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Trial registered on ANZCTR


Registration number
ACTRN12619001655134p
Ethics application status
Not yet submitted
Date submitted
15/10/2019
Date registered
27/11/2019
Date last updated
27/11/2019
Date data sharing statement initially provided
27/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study investigating different combinations of Cytarabine, Midistaurin, Pracinostat and Venetoclax in elderly patients with Acute Myeloid Leukaemia to extend remission.
Scientific title
AMLM25: An ALLG Phase 2 study to Investigate Novel Triplets to Extend Remission with VENetoclax in Elderly (INTERVENE) Acute Myeloid Leukaemia
Secondary ID [1] 299043 0
AMLM25
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia 314060 0
Condition category
Condition code
Cancer 312446 312446 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial will be run in two parts.
Depending on which Part of the trial is open for recruitment, patients eligible after screening will be registered to either
1. Part 1 - The dose finding Run-in phase or
2. Part 2 - The randomised phase 2 study

Patients will be put into groups according to cytogenetic risk. If cytogenetic results are not available or not informative, patients will be allocated to the adverse risk group.

Part 1 -The run-in phase will examine:

1. For non-adverse risk patients: Low dose Cytarabine (LDAC) + venetoclax + midostaurin
LDAC 20mg/m2 subcutaneously on Days 1-10
Venetoclax either 400mg (tablets) daily on days 1-28 or 600mg (tablets) daily on Days 1-28
Midostaurin 50mg (tablets) daily o days 11-28 or 50mg (tablets) twice a day on days 11-28.
The dose will depend on which group the patient is in and how well tolerated the different levels are.
2. For adverse risk patients: Low dose Cytarabine + venetoclax + pracinostat (This category includes patients with no cytogenetic analysis available at screening)
LDAC 20mg/m2 subcutaneously on Days 1-10
Venetoclax either 400mg (tablets) daily on days 1-28 or 600mg (tablets) daily on Days 1-28
Pracinostat 45mg (tablets) daily on days 10,12,14,17,19,21 or 45mg (tablets) daily on days 10,12,14,17,19,21,24,26,28


If initial triplet dose levels are deemed intolerable, other dose schedules will be explored. These will include shorter durations of exposure of either midostaurin or pracinostat.

In this manner, the run-in phase will determine the recommended phase 2 dose (RP2D) of Low dose Cytarabine + Venetoclax with midostaurin or pracinostat


In Part 2 - phase 2, eligible patients will be stratified based on their karyotype and randomised 2:1 to either:

Low dose Cytarabine + venetoclax + midostaurin (non-adverse karyotype) or
Low dose Cytarabine + venetoclax + pracinostat (adverse karyotype) versus
Low dose Cytarabine + venetoclax (comparator arm).

Drug schedules:

1. Low dose Cytarabine + venetoclax + midostaurin
a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle.
b. Venetoclax (Tablets) RP2D (will be gradually increased each day Day1-3/4)
Depending on dose of Venetoclax the ramp up will be as follows.
For the venetoclax 400mg dose level:
• In cycle 1, venetoclax will be administered with a 3-day ramp up beginning with 100mg dose on Day 1, 200mg dose on Day 2, 400mg dose on Day 3. Venetoclax will continue at 400mg daily thereafter.
For the venetoclax 600mg dose level:
• In cycle 1, venetoclax will be administered with a 4-day ramp up beginning with 100mg on Day 1, 200mg on Day 2, 400mg on Day 3 and 600mg on Day 4. Venetoclax will continue at 600mg daily thereafter.


c. Midostaurin (Tablets) RP2D

2. LDAC + venetoclax + pracinostat (Tablets)
a. LDAC 20mg/m2 sc daily D1-10 of each cycle.
b. Venetoclax RP2D (r(will be gradually increased each day Day1-3/4)
Depending on dose of Venetoclax the ramp up will be as follows.
For the venetoclax 400mg dose level:
• In cycle 1, venetoclax will be administered with a 3-day ramp up beginning with 100mg dose on Day 1, 200mg dose on Day 2, 400mg dose on Day 3. Venetoclax will continue at 400mg daily thereafter.
For the venetoclax 600mg dose level:
• In cycle 1, venetoclax will be administered with a 4-day ramp up beginning with 100mg on Day 1, 200mg on Day 2, 400mg on Day 3 and 600mg on Day 4. Venetoclax will continue at 600mg daily thereafter.
c. Pracinostat RP2D

3. LDAC + venetoclax
a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle.
b. Venetoclax 600mg (Tablets) D1-28 (will be gradually increased each day Day1-4)
Venetoclax will be administered with a 4-day ramp up beginning with 100mg on Day 1, 200mg on Day 2, 400mg on Day 3 and 600mg on Day 4.

