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Trial registered on ANZCTR


Registration number
ACTRN12623000851662p
Ethics application status
Not yet submitted
Date submitted
7/06/2023
Date registered
8/08/2023
Date last updated
8/08/2023
Date data sharing statement initially provided
8/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
ALLG AMLM28/D1: Achieving Durable remissions via Adaptive Pro-survival Targeting in Acute Myeloid Leukaemia (AML) (ADAPT): The ADAPT Platform trial - Domain 1
Scientific title
ALLG AMLM28/D1: Achieving Durable remissions via Adaptive Pro-survival Targeting in Acute Myeloid Leukaemia (AML) (ADAPT): The ADAPT Platform trial - Domain 1
Secondary ID [1] 309848 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia 330290 0
Condition category
Condition code
Cancer 327149 327149 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be enrolled into the AMLM28 Master Protocol and commence on Venetoclax and Azacitidine (VEN-AZA). Subsequent adaptive interventions will be based on the patient’s response to treatment after starting VEN-AZA.

Domain 1 is an experimental treatment arm within the AMLM28 ADAPT platform trial to determine the utility of adding navitoclax to VEN-AZA for patients with suboptimal response to VEN-AZA.
There will be two strata within this treatment arm:
· Stratum 1- AML with TP53 aberrations: TP53 mutation, del 17p or monosomy 17 identified. Patients may enter this stratum after at least 1 cycle of VEN-AZA
· Stratum 2- AML with MRD persistence: BM blasts less than 10 percent but with persistently detectable measurable residual disease greater than or equal to 0.1percent by end of cycle 4 of VEN-AZA by flow cytometry.

Domain 1 treatment schedule is the same for both strata includes treatment with VEN-AZA + Navitoclax and encompasses 2 phases noted below:

1. Safety run-in phase (for tolerability of navitoclax in combination with VEN-AZA)
- Navitoclax 100mg per day (oral tablet) - Days -14 to -8 in cycle 1 only
- Break (Days -7 to -1)
- Venetoclax 400 mg per day (oral tablet), days 1-14
- Azacitidine 75mg/m2 per day (intravenously), days 1-5.
- Navitoclax 100mg per day (oral tablet), Days 6 to 14

Dose tolerability will be assessed and lower levels of dosage of Navitoclax and Azacitidine can be explored:
- Navitoclax 100mg per day (oral tablet) in cycle 1 only (Day -14 to -8) + Azacitidine 37mg/m2 per day (intravenously), days 1-5
- Navitoclax 75mg per day (oral tablet) in cycle 1 only (Day -14 to -8) + Azacitidine 37mg/m2 per day (intravenously), days 1-5
- Venetoclax dose modification will not be explored
For patients with TP53 mutation, del(17p) or monosomy 17 and active disease (bone marrow blasts greater than or equal to 5%), a modified dosing schedule is permitted if the platelet count is greater than 25 x 10^9/L and less than 75 x 10^9/L:
- Venetoclax (oral tablet) 400 mg day 1-14
- Azacitidine (intravenously) 75mg/m2 per day 1-5
- Navitoclax (oral tablet) 50 mg per day D6-14 (D-14 to -8 in cycle 1 only)

The overall duration of study treatment is twelve cycles. Each cycle will be 28-days in length, commencing from VEN-AZA, apart from Cycle 1 which, when accounting for the Navitoclax monotherapy lead in, will be 42 days

2. Dose-expansion phase
Once the Recommended Phase 1 Dose (RP2D) is determined, enrolment into a dose-expansion phase may occur within 6 weeks of completion of the safety phase after approval from management committees specifically designated to the AMLM28 trial. Participants will receive the recommended dosing schedule for up to twelve 28-day cycles at the Recommended Phase 2 Dose (RP2D) determined in the safety run-in phase.

