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Trial registered on ANZCTR


Registration number
ACTRN12619000280101p
Ethics application status
Submitted, not yet approved
Date submitted
18/02/2019
Date registered
25/02/2019
Date last updated
25/02/2019
Date data sharing statement initially provided
25/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM22/D2-The International Acute myeloid leukaemia (AML) Platform Consortium (IAPC) trial is a randomised, multi-arm study platform to compare the efficacy of experimental therapies versus standard of care in subjects with acute myeloid leukaemia in first complete remission. Domain 2 is investigating the safety and efficacy of Venetoclax as a maintenance therapy alone or in combination with low dose cytarabine (LDAC).
Scientific title
AMLM22/D2-The International Acute myeloid leukaemia (AML) Platform Consortium (IAPC) trial is a randomised, multi-arm study platform to compare the efficacy of experimental therapies versus standard of care in subjects with acute myeloid leukaemia in first complete remission. Domain 2 is investigating the safety and efficacy of Venetoclax as a maintenance therapy alone or in combination with low dose cytarabine (LDAC).
Secondary ID [1] 297388 0
NIL
Universal Trial Number (UTN)
Trial acronym
AMLM22/D2
Linked study record
ACTRN12619000248167p is linked to this as both are sub-studies of the main platform study

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia (AML) 311544 0
Condition category
Condition code
Cancer 310182 310182 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Domain 2 is AMLM22/D2, it has 3 treatment arms:
Arm 1: Venetoclax (investigational product) plus Low-dose cytarabine (LDAC). Recommended dose of Venetoclax is 600mg daily, taken orally on days 1-28 of each cycle. Low dose cytarabine (LDAC) is given subcutaneously (under the skin) at a dose of 20mg/m2 daily on days 1-10 of each 28-day cycle, following administration of venetoclax. Each cycle is 28 days. Total treatment duration is expected to be 24 months.
Arm 2: Venetoclax monotherapy. Recommended dose of Venetoclax is 800mg daily, taken orally on days 1-28 of each cycle. Each cycle is 28 days. Total treatment duration is expected to be 24 months.
Arm 3: Standard of care (generally observation)
Patients randomised to receive venetoclax will be asked to return any unused tablets at each visit.
Intervention code [1] 313695 0
Treatment: Drugs
Comparator / control treatment
Patients that are randomised to treatment arm 3: standard of care, will receive standard of care treatment for AML remission, which is generally observation. This is the care they would normally receive if they weren't on a trial.
Control group
Active

Outcomes
Primary outcome [1] 319128 0
Failure-free survival - this is the time from randomisation until the time of the earliest leukaemia event (relapse). Data to monitor failure-free survival (disease monitoring and minimal residual disease (MRD) testing) will be collected from patient's at various protocol specified times points throughout the study.
Timepoint [1] 319128 0
Time from randomisation until the time of the earliest leukaemia event- either MRD progression, MRD relapse, clinical relapse or death.
Patients will be followed for survival, by telephone, every month for the first year and then every 3 months until death, withdrawal of consent for further follow-up, study end, or until a subject is lost to follow-up.
Treatment is expected to be for up to 24months
Follow up will continue until death, withdrawal of consent from study or until a patient is lost to follow up
Secondary outcome [1] 367054 0
Safety (pilot phase)- Occurrence of related CTCAE grade 3-5 non-hematologic adverse events, related CTCAE grade 4-5 neutropenia or thrombocytopenia or grade 3-5 febrile neutropenia.
Timepoint [1] 367054 0
Analysis of these adverse events will be conducted on all patients in the safety set (defined as all patients in an experimental arm that received at least one dose of the study drug associated with that arm and all patients in the appropriate Standard of care (SoC) control arm who did not receive a dose of a drug associated with a study arm in the relevant domain), in the first 6 months following randomisation.
Summary tables of newly emerging and worsening adverse events and laboratory tests (based on the worst CTCAE grade per patient), both severe (greater than or equal to Grade 3) and of any grade, will be reported by type, treatment arm and by cycles (for each of the first 6 cycles).
Data on adverse events will be collected from participants at each visit and upto 28 days after last treatment dose.
Secondary outcome [2] 367055 0
Relapse free survival- Time from the date of randomisation to the date of relapse or death from any cause. Relapse data will be collected from the patient and the patients hospital records.






Timepoint [2] 367055 0
Time from the date of randomisation to the earlier of the date of relapse or death from any cause, (censored and not censored for SCT).
Patients will be followed for survival, by telephone, every month for the first year and then every 3 months until death, withdrawal of consent for further follow-up, study end, or until a subject is lost to follow-up.
Follow up will continue until death, withdrawal of consent from study or until a patient is lost to follow up
Treatment is expected to be for up to 24 months
Secondary outcome [3] 367056 0
MRD erasure -Eradication of MRD that was detected at screening in bone marrow or peripheral blood within 6 months of study randomisation. This will be assessed using flow cytometry and/or molecular methods (ie.quantitative PCR)






Timepoint [3] 367056 0
Eradication of MRD detected at screening within 6 months of study randomisation
Secondary outcome [4] 367057 0
Quality of life







Timepoint [4] 367057 0
The FACIT-Fatigue Scale and the EQ-5D score at baseline, 6, 12, 18 and 24 months

