The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12612000848808
Ethics application status
Approved
Date submitted
3/08/2012
Date registered
13/08/2012
Date last updated
9/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A programme of development for older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome
Scientific title
A Phase II study assessing the complete remission rate and overall survival of older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome that undergo less intensive treatment
Secondary ID [1] 280965 0
AMLM20
Secondary ID [2] 292405 0
EudraCT Number: 2011-000749-19
Secondary ID [3] 292406 0
ISRCTN (International Standard Randomised Controlled Trial) Number: ISRCTN40571019
Universal Trial Number (UTN)
Trial acronym
AMLM20
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia (AML) 287075 0
myelodysplastic syndrome 287076 0
Condition category
Condition code
Cancer 287398 287398 0 0
Leukaemia - Acute leukaemia
Blood 287399 287399 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be randomised to standard treatment, Low Dose Ara-C, versus one of four alternative novel treatment approaches. The available treatment arms are thus:

Arm1: Low dose Ara-C and AC220 (quizartinib)
Arm 2: Low dose Ara-C combined with ganetespib: closed no longer active
Arm 3: Low dose Ara-C combined with tosedostat: closed no longer active
Arm 4: Low dose Ara-C + Selinexor
Arm 5: Low dose Ara-C combined with Lenalidomide

During the course of the Programme other novel therapies (Drug X) are expected to become available, and will be considered for inclusion in this comparison.

The current treatment arm available in Australia is Arm 3: Low Dose Ara-C combined with Tosedostat.

Arm 1: Low Dose Ara-C and AC220 (Quizartinib)

Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given).

AC220 will be taken in a dose of 90mg (three 30mg tablets or oral solution) orally, daily for 21 consecutive days commencing on day 1 of each Low dose Ara-C treatment.

Arm 2: Low dose Ara-C combined with Ganetespib

Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given).

The dose of ganetespib (120mg/m2) will be given as a 1 hour intravenous infusion commencing on day 1 of each Low dose Ara-C treatment, irrespective of when each course of the Low dose Ara-C is started. This will be repeated on days 8, 15, 22 and 29 of each Low dose Ara-C course. Four courses will be given at 4 to 6 week intervals.

Arm 3: Low Dose Ara-C combined with Tosedostat

Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given).

Tosedostat will be taken in a dose of 120mg (2 capsules) orally once a day with a glass of water after food, preferably in the morning at about the same time every day to ensure an even dose interval. Treatment should commence on day 1 of the first course of Low dose Ara-C and continue daily for 6 months. Patients may stay on treatment if they are deriving benefit.

Arm 4: Low Dose Ara-C and Selinexor

Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given).

For each course of Low Dose Ara-C, selinexor dosing will take place on days 1 & 3 of each week between Low Dose Ara-C courses. The dose of Selinexor will be 30mg/m2, starting at day 12, where day 1 is the first day of Low Dose Ara-C. Four courses of Low Dose Ara-C + Selinexor are intended. The interval between the courses can vary, but it is intended that Selinexor will be given on 2 days per week for each week between Low Dose Ara-C. On completion of the Low Dose Ara-C courses Selinexor will continue once weekly at 40 mg/m2 to be given on the same day each week. The aim is to give 6 months of maintenance treatment but patients will be permitted to continue if it is thought that they are deriving benefit.

Arm 5: Low dose Ara-C combined with Lenalidomide

Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given).

Lenalidomide is administered orally once daily in a flat 10mg dose for 21 days, where day 1 is day 1 of LD Ara-C. This course will be repeated after a 2 week rest period and continue for four courses. Patients who are considered to be benefiting after having received the planned four courses i.e. continue in remission or have stable disease, should continue to receive treatment until disease progression in the following schedule:
- Low dose Ara-C + lenalidomide at 4-6 weekly intervals, or
- Lenalidomide only, at 4 weekly intervals, if patient has experienced significant Low dose Ara-C toxicity (equivalent to ongoing grade 3 haematological toxicity)
Intervention code [1] 285405 0
Treatment: Drugs
Comparator / control treatment
Low dose Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given).
Control group
Active

