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Trial registered on ANZCTR


Registration number
ACTRN12619001031156p
Ethics application status
Not yet submitted
Date submitted
7/06/2019
Date registered
18/07/2019
Date last updated
18/07/2019
Date data sharing statement initially provided
18/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A placebo controlled study to compare ivosidenib or enasidenib in patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome.
Scientific title
AMLM23- placebo-controlled study to compare the event free survival of patients receiving ivosidenib or enasidenib in patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome.
Secondary ID [1] 298382 0
HOVON150/AMLSG29-18
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia 313058 0
Myelodysplastic syndrome 313059 0
Condition category
Condition code
Cancer 311553 311553 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be randomised depending on whether they have an isocitrate dehydrogenases 1 (IDH1) or isocitrate dehydrogenases 2 (IDH2) mutation.
IDH1 Cohort will recieve
Induction cycle 1 (Cycle equals 28 days)
Cytarabine 200 mg/m2, continuous 24-hour Intravenous infusion, Days 1 to 7.
Daunorubicin 60 mg/m2 Intravenous, (1hr infusion) Days 1,2,3
Placebo or Ivosidenib 500 mg, Orally (tablet) once a day for the whole cycle.

Induction Cycle 2 (Cycle equals 28 days)
Cytarabine 2000 mg/m2, 3 hr Intravenous infusions 1000 mg/m2 every 12 hrs, Days 1 to 6
Daunorubicin (Only for patients less than 60 years of age) 60 mg/m2 Intravenous, 1hr infusion,Days 1 to 3.
Patients over 60 do not receive Daunorubicin in cycle 2.
Placebo or Ivosidenib 500 mg orally Days 1 to start of consolidation treatment

Consolidation treatment
Cytarabine
3000 mg/m2 (age less than or equal to 60yrs), 3hr Intravenous infudion, 1500 mg every 12 hrs × 6 doses, Days1-3
2000 mg/m2 (age greater than or equal to 61yrs), 3-hour Intravenous infusion, 1000 mg every 12 hrs × 6 doses, Days1-3
Placebo or Ivosidenib 500 mg, orally once a day until start of maintenance

Maintenance
Placebo or Ivosidenib 500 mg, orally Days 1 to 730 (aprox 2 years)

IDH2 Cohort will recieve
Induction Cycle 1
Cytarabine 200 mg/m2, continuous 24-hour intravenous infusion, Days 1 to 7
Daunorubicin 60 mg/m2 Intravenous, (1hr infusion) Days 1,2,3
Placebo or Enasidenib 100 mg, Orally, once a day for the whole cycle

Induction cycle 2
Cytarabine 2000 mg/m2, 3 hr Intravenous infusions 1000 mg/m2 every 12 hrs, Days1 to 6.
Daunorubicin (Only for patients less than or equal to 60 years of age) 60 mg/m2 Intravenous, (1hr infusion) Days 1 to 3
Placebo or Enasidenib 100 mg Orally, once a day until start of consolidation treatment.

Consolidation treatment
Cytarabine
3000 mg/m2 (age less than or equal to 60yrs), 3hr Intravenous infusion, 1500 mg every 12 hrs × 6 doses, Days1-3
2000 mg/m2 (age greater than or equal to 61yrs), 3-hour Intravenous infusion, 1000 mg every 12 hrs × 6 doses, Days1-3
Placebo or Enasidenib 100 mg, Orally, once a day until start of maintenance

Maintenance
Placebo or Enasidenib, 100 mg, Orally, Day 1 to 730 (aprox 2 years)
Drug accountability will be performed by each site for each patient, this may involve patient diaries to record compliance. The number of cycles a patient receives will be determined by the treating clinician by assessing blood results, physical health and tolerance.
Intervention code [1] 314625 0
Treatment: Drugs
Comparator / control treatment
For this trial the comparator is treatment with placebo versus treatment with ivosidenib or enasidenib. (Placebo oral tablets containing microcrystalline cellulose)
Control group
Placebo

Outcomes
Primary outcome [1] 320264 0
The number of patients who have achieved event free survival (EFS).
This outcome will be assessed by reviewing patients medical records, results, speaking with the patient etc.
Timepoint [1] 320264 0
EFS will be analysed at 4.5 years from when the first patient was randomised on the trial.
Secondary outcome [1] 371036 0
The number of patients who are alive - Overall survival (OS)
This outcome will be assessed by reviewing patients medical records and by contacting the patient.
Timepoint [1] 371036 0
Overall survival will be analysed at 42 months from when the first patient was randomised.

