ANZCTR - Registration

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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

1/06/2020

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]

HOVON150/AMLSG29-18

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Acute myeloid leukaemia

Myelodysplastic syndrome

Condition category

Condition code

Cancer

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]

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]

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]

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]

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]

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]

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]

At the end of study, this is expected to occur 14 years after the registration of the first patient.

Secondary outcome [3]

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]

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]

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]

At the end of study, this is expected to occur 14 years after the registration of the first patient

Secondary outcome [5]

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]

At the end of study, this is expected to occur 14 years after the registration of the first patient

Secondary outcome [6]

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]

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]

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]

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

Gender

Both males and females

Can healthy volunteers participate?

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

Not yet recruiting

Date of first participant enrolment

Anticipated

1/06/2020

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 hospital [1]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [2]

The Alfred - Melbourne

Recruitment hospital [3]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [4]

Box Hill Hospital - Box Hill

Recruitment hospital [5]

The Canberra Hospital - Garran

Recruitment hospital [6]

Concord Repatriation Hospital - Concord

Recruitment hospital [7]

Flinders Medical Centre - Bedford Park

Recruitment hospital [8]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [9]

Royal Hobart Hospital - Hobart

Recruitment hospital [10]

Calvary Mater Newcastle - Waratah

Recruitment hospital [11]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [12]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [13]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [14]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [15]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [16]

Royal North Shore Hospital - St Leonards

Recruitment hospital [17]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [18]

Royal Perth Hospital - Perth

Recruitment hospital [19]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [20]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [21]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment hospital [22]

The Townsville Hospital - Douglas

Recruitment hospital [23]

Westmead Hospital - Westmead

Recruitment postcode(s) [1]

5000 - Adelaide

Recruitment postcode(s) [2]

3004 - Melbourne

Recruitment postcode(s) [3]

3084 - Heidelberg

Recruitment postcode(s) [4]

3128 - Box Hill

Recruitment postcode(s) [5]

2605 - Garran

Recruitment postcode(s) [6]

2139 - Concord

Recruitment postcode(s) [7]

5042 - Bedford Park

Recruitment postcode(s) [8]

6150 - Murdoch

Recruitment postcode(s) [9]

7000 - Hobart

Recruitment postcode(s) [10]

2298 - Waratah

Recruitment postcode(s) [11]

3168 - Clayton

Recruitment postcode(s) [12]

4102 - Woolloongabba

Recruitment postcode(s) [13]

4029 - Herston

Recruitment postcode(s) [14]

3050 - Parkville

Recruitment postcode(s) [15]

3000 - Melbourne

Recruitment postcode(s) [16]

2065 - St Leonards

Recruitment postcode(s) [17]

2050 - Camperdown

Recruitment postcode(s) [18]

6000 - Perth

Recruitment postcode(s) [19]

6009 - Nedlands

Recruitment postcode(s) [20]

3065 - Fitzroy

Recruitment postcode(s) [21]

2010 - Darlinghurst

Recruitment postcode(s) [22]

4814 - Douglas

Recruitment postcode(s) [23]

2145 - Westmead

Recruitment outside Australia

Country [1]

Netherlands

State/province [1]

Country [2]

Austria

State/province [2]

Country [3]

Germany

State/province [3]

Country [4]

Switzerland

State/province [4]

Country [5]

Belgium

State/province [5]

Country [6]

France

State/province [6]

Country [7]

Spain

State/province [7]

Country [8]

Luxembourg

State/province [8]

Country [9]

Norway

State/province [9]

Country [10]

Sweden

State/province [10]

Country [11]

Lithuania

State/province [11]

Country [12]

Finland

State/province [12]

Country [13]

Estonia

State/province [13]

Country [14]

United States of America

State/province [14]

Country [15]

Ireland

State/province [15]

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

HOVON (the Haemato Oncology Foundation for Adults in the Netherlands)

Address [1]

Amsterdam UMC, location VUMC,
P.O.Box 7057
1007 MB Amsterdam

Country [1]

Netherlands

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Leukemia Foundation

Address [2]

1/33 Flemington Rd, North Melbourne VIC 3051

Country [2]

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]

Other Collaborative groups

Name [1]

AMLSG (Acute Myeloid Leukemia Study Group)

Address [1]

Department of Internal Medicine III
University Hospital Ulm
Albert-Einstein-Allee 23
89081 Ulm,

Country [1]

Germany

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Metro South HREC

Ethics committee address [1]

Centres for Health Research
Level 7, Translational Research Institute Building
Princess Alexandra Hospital
Ipswich Road, Woolloongabba Qld 4102

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

14/11/2019

Approval date [1]

05/03/2020

Ethics approval number [1]

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

Prof Paula Marlton

Address

Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba QLD 4102

Country

Australia

Phone

+61 7 3176 2111

Fax

Paula.Marlton@health.qld.gov.au

Contact person for public queries

Name

Ms Delaine Smith

Address

Australasian Leukaemia & Lymphoma Group
Ground Floor
35 Elizabeth St
Richmond
Vic 3121

Country

Australia

Phone

+61 3 8373 9701

Fax

delaine.smith@allg.org.au

Contact person for scientific queries

Name

Ms Delaine Smith

Address

Australasian Leukaemia & Lymphoma Group
Ground Floor
35 Elizabeth St
Richmond
Vic
3121

Country

Australia

Phone

+61 3 8373 9701

Fax

delaine.smith@allg.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

Trial Review