Outcomes
Primary outcome [1] 287664 0
Complete remission (CR) defined as:
* Cellularity of marrow should be at least 20% with evidence of tri-lineage regeneration.
* Less than 5% blasts.
* No Auer rods.
* No extra-medullary disease.
* Peripheral blood count recovery to 100 x10^9/l
* Neutrophil recovery to 1.0 x 10^9/l

Timepoint [1] 287664 0
10-14 days after completion of cycle 1
Secondary outcome [1] 298604 0
overall survival
Timepoint [1] 298604 0
After 25% and 50% of the required number of events have been seen

Eligibility
Key inclusion criteria
1. Acute myeloid leukaemia (except Acute Promyelocytic Leukaemia) as defined by the WHO Classification. This can be any type of de novo or secondary AML – or high risk Myelodysplastic Syndrome (greater than 10% blasts, RAEB-2). MDS patients who have received azacitidine are not eligible for this trial, but patients with less than 10% who have failed a demethyation agent and developed AML may enter the trial.
2. Over the age of 60
3. Given written informed consent.

For the AC220 (quizartinib), tosedostat and ganetespib interventions:
4. Cardiac criteria must be met
5. Electrolyte levels of Potassium, Magnesium and Calcium (adjusted) must be within the institutional normal range

Male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential.
Minimum age
60 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Less than 60 years of age
2. Previously received cytotoxic chemotherapy for AML (hydroxycarbamide, or similar low-dose therapy, to control the white count is not an exclusion criterion. Previous treatment with a demethylating agent for MDS less than 10% blasts is not an exclusion).
3. Blast transformation of chronic myeloid leukaemia (CML)
4. Concurrent active malignancy under treatment
5. Pregnant or lactating
6. Acute Promyelocytic Leukaemia
7. Known infection with human immunodeficiency virus (HIV)
8. Total bilirubin greater than or equal to 1.5 x ULN, unless due to Gilbert’s syndrome
9. Aspartate aminotransferase (AST) greater than or equal to 2.5 x UL and/or alkaline phosphatase greater than or equal to 2.5 x ULN
10. Serum creatinine greater than or equal to 175µmol/L
11. History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 6 months

For AC220 (Quizartinib), Tosedostat and Ganetespib treatment the following criteria make a patient ineligible for that randomisation:
12. A myocardial infarction within 12 months
13. Uncontrolled angina within 6 months
14. Current or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, unless an echocardiogram (ECHO) or Multiple Gated Acquisition Scan (MUGA) performed either within 1 month prior to study screening or during screening results in a left ventricular ejection fraction (LVEF) that is greater than or equal to 45% (or institutional lower limit of normal value).
15. Diagnosed or suspected congenital long QT syndrome. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes [TdP]) or any history of arrhythmia will be discussed with the Clinical Coordinator/Safety Physician prior to patient’s entry into the study.
16. Prolonged QTcF interval on pre-entry ECG (greater than or equal to 450 ms)
17. Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker)
18. Heart rate less than 50/minute on pre-entry ECG
19. Uncontrolled hypertension
20. Obligate need for a cardiac pacemaker
21. Complete left bundle branch block
22. Uncontrolled atrial fibrillation

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)
Central enrolment will be conducted through the international trial centre.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
random sequence number generation by a computer
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Arms Australia participating on were closed.
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,NT,QLD,TAS

