neither the Investigator nor the Coordinating Centre will know whether the patient has been allocated Sorafenib or Placebo.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The patient’s ID and drug box allocation must be written on the M16 Randomisation Form and it is the site’s responsibility to communicate this with their local pharmacy department to ensure the patient is allocated the correct treatment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 267089 0
Charities/Societies/Foundations
Name [1] 267089 0
Leukaemia Foundation of Australia (LFA)
Address [1] 267089 0
Bell City
Ground Floor 205 Bell Street
PRESTON VIC 3072
Country [1] 267089 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Leukaemia Foundation of Australia
Address
Bell City
Ground Floor 205 Bell Street
PRESTON VIC 3072
Country
Australia
Secondary sponsor category [1] 264178 0
Other Collaborative groups
Name [1] 264178 0
Australasian Leukaemia and Lymphoma Group
Address [1] 264178 0
Ground Floor, 35 Elizabeth Street, Richmond, Victoria Australia 3121
Country [1] 264178 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 267066 0
The Royal Melbourne Hospital
Ethics committee address [1] 267066 0
The Royal Melbourne Hospital
300 Grattan Street
Parkville Victoria 3050
Ethics committee country [1] 267066 0
Australia
Date submitted for ethics approval [1] 267066 0
02/05/2012
Approval date [1] 267066 0
15/08/2012
Ethics approval number [1] 267066 0
Ethics committee name [2] 297749 0
Alfred Hospital Melbourne
Ethics committee address [2] 297749 0
Alfred Hospital Melbourne
Commercial Road
Melbourne, Victoria 3004
Ethics committee country [2] 297749 0
Australia
Date submitted for ethics approval [2] 297749 0
Approval date [2] 297749 0
05/10/2012
Ethics approval number [2] 297749 0
Ethics committee name [3] 297750 0
ACT Health
Ethics committee address [3] 297750 0
PO Box 11
Woden, ACT, 2061
Ethics committee country [3] 297750 0
Australia
Date submitted for ethics approval [3] 297750 0
Approval date [3] 297750 0
19/06/2013
Ethics approval number [3] 297750 0
Ethics committee name [4] 297751 0
The Queen Elizabeth Hospital
Ethics committee address [4] 297751 0
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South, SA, 5011
Ethics committee country [4] 297751 0
Australia
Date submitted for ethics approval [4] 297751 0
Approval date [4] 297751 0
07/08/2012
Ethics approval number [4] 297751 0
Ethics committee name [5] 297752 0
Royal Adelaide Hospital
Ethics committee address [5] 297752 0
Royal Adelaide Hospital
Level 3, Hanson Institute, IMVS Building
North Terrace
Adelaide, South Australia, 5000
Ethics committee country [5] 297752 0
Australia
Date submitted for ethics approval [5] 297752 0
Approval date [5] 297752 0
14/04/2014
Ethics approval number [5] 297752 0
Ethics committee name [6] 297753 0
Sir Charles Gairdner Hospital
Ethics committee address [6] 297753 0
Sir Charles Gairdner Hospital
Level 2 A Block
Hospital Avenue
Nedlands, Western Australia, 6009
Ethics committee country [6] 297753 0
Australia
Date submitted for ethics approval [6] 297753 0
Approval date [6] 297753 0
24/03/2014
Ethics approval number [6] 297753 0

Summary
Brief summary
This study aims to determine the safety and efficacy of treatment with the drug Sorafenib, in combination with intensive chemotherapy for adults with previously untreated acute myeloid leukaemia (AML).

Who is it for?
You may be eligible to join this study if you are aged between 15-65 years and have been diagnosed with AML with FLT3-ITD mutation. You must have received no previous treatment for AML.

Trial details
All participants in this trial will undergo intensive chemotherapy over a period of minimum twelve months. Participants will be randomly (by chance) allocated to one of two groups. One group will receive the oral drug Sorafenib whilst undergoing chemotherapy and for a period of 12 months afterwards. The other group will receive a placebo (inactive) treatment in conjunction with chemotherapy. Participants will not know which group they are in until completion of the trial.

Participants will be assessed at regular timepoints for a period of up to 5 years to determine the safety and clinical benefit of Sorafenib treatment in combination with chemotherapy.

Treatment Duration will be a minimum of 1 year.


This Phase II study will:

Investigate the clinical benefit of frontline Sorafenib in combination with chemotherapy and during maintenance therapy in adult AML

Optimise the dosing schedule of Sorafenib based on the kinetics of circulating FLT3 ligand levels after chemotherapy

Investigate the clinical benefit of Sorafenib in relation to additional molecular AML lesions

Identify pharmacokinetic and pharmacodynamic correlates of response predictive of treatment outcome.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32615 0
A/Prof Andrew Wei
Address 32615 0
Alfred Hospital
Commercial Road
Melbourne, Victoria, 3004
Country 32615 0
Australia
Phone 32615 0
+61 (0)3 9076 3451
Fax 32615 0
+61 (0)3 9076 2298
Email 32615 0
andrew.wei@monash.edu
Contact person for public queries
Name 15862 0
Ms Delaine Smith
Address 15862 0
Australasian Leukaemia & Lymphoma Group
Ground Floor, 35 Elizabeth Street
Richmond, Victoria, 3121
Country 15862 0
Australia
Phone 15862 0
+61 (0)3 8373 9710
Fax 15862 0
Email 15862 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 6790 0
A/Prof Andrew Wei
Address 6790 0
Alfred Hospital
Commercial Road
Melbourne, Victoria, 3004
Country 6790 0
Australia
Phone 6790 0
+61 (0)3 9076 3451
Fax 6790 0
Email 6790 0
andrew.wei@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be publicly available as it is the aggregate data that is under investigation.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary