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Trial registered on ANZCTR


Registration number
ACTRN12619001031156
Ethics application status
Approved
Date submitted
7/06/2019
Date registered
18/07/2019
Date last updated
28/05/2024
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)
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
To compare event-free survival (EFS) between ivosidenib/enasidenib and placebo in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed AML or MDS-EB2, with an IDH1 or IDH2 mutation, eligible for intensive chemotherapy. This outcome will be assessed by reviewing patients medical records, results, speaking with the patient etc.
Timepoint [1] 320264 0
The final primary endpoint analysis will take place after 283 events for EFS have been observed in both the experimental and control treatment arm (~5 years after the
randomization of the first patient)
Secondary outcome [1] 371036 0
To determine if treatment with ivosidenib/enasidenib, as compared to placebo prolongs
overall survival (OS). This outcome will be assessed by reviewing patients medical records and by contacting the patient.
Timepoint [1] 371036 0
The final analysis of the key secondary endpoint will be conducted when 252 events for OS in both in the experimental and control treatment arm have occurred (~7 years after the randomization of the first patient).
Secondary outcome [2] 383480 0
To compare relapse-free survival (RFS), cumulative incidence of relapse (CIR) and cumulative incidence of death (CID) after CR/CRi between treatment including ivosidenib/enasidenib and treatment including placebo. This outcome will be assessed by reviewing patients medical records and by contacting the patient. This is a composite outcome.
Timepoint [2] 383480 0
At the end of study, this is expected to occur 14 years after the registration of the first patient.
Secondary outcome [3] 383481 0
To evaluate minimal residual disease (MRD) status at sequential time points throughout treatment and CRMRD- rate between treatment including ivosidenib/enasidenib vs. placebo, using molecular and/or flow cytometric techniques.
Timepoint [3] 383481 0
At the end of study, this is expected to occur 14 years after the registration of the first patient. This will be assessed at baseline, after induction cycle 2, after consolidation cycle 3, day 1 of maintenance, day 168 of maintenance, when ceasing protocol treatment, and at relapse.
Secondary outcome [4] 383482 0
To assess the safety and tolerability of treatment including ivosidenib/enasidenib vs. placebo by comparing the frequency and severity of adverse events according to CTCAE.
Timepoint [4] 383482 0
At the end of study, this is expected to occur 14 years after the registration of the first patient
Secondary outcome [5] 383483 0
To compare complete remission (CR/CRi) rates for treatment including ivosidenib/enasidenib vs. placebo. This outcome will be assessed by reviewing patients medical records and by contacting the patient.
Timepoint [5] 383483 0
At the end of study, this is expected to occur 14 years after the registration of the first patient
Secondary outcome [6] 383484 0
To assess the time to hematopoietic recovery (ANC 0.5 and 1.0x109/l; platelets 50 and 100x109/l) after each chemotherapy treatment cycle. This outcome will be assessed by reviewing patients medical records and by contacting the patient.
Timepoint [6] 383484 0
At the end of study, this is expected to occur 14 years after the registration of the first patient. This will be assessed after each chemotherapy treatment cycle.
Secondary outcome [7] 383485 0
To determine quality of life (QoL) during maintenance treatment with ivosidenib/enasidenib vs. placebo. This will be assessed using the EQ-5D-5L and QLQ-C-30 assessment tools.
Timepoint [7] 383485 0
At the end of study, this is expected to occur 14 years after the registration of the first patient. This will be assessed at baseline, day 1 of maintenance, and month 3, 6, 9, 12, 18 and 24.

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
Sex
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)
central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
The study consists of two parallel, multi-center, randomized sub-trials, each of which aims to compare the efficacy of one specific IDH inhibitor (ivosidenib or enasidenib) with that of placebo when administered in combination with induction chemotherapy, consolidation therapy and as a mono maintenance therapy.

The trial is planned to power both the primary endpoint (EFS) and the key secondary endpoint (OS). Based on the combined data of previous international studies from the international sponsor an EFS at 24 and 60 months in the control arm of 35% and 25%, respectively, and an OS at 30 and 60 months in the control arm of 50% and 40%, respectively.

Assuming a hazard ratio (HR) of 0.70 for EFS (which corresponds to an increase in EFS at 24-months from 35% in the control arm to 48% in the treatment arm), a total of 283 EFS events are needed to achieve 84% power with an overall 2-sided significance level a = 0.05 and two planned interim analyses (a futility analysis at 33% and a superiority analysis at 67% of the EFS events). Considering a 48-month accrual, 12 months of follow-up after the last patient has been randomized and an overall drop-out rate (in EAST software terms) in both trial arms of 10%, approximately a total of 484 patients need to be randomized to the two treatment arms in a 1:1 ratio. Assuming an additional 24 months of follow-up for OS (i.e., 36 months of follow-up after the last patient has been randomized), this sample size would allow 80% power to detect a HR of 0.70 for OS (which corresponds to an increase in OS at 30-months from 50% in the control arm to 62% in the treatment arm) at an overall 2-sided a = 0.05, based on a total of 252 OS events and assuming one planned interim analysis for OS (at the time of the final analysis of EFS).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2020
Actual
21/10/2020
Date of last participant enrolment
Anticipated
31/08/2024
Actual
Date of last data collection
Anticipated
3/12/2029
Actual
Sample size
Target
968
Accrual to date
923
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 16794 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 16795 0
The Alfred - Melbourne
Recruitment hospital [3] 16796 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 16799 0
Concord Repatriation Hospital - Concord
Recruitment hospital [5] 16800 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [6] 16801 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [7] 16802 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 16803 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [9] 16804 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [10] 16805 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [11] 16806 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [12] 16807 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [13] 16808 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [14] 16809 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [15] 16810 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [16] 16811 0
Royal Perth Hospital - Perth
Recruitment hospital [17] 16812 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [18] 16813 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [19] 16815 0
The Townsville Hospital - Douglas
Recruitment hospital [20] 16816 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 30417 0
5000 - Adelaide
Recruitment postcode(s) [2] 30418 0
3004 - Melbourne
Recruitment postcode(s) [3] 30419 0
3084 - Heidelberg
Recruitment postcode(s) [4] 30422 0
2139 - Concord
Recruitment postcode(s) [5] 30423 0
5042 - Bedford Park
Recruitment postcode(s) [6] 30424 0
6150 - Murdoch
Recruitment postcode(s) [7] 30425 0
7000 - Hobart
Recruitment postcode(s) [8] 30426 0
2298 - Waratah
Recruitment postcode(s) [9] 30427 0
3168 - Clayton
Recruitment postcode(s) [10] 30428 0
4102 - Woolloongabba
Recruitment postcode(s) [11] 30429 0
4029 - Herston
Recruitment postcode(s) [12] 30430 0
3050 - Parkville
Recruitment postcode(s) [13] 30431 0
3000 - Melbourne
Recruitment postcode(s) [14] 30432 0
2065 - St Leonards
Recruitment postcode(s) [15] 30433 0
2050 - Camperdown
Recruitment postcode(s) [16] 30434 0
6000 - Perth
Recruitment postcode(s) [17] 30435 0
6009 - Nedlands
Recruitment postcode(s) [18] 30436 0
3065 - Fitzroy
Recruitment postcode(s) [19] 30438 0
4814 - Douglas
Recruitment postcode(s) [20] 30439 0
2145 - Westmead
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
Country [4] 22590 0
Switzerland
State/province [4] 22590 0
Country [5] 22591 0
Belgium
State/province [5] 22591 0
Country [6] 22592 0
France
State/province [6] 22592 0
Country [7] 22593 0
Spain
State/province [7] 22593 0
Country [8] 22594 0
Luxembourg
State/province [8] 22594 0
Country [9] 22595 0
Norway
State/province [9] 22595 0
Country [10] 22596 0
Sweden
State/province [10] 22596 0
Country [11] 22597 0
Lithuania
State/province [11] 22597 0
Country [12] 22598 0
Finland
State/province [12] 22598 0
Country [13] 22599 0
Estonia
State/province [13] 22599 0
Country [14] 22600 0
United States of America
State/province [14] 22600 0
Country [15] 22601 0
Ireland
State/province [15] 22601 0
Country [16] 25102 0
New Zealand
State/province [16] 25102 0
Auckland & Welington

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)
Country [1] 302918 0
Netherlands
Funding source category [2] 305854 0
Charities/Societies/Foundations
Name [2] 305854 0
Leukemia Foundation
Country [2] 305854 0
Australia
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
Approved
Ethics committee name [1] 303488 0
Metro South HREC
Ethics committee address [1] 303488 0
Ethics committee country [1] 303488 0
Australia
Date submitted for ethics approval [1] 303488 0
14/11/2019
Approval date [1] 303488 0
05/03/2020
Ethics approval number [1] 303488 0

Summary
Brief summary
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
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
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 Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.