Each cycle will be 28 days in length.
Intervention code [1] 315518 0
Treatment: Drugs
Comparator / control treatment
Low dose Cytarabine + venetoclax
a. Low dose Cytarabine 20mg/m2 subcutaneously daily D1-10 of each cycle.
b. Venetoclax 600mg (Tablets) D1-28 (ramp up in cycle 1 only)
Control group
Active

Outcomes
Primary outcome [1] 321334 0
Part 1
For patients receiving Midostaurin, the occurrence of dose-limiting toxicity (DLT). This will be assessed by observing the patients blood results and adverse events.
Timepoint [1] 321334 0
During Cycle 1 of the run in Phase (Part 1) Daily from baseline to the end of cycle 1.
Primary outcome [2] 321335 0
Part 2
Achievement of a clinical response.
Response will be assessed with a bone marrow aspirate and biopsy.
Timepoint [2] 321335 0
To be measured within the first four cycles of therapy of the randomised phase (Part 2)
From baseline until the end of cycle 4, e.g. after each cycle from baseline to end of cycle 4.
Primary outcome [3] 321979 0
For patients receiving Pracinostat, the occurrence of dose-limiting toxicity (DLT). This will be assessed by observing the patients blood results and adverse events.
Timepoint [3] 321979 0
During Cycle 1 of the run in Phase (Part 1) Daily from baseline to the end of cycle 1.
Secondary outcome [1] 374692 0
Occurrence of related non-haematologic adverse events, neutropenia or thrombocytopenia febrile neutropenia. These will be assessed by observing the participants medical records, blood results and medical exams. The participant may also report such events.
Timepoint [1] 374692 0
To be measured during Part 2 of the trial for each patient from baseline until 30 days after the administration of the last study treatment.
Secondary outcome [2] 374693 0
OS (Overall Survival)
Timepoint [2] 374693 0
To be recorded from the time of registration until the time of last contact.

Eligibility
Key inclusion criteria
- Age, greater than or equal to 60 years.
- AML (excluding acute promyelocytic leukaemia and core binding factor AML) stratified by MRC 2010 criteria
a. Non-adverse cytogenetic risk or
b. Adverse cytogenetic risk (inclusive of failed cytogenetic analysis)
- ECOG performance status 0-2
- No prior treatment for AML (except hydroxyurea or thioguanine)
- Adequate liver function (AST or ALT less than 1.5x ULN and bilirubin les than or equal to 1.5x ULN*). *unless considered related to AML or Gilbert’s syndrome
- Adequate renal function as demonstrated by a Cockcroft Gault formula creatinine clearance of greater than 30mL/min.
Minimum age
60 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Any serious medical, psychological or social problem which the investigator feels may interfere with the procedures or evaluations of the study including:
a. Malabsorption syndrome or other condition that precludes enteral route of administration
b. Significant cardiovascular disability status of New York Heart Association Class greater than 2.
c. Significant chronic respiratory disease that requires continuous oxygen
- WBC greater than 25x109/L. Hydroxyurea may be used to control the white blood cell count
- Acute promyelocytic leukaemia
- Core binding factor AML including t(8;21)(q22;q22) or inv(16)(p13. 1q22)/t(16;16)(p13.1;q22)
- Antecedent chronic myeloid leukaemia (CML) or CML in blast phase
- Antecedent myelofibrosis (including primary and secondary)
- Active CNS leukaemia
- Prior exposure to venetoclax, FLT3 inhibitors or pracinostat
- Exposure to other investigational agents within 30 days or 5 half lives
- Known hypersensitivity to any of the investigational agents
- History of other malignancy requiring active systemic treatment or which is likely to result in an expected survival time of less than 2 years
- Subject is known to be positive for HIV
- Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
a. Clinically significant active systemic infection (viral, bacterial or fungal) requiring therapy
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
- Active bleeding or clinically relevant prolongation of APTT or INR
- QT-interval corrected according to Fridericia’s formula (QTcF) greater than 450ms
- 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 cytochrome P450 3A (CYP3A inhibitors)
c. Moderate or strong CYP3A inducers
- 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
- (For Pracinostat containing arm only) Current smokers (use of patches, chewing gums or vaping nicotine containing fluids is permitted). Patients who stopped smoking at least 8 days prior to first pracinostat dosing can be enrolled, provided they refrain from smoking during the whole study.
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 4 months after stopping medication. Highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
c. Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject
d. Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
e. In case of use of oral contraception women should also add a barrier method of contraception, particularly as it is currently unknown whether midostaurin may reduce the effectiveness of hormonal contraceptives.
f. Sexually-active males unless they use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment to avoid conception or embryo-fetal harm.