All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.
Intervention code [1] 326284 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335022 0
To establish a recommended phase 2 dose (RP2D) for the expansion phase of this domain, assessed by incidence of dose limiting toxicities (DLT) during the first cycle of treatment.
Dose limiting toxicity assessed by the occurrence of treatment-emergent adverse events (TEAEs) graded by the trial management committee (TMC) per the following definitions:
1) Grade 4 neutropenia and-or thrombocytopenia in the absence of MDS or AML that persists for 21 days or more after the last dose of drug in cycle 1 and is considered related to study therapy
2) Grade 3 non-haematological toxicity or higher occurring in cycle 1 that is considered related to study therapy and does not resolve to Grade 1 or less within 7 days despite medical management and-or is deemed clinically significant by the TMC.
Timepoint [1] 335022 0
The occurrence of dose-limiting toxicities (DLTs) assessed at any time during the first treatment cycle (cycle 1)
Primary outcome [2] 335023 0
Stratum 1- AML with TP53 aberrations:
Overall survival (OS)
Timepoint [2] 335023 0
OS is measured from day 1 of therapy to the date of death from any cause
Primary outcome [3] 335024 0
Stratum 2- AML with Measurable Residucal Disease (MRD) persistence:
Progression free survival (PFS) as assessed by blood tests.
Timepoint [3] 335024 0
PFS is measured in days from day 1 of therapy to the earliest date of progression (morphologic relapse) or date of death without prior progression.
Secondary outcome [1] 422746 0
Assess safety and tolerability of navitoclax treatment combined with VEN-AZA. Adverse events will be assessed at each treatment visit.
The occurrence of related Common Terminology Criteria for Adverse Events (CTCAE) (V5) grade 2-5 non-haematologic adverse events.
The occurrence of related CTCAE (V5) grade 3-5 neutropenia or thrombocytopenia or grade 3-5 febrile neutropenia.
Timepoint [1] 422746 0
Adverse events will be assessed at each treatment visit, scheduled on days 4, 8, 11, 15, 18, 22, 25, 28 post-commencement of intervention.
Secondary outcome [2] 422747 0
Overall Survival (for stratum 2: AML with MRD persistence)
Timepoint [2] 422747 0
OS is measured from day 1 of therapy to the date of death from any cause
Secondary outcome [3] 422748 0
Assess Quality of Life (QOL) using questionnaires European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EQ-5D. Both measures will be assessed as a composite secondary outcome
Timepoint [3] 422748 0
At baseline, Day 1 of treatment cycle 2, Day 1 of treatment cycle 4, Day 1 of treatment cycle 7 and Day 1 of treatment cycle 10

Eligibility
Key inclusion criteria
1. Meets inclusion criteria outlined in the AMLM28 ADAPT Master Protocol
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
3. Presence of either of the following criteria:
a. Mutated TP53, del17p or monosomy 17 at diagnosis (stratum 1). Patients eligible for this stratum can enroll after at least 1 cycle of VEN-AZA.
b. Less than 10percent BM blasts but with persistently detectable measurable residual disease more than or equal to 0.1percent by end of cycle 4 of VEN-AZA by flow cytometry (stratum 2)
4. Adequate renal function as demonstrated by a creatinine clearance more than or equal to 30 ml per minute; calculated by the Cockroft Gault formula or measured by 24-hour urine collection
5. Adequate liver function as demonstrated by
a. Aspartate aminotransferase (AST) less than or equal to 3.0 x Upper Limit Normal (ULN)
b. Alanine aminotransferase (ALT) less than or equal to 3.0 x ULN
c. Bilirubin less than or equal to 2.0 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
6. Platelet count criteria
a. For patients enrolling to stratum 1 with BM blasts greater than or equal to 5percent at domain entry: platelet count greater than or equal to 25 x 10^9 per Litre (L)
b. For all other patients, platelet count greater than or equal to 75 x 10^9 per L
7. Neutrophil count criteria
a. For patients with BM blasts greater than 5 percent, neutrophil count greater than or equal to 0.5 x 10^9 per L
8. Coagulation profile: Activated Partial Thromboplastin Clotting Time (APTT) and Prothrombin Time (PT) less than or equal to 1.5 x ULN
9. Patient agrees to follow the recommended contraception procedures for this domain, see below:
Female patients must be either:
a) postmenopausal defined as:
i. Age more than 55 years with no menses for 12 or more months without an alternative medical cause.
ii. Age less than or equal to 55 years with no menses for 12 or more months without an alternative medical cause AND an Follicle Stimulating Hormone (FSH) level greater than 40 International Units (IU) per L
OR
b) Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
OR
c) Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control starting at day 1 through at least 180 days after the last dose of study drug.
Male patients who are sexually active, must agree, from day 1 through at least 180 days after the last dose of study drug, to practice the protocol specified Contraception outlined below. Male patients must agree to refrain from sperm donation from initial study drug administration through at least 90 days after the last dose of study drug.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Presence of any general exclusion criteria outlined in the AMLM28 ADAPT Master Protocol
2. Prior allogeneic stem cell transplantation for AML
3. WCC greater than 25 x 10^9 per L. Hydroxyurea and/or thioguanine may be used for cytoreduction.
4. The patient is unable to swallow tablets, or has malabsorptive issues that in the investigator’s opinion will interfere with absorption of study drugs
5. 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: patients 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.
6. 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 are prohibited
7. 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
8. Treatment with prior anti-leukemic therapy within 14 days prior to the first dose of study drug.
9. History of other malignancy requiring active systemic treatment, or which is likely to result in an expected survival time of less than 2 years.
10. The patient is HIV positive
11. Known hypersensitivity to any of the investigational agents
12. The patient has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation
13. Patient requiring medical treatment with antiplatelet or anticoagulants, or herbal supplement that affects platelet function within 7 days prior to the first dose of study drug.
14. Patient has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or patient with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or gated cardiac blood pool scan performed within 1 month prior to study entry results in a left ventricular ejection fraction that is greater than or equal to 45percent.
15. Active bleeding or history of major bleeding (Grade 3 or above) within the last 12 months