Eligibility
Key inclusion criteria
Age greater than or equal to 18 years
Newly diagnosed AML or MDS-EB2 defined according to WHO criteria, with a documented
IDH1 or IDH2 gene mutation (as determined by the clinical trial assay)
Considered to be eligible for intensive chemotherapy.
ECOG/WHO performance status less than or equal to 2
Adequate hepatic function .
Adequate renal function
Able to understand and willing to sign an informed consent form (ICF).
Female patients of reproductive potential must undergo a pregnancy test prior to starting
study drug and this test must have a negative result.
Females of reproductive potential as well as fertile men and their partners who are females of reproductive potential must agree to abstain from sexual intercourse or to use a highly effective form of contraception from the time of giving informed consent, during the study,
Subject agrees not to participate in another interventional study while on treatment
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Prior chemotherapy for AML or MDS-EB2.
Dual IDH1 and IDH2 mutations..
Acute promyelocytic leukemia (APL)
Blast crisis after chronic myeloid leukemia (CML).
Taking medications with narrow therapeutic windows with potential interaction with
investigational medication
Breast feeding at the start of study treatment.
Active infection, including hepatitis B or C or HIV infection that is uncontrolled at
randomization.
Patients with a currently active second malignancy.
Significant active cardiac disease within 6 months prior to the start of study treatment.
Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
Any other medical condition deemed by the Investigator to be likely to interfere with a
patient’s ability to give informed consent or participate in the study.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/12/2019
Actual
Date of last participant enrolment
Anticipated
4/12/2023
Actual
Date of last data collection
Anticipated
3/12/2029
Actual
Sample size
Target
968
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 21540 0
Netherlands
State/province [1] 21540 0
Country [2] 21541 0
Austria
State/province [2] 21541 0
Country [3] 21542 0
Germany
State/province [3] 21542 0

Funding & Sponsors
Funding source category [1] 302918 0
Other Collaborative groups
Name [1] 302918 0
HOVON (the Haemato Oncology Foundation for Adults in the Netherlands)
Address [1] 302918 0
Amsterdam UMC, location VUMC,
P.O.Box 7057
1007 MB Amsterdam
Country [1] 302918 0
Netherlands
Primary sponsor type
Other Collaborative groups
Name
HOVON (the Haemato Oncology Foundation for Adults in the Netherlands)
Address
Amsterdam UMC, location VUMC,
P.O.Box 7057
1007 MB Amsterdam
Country
Netherlands
Secondary sponsor category [1] 302880 0
Other Collaborative groups
Name [1] 302880 0
AMLSG (Acute Myeloid Leukemia Study Group)
Address [1] 302880 0
Department of Internal Medicine III
University Hospital Ulm
Albert-Einstein-Allee 23
89081 Ulm,
Country [1] 302880 0
Germany

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 303488 0
Metro South HREC
Ethics committee address [1] 303488 0
Centres for Health Research
Level 7, Translational Research Institute Building
Princess Alexandra Hospital
Ipswich Road, Woolloongabba Qld 4102
Ethics committee country [1] 303488 0
Australia
Date submitted for ethics approval [1] 303488 0
01/08/2019
Approval date [1] 303488 0
Ethics approval number [1] 303488 0

Summary
Brief summary
The purpose of this study is to investigate the efficacy and safety of Ivosidenib and Enasidenib in patients with acute myeloid Leukaemia or myelodysplastic syndrome (MDS).

Who is it for?
You may be eligible for this study if you are an adult who has been diagnosed with AML or MDS with either an IDH1 or IDH2 mutation, with no previous chemotherapy treatment.

Study details
Participants in this study will receive the following treatments:

1.Up to two cycles of Induction: Cytarabine for 6 days and Daunorubicin once a day for 3 days through an infusion in the vein. You will be randomly assigned either a placebo (no treatment) or Enasidenib or Ivosidenaib orally with a tablet once a day for the whole cycle.

2.Up to three cycles of consolidation: Cytarabine twice a day through an infusion in the vein over 3 days. You may then receive either a placebo (no treatment) or Enasidenib or Ivosidenaib orally with a tablet once a day until the end of consolidation.

3.Maintenance treatment will be either a placebo (no treatment), Enasidenib or Ivosidenaib for up to two years.

All participants will undertake blood tests, bone marrow biopsies, scans and questionnaires.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93830 0
Prof Paula Marlton
Address 93830 0
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba QLD 4102
Country 93830 0
Australia
Phone 93830 0
+61 7 3176 2111
Fax 93830 0
Email 93830 0
Paula.Marlton@health.qld.gov.au
Contact person for public queries
Name 93831 0
Ms Delaine Smith
Address 93831 0
Australasian Leukaemia & Lymphoma Group
Ground Floor
35 Elizabeth St
Richmond
Vic 3121
Country 93831 0
Australia
Phone 93831 0
+61 3 8373 9701
Fax 93831 0
Email 93831 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 93832 0
Ms Delaine Smith
Address 93832 0
Australasian Leukaemia & Lymphoma Group
Ground Floor
35 Elizabeth St
Richmond
Vic
3121
Country 93832 0
Australia
Phone 93832 0
+61 3 8373 9701
Fax 93832 0
Email 93832 0
delaine.smith@allg.org.au

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
No Results