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 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
Recruitment outside Australia
Country [1] 21848 0
New Zealand
State/province [1] 21848 0

Funding & Sponsors
Funding source category [1] 303579 0
Government body
Name [1] 303579 0
Medical Research Future Fund (MRFF)
Address [1] 303579 0
Department of Health
GPO Box 9848
Canberra ACT 2601
Australia
Country [1] 303579 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The Australasian Leukaemia and Lymphoma Group
Address
ALLG
35 Elizabeth St
Richmond
VIC 3121
Country
Australia
Secondary sponsor category [1] 303662 0
None
Name [1] 303662 0
Address [1] 303662 0
Country [1] 303662 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 304108 0
ALFRED HEALTH HREC
Ethics committee address [1] 304108 0
Alfred Health
55 Commercial Rd,
Melbourne VIC 3004
Ethics committee country [1] 304108 0
Australia
Date submitted for ethics approval [1] 304108 0
02/12/2019
Approval date [1] 304108 0
Ethics approval number [1] 304108 0

Summary
Brief summary
The purpose of this study is to investigate the combination and efficacy and safety of Low dose Cytarabine, Venetoclax, Midostaurin and Pracinostat in patients with acute myeloid Leukaemia (AML).

Who is it for?
You may be eligible for this study if you are an adult over 60 years of age who has been diagnosed with AML, with no previous chemotherapy treatment.

Study details
Participants in this study will receive the following treatments:
Depending on which Part of the trial is open for recruitment, patients eligible after screening will be registered to either
1. Part 1 - The dose finding Run-in phase or
2. Part 2 - The randomised phase 2 study

The Run-Phase patients will receive either:
LDAC (Low dose cytarabine) + venetoclax + midostaurin
or
LDAC (Low dose cytarabine) + venetoclax + pracinostat

The Randomised Phase patients will receive:
1. LDAC + venetoclax (Tablets) + midostaurin (Tablets)
a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle.
b. Venetoclax (Tablets) RP2D (ramp up in cycle 1 only)
c. Midostaurin (Tablets) RP2D
or
2. LDAC + venetoclax + pracinostat
a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle.
b. Venetoclax (Tablets)RP2D (ramp up in cycle 1 only)
c. Pracinostat (Tablets) RP2D
or
3. LDAC + venetoclax
a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle.
b. Venetoclax 600mg (Tablets)D1-28 (ramp up in cycle 1 only)

All participants will undertake blood tests, bone marrow biopsies and questionnaires.
This study aims to establish whether the combination of treatments, can control the disease more effectively for a longer duration.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95834 0
A/Prof Andrew Wei
Address 95834 0
The Alfred Hospital
Commercial Road,
Melbourne
VIC 3004
Country 95834 0
Australia
Phone 95834 0
+61 3 9076 3451
Fax 95834 0
Email 95834 0
delaine.smith@allg.org.au
Contact person for public queries
Name 95835 0
Ms Delaine Smith
Address 95835 0
ALLG
35 Elizabeth St
Richmond
VIC 3121
Country 95835 0
Australia
Phone 95835 0
+61 3 8373 9701
Fax 95835 0
Email 95835 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 95836 0
Ms Delaine Smith
Address 95836 0
ALLG
35 Elizabeth St
Richmond
VIC 3121
Country 95836 0
Australia
Phone 95836 0
+61 3 8373 9701
Fax 95836 0
Email 95836 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