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/02/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 314034 0
Other Collaborative groups
Name [1] 314034 0
Australasian Leukaemia and Lymphoma Group (ALLG)
Country [1] 314034 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
ALLG Ground floor, 35 Elizabeth St Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 315924 0
None
Name [1] 315924 0
None
Address [1] 315924 0
None
Country [1] 315924 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 313168 0
Peter MacCallum Cancer Centre Ethics Committee
Ethics committee address [1] 313168 0
305 Grattan Street, Melbourne VIC 3000
Ethics committee country [1] 313168 0
Australia
Date submitted for ethics approval [1] 313168 0
25/09/2023
Approval date [1] 313168 0
Ethics approval number [1] 313168 0

Summary
Brief summary
This platform trial aims to provide an overarching research framework that will enable research questions to be addressed prospectively and systematically for AML patients receiving VEN-AZA. Domain 1 of the AMLM28 ADAPT platform trial aims to determine the utility of adding navitoclax to VEN-AZA for patients with suboptimal response to VEN-AZA by offering therapeutic interventions for patients with TP53 aberrations or MRD persistence..

Who is it for?
You may be eligible for this study if you are aged 18 and above and have been diagnosed with AML.

Study details
Domain 1 (ADAPT-Rx) consists of two different strata:
- TP53 stratum - Patients who are found to have TP53 aberrations during or after cycle 1 may be eligible
- Measurable Residual Disease (MRD) persistence stratum
Participants who are eligible to commence Domain 1 ADAPT-Rx therapy for either strata will receive an oral dose of navitoclax once daily for 7 days prior to commencing the VEN-AZA and Navitoclax (from day 6) treatment cycle,

All patients will initially be enrolled into the AMLM28 Master Protocol.
If during or after cycle 1 VEN-AZA, the patient is found to have one or more TP53 aberrations, the patients may be assessed for eligibility to commence Domain 1 ADAPT-Rx therapy (TP53 stratum).

If after cycle 4, the patient is found to have persistent MRD by flow cytometry, the patient may be assessed for eligibility to commence Domain 1 ADAPT-Rx therapy (MRD persistence stratum).

If more than 1 treatment arm is open to recruitment in domain 1, and if the patient is eligible for more than 1 treatment arm, the patient will be randomised to one of the available treatment arms. The patient will then be given the consent form for that treatment arm and screened. If the patient passes screening, they will be registered to that treatment arm. If the patient fails screening, they will be randomised to another treatment arm and screened accordingly.


It is hoped this research will deliver adaptive interventions to improve clinical outcomes in patients receiving frontline VEN-AZA for newly diagnosed AML.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127230 0
A/Prof Andrew Wei
Address 127230 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 127230 0
Australia
Phone 127230 0
+61 3 8559 5000
Fax 127230 0
Email 127230 0
andrew.wei@petermac.org
Contact person for public queries
Name 127231 0
Ms Delaine Smith
Address 127231 0
Australasian Leukaemia and Lymphoma Group
Ground Floor, 35 Elizabeth Street
Richmond VIC 3121
Country 127231 0
Australia
Phone 127231 0
+61 3 8373 9701
Fax 127231 0
Email 127231 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 127232 0
Ms Delaine Smith
Address 127232 0
Australasian Leukaemia and Lymphoma Group
Ground Floor, 35 Elizabeth Street
Richmond VIC 3121
Country 127232 0
Australia
Phone 127232 0
+61 3 8373 9701
Fax 127232 0
Email 127232 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
Individual patient data will not be shared publicly. Aggregate patient data and final results will be presented in the final report.


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.