Funding & Sponsors
Funding source category [1] 285751 0
Other Collaborative groups
Name [1] 285751 0
Australasian Leukaemia and Lymphoma Group
Address [1] 285751 0
Ground Floor, 35 Elizabeth Street, Richmond, Victoria, Australia 3121
Country [1] 285751 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Ground Floor, 35 Elizabeth Street, Richmond, Victoria, Australia 3121
Country
Australia
Secondary sponsor category [1] 284578 0
None
Name [1] 284578 0
Address [1] 284578 0
nil
Country [1] 284578 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287758 0
NSW Government Health, North Sydney Local Health District
Ethics committee address [1] 287758 0
Research Office,
Kolling Building, Level 13
Royal North Shore Hospital
St Leonards NSW 2065
Ethics committee country [1] 287758 0
Australia
Date submitted for ethics approval [1] 287758 0
27/04/2015
Approval date [1] 287758 0
22/07/2015
Ethics approval number [1] 287758 0
RESP/15/69
Ethics committee name [2] 298161 0
Human Research Ethics Committee (Tasmania) Network
Ethics committee address [2] 298161 0
Office of Research Services
University of Tasmania
Private Bag 1
Hobart, Tasmania, 7001
Ethics committee country [2] 298161 0
Australia
Date submitted for ethics approval [2] 298161 0
Approval date [2] 298161 0
14/08/2015
Ethics approval number [2] 298161 0
H0015175
Ethics committee name [3] 298162 0
Menzies School of Health Research
Ethics committee address [3] 298162 0
John Mathews Building
Royal Darwin Hospital Campus
Rocklands Drive
Casuarina, Northern Territory, 0810
Ethics committee country [3] 298162 0
Australia
Date submitted for ethics approval [3] 298162 0
20/10/2015
Approval date [3] 298162 0
15/12/2015
Ethics approval number [3] 298162 0
2015-2502
Ethics committee name [4] 298163 0
ACT Health Research Ethics and Governance Office
Ethics committee address [4] 298163 0
Building 10 Level 6
Canberra Hospital
PO Box 11
Woden, ACT, 2606
Ethics committee country [4] 298163 0
Australia
Date submitted for ethics approval [4] 298163 0
Approval date [4] 298163 0
28/01/2016
Ethics approval number [4] 298163 0
ETH.11.15.224

Summary
Brief summary
This study aims to assess a number of new treatments over time. The aim is to continue to improve treatment by comparing a number of new drugs which have shown some benefit in early stage trials with the existing standard treatment. The current treatment option which will be tested in Australia is standard treatment, low dose Cytarabine alone compared with standard treatment, low dose Cytarabine in combination with Tosedostat in elderly patients with either acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS).

Who is it for?
You may be eligible to join this study if you are aged 60 years or over and have been diagnosed with AML or MDS. You must have received no previous treatment for AML.

Trial details

Additional experimental treatments may be added or removed from the study as further information becomes available. The current treatment option which will be tested in Australia is standard treatment, low dose Cytarabine alone compared with standard treatment, low dose Cytarabine in combination with Tosedostat in elderly patients with either acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS).

All participants in this trial will undergo chemotherapy for four cycles. Participants will be randomly (by chance) allocated to one of two groups. One group will receive the together subcutaneous injections of low dose cytarabine together with Tosedostat tablets in a dose of 120mg (2 capsules) orally once a day with a glass of water after food, preferably in the morning at about the same time every day to ensure an even dose interval. Treatment should commence on day 1 of the first course of Low dose Ara-C and continue daily for 6 months. Patients may stay on treatment if they are deriving benefit. The other group will receive low dose cytarabine by subcutaneous injection alone. Participants will be assessed at regular timepoints until the end of the trial to determine the safety and clinical benefit of tosedostat treatment in combination with low dose cytarabine, compared to the current effective treatment of low dose cytarabine alone.

Treatment Duration will be a minimum of 4 courses between 28 and 42 days each.

This Phase II/III study will:

Investigate the survival benefit, the rate of remission and safety of the patients allocated to each group and compare the groups to each other
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34530 0
A/Prof Andrew Wei
Address 34530 0
Alfred Hospital
Commercial Rd
Melbourne, Victoria, 3004
Country 34530 0
Australia
Phone 34530 0
+61 (0)3 9076 3451
Fax 34530 0
+61 (0)3 9076 2298
Email 34530 0
andrew.wei@monash.edu
Contact person for public queries
Name 17777 0
Ms Amanda Jager
Address 17777 0
Australasian Leukaemia & Lymphoma Group
Ground Floor, 35 Elizabeth Street
Richmond, Victoria, 3121
Country 17777 0
Australia
Phone 17777 0
+61 (0)3 8373 9714
Fax 17777 0
+61 (0)3 9429 8277
Email 17777 0
amanda.jager@allg.org.au
Contact person for scientific queries
Name 8705 0
A/Prof Andrew Wei
Address 8705 0
Alfred Hospital
Commercial Rd
Melbourne, Victoria, 3004
Country 8705 0
Australia
Phone 8705 0
+61 (0)3 9076 3451
Fax 8705 0
Email 8705 0
andrew.wei@monash.edu

No information has been provided regarding IPD availability
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