Eligibility
Key inclusion criteria
1. Provision of written informed consent
2. Provision of written informed consent to the ALLG NBCR
3. Age 18+ (Age 16-17 permitted if consent for minor PICF approved by the authorizing HREC)
4. AML (excluding APL) in first complete remission with bone marrow blasts <5%
5. Subject has achieved remission after intensive chemotherapy (e.g. 7+3 or equivalent +/- subsequent consolidation therapy)
6. ECOG 0-2
7. Subject must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hours urine collection
8. Subject must have adequate liver function as demonstrated by:
a. aspartate aminotransferase (AST) greater than or equal to 3.0 × ULN
b. alanine aminotransferase (ALT) greater than or equal to 3.0 × ULN
c. bilirubin greater than or equal to 1.5 × ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
9. Agrees to follow the recommended contraception procedures for this treatment domain
Minimum age
16 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Chemotherapy or investigational agents within 28 days of planned study cycle 1 day
2. Impaired hematologic recovery 8 weeks after last chemotherapy
a. Grade 2 anemia (Hb <100g/L)
b. Grade 4 neutropenia (N <0.5 x 109/L)
c. Grade 3 thrombocyotopenia (Plt <50 x 109/L)
3. History of other malignancy requiring active systemic treatment or which is likely to result in an expected survival time of < 2 years
4. Viral infection with known HIV or viral hepatitis type B or C not adequately controlled by antiviral medication
5. Prior bone marrow or stem cell transplantation
6. There is an intent to undertake a stem cell transplant procedure within the next 3 months
7. Subject is HIV positive
8. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
b. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
9. Treatment with any of the following within 7 days prior to the first dose of study drug:
a. Steroid therapy for anti-neoplastic intent
b. Moderate or strong CYP3A inducers
c. Moderate or strong cytochrome CYP3A inhibitors may be used with caution with appropriate dose modifications for venetoclax
10. Administration or consumption of any of the following within 3 days prior to the first dose of study drug:
a. Grapefruit or grapefruit products
b. Seville oranges (including marmalade containing Seville oranges)
c. Star fruit
11. Subject not able to comply with domain-specific contraception recommendations

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)
Randomisation will occur by a central randomization procedure, in a 2-step process.
Participants will first be randomised to an eligible domain based on physical and disease characteristics. They will then be randomised to a treatment arm within that domain.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Not yet 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,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 302008 0
Charities/Societies/Foundations
Name [1] 302008 0
Australian Leukaemia and Lymphoma Group (ALLG)
Address [1] 302008 0
35 Elizabeth Street
Richmond, VIC 3121
Country [1] 302008 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Australian Leukaemia and Lymphoma Group (ALLG)
Address
35 Elizabeth Street
Richmond, VIC 3121
Country
Australia
Secondary sponsor category [1] 301790 0
Commercial sector/Industry
Name [1] 301790 0
Abbvie Pty Ltd
Address [1] 301790 0
Level 7, 241 O’Riordan Street,
Mascot, NSW 2020
Country [1] 301790 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 302683 0
Alfred Hospital ethics Committee
Ethics committee address [1] 302683 0
55 Commercial Road
Melbourne, VIc 3004
Ethics committee country [1] 302683 0
Australia
Date submitted for ethics approval [1] 302683 0
09/01/2019
Approval date [1] 302683 0
Ethics approval number [1] 302683 0

Summary
Brief summary
This study will evaluate the safety and efficacy of venetoclax alone or in combination with low-dose cytarabine (LDAC) for Acute Myeloid Leukemia

Who is it for?
You may be eligible to join this study if you are aged 16 and above and have Acute Myeloid Leukemia in first complete remission.

Study details
This study is part of the International AML Platform Consortium. Participants in this study will be randomly allocated (by chance) to one of three treatment groups. Participants in one group will receive standard care which is generally observation. Participants in the other groups will receive the drug Venetoclax daily for a total of 24 months or Venetoclax in combination with low-dose cytarabine (LDAC) for a total of 24 months.

As part of the study, participants will have blood tests at the start of each cycle (every 28 days) as well as additional blood tests depending on the treatment arm you have been randomised to. These additional blood tests are to monitor the level of neutrophils (type of white blood cell that is important in fighting infection) and platelets (platelets help your blood clot)
We hope that the results from this trial will be used to help these new treatments which may be better for people with AML than what is currently available become accessible to the general population at faster than the normal process.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 43466 0
A/Prof Andrew Wei
Address 43466 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 43466 0
Australia
Phone 43466 0
+61 3 9076 3392
Fax 43466 0
Email 43466 0
andrew.wei@monash.edu
Contact person for public queries
Name 43467 0
A/Prof Andrew Wei
Address 43467 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 43467 0
Australia
Phone 43467 0
+61 3 9076 3392
Fax 43467 0
Email 43467 0
andrew.wei@monash.edu
Contact person for scientific queries
Name 43468 0
A/Prof Andrew Wei
Address 43468 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 43468 0
Australia
Phone 43468 0
+61 3 9076 3392
Fax 43468 0
Email 43468 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
Individual patient data will not be shared publically. Aggregate patient data and final results will be presented in the final report
What supporting documents are/will be available?
Study protocol
Summary results
No Results