Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000006549
Ethics application status
Approved
Date submitted
6/11/2023
Date registered
8/01/2024
Date last updated
26/05/2024
Date data sharing statement initially provided
8/01/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM26/T3 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - Low-dose cytarabine (LDAC) + Venetoclax
Scientific title
AMLM26/T3- INTERCEPT (Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in Acute Myeloid Leukaemia (AML)): A Multi-arm, Precision-based, Recursive, Platform Trial - LDAC + Venetoclax
Secondary ID [1] 310868 0
AMLM26/T3-INTERCEPT
Universal Trial Number (UTN)
Trial acronym
Linked study record
ACTRN12621000439842 is the AMLM26 Intercept Master Protocol. The AMLM26 Intercept trial is a platform trial investigating many new investigational agents and combinations for AML patients with rising measurable residual disease (MRD) or early morphologic relapse. The treatment arm described in this registration form is for one treatment arm included on the platform - LDAC + Venetoclax

Health condition
Health condition(s) or problem(s) studied:
acute myeloid leukaemia 331908 0
Condition category
Condition code
Cancer 328642 328642 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The ALLG AMLM26 INTERCEPT trial is an adaptive trial allowing the testing of multiple new therapeutic options targeting various AML biomarkers in a staged manner. The Master Protocol outlines the overall study structure (this is detailed in ANZCTR entry ACTRN12621000439842). There will be separate domains for each AML biomarker being investigated. Each domain will have at least one investigational agent. Each investigational agent may be used on its own and/or in combination with other agents. Each option will be a different treatment arm within a domain. Separate Therapy-Specific Protocol Appendices will include treatment-specific information for each investigational agent including all of the treatment arms specific to that investigational agent. Each treatment arm may be targeted to a specific AML biomarker (domain) and/or may be used when patients have no targetable option available. This entry is for the treatment arm LDAC + Venetoclax.

Each cycle will be 28-days in length. Venetoclax will be administered orally once daily Days 1–28, of a 28-day cycle for 12 cycles, with a designated dose of 600 mg daily. Please note that Venetoclax dose ramp-up is required only for patients commencing therapy with bone marrow blasts of greater than or equal to 5%: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3 and 600 mg on day 4 onwards. LDAC (20 mg/m2) is administered subcutaneously once daily following administration of Venetoclax on Days 1-10 of every cycle.

Patients will be asked to complete a dose diary to confirm the tablets were taken. Patients will also be asked to return the LDAC and Venetoclax bottles (with unused tablets or empty containers) to the hospital. This is to monitor compliance with the treatment.
Intervention code [1] 327286 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336439 0
To determine the MRD response of patients with NPM1 mutated AML in the MRD failure stratum to their first-exposure to decision rule guided therapy with LDAC + Venetoclax.
Timepoint [1] 336439 0
The primary endpoint is MRD response within 100 days of Cycle 1 Day 1. MRD response is defined as a reduction of greater than or equal to 1-log in the molecular marker, and/or MRD negativity, or less than 0.1% aberrant disease by flow cytometry
Secondary outcome [1] 428549 0
To determine the durability of the response of AML patients to LDAC + Venetoclax
Timepoint [1] 428549 0
Relapse-free survival (RFS): Measured from the date of molecular response to the earlier of the date of progression or the date of death without prior progression. MRD response is defined as a reduction of greater than or equal to 1-log in the molecular marker, and/or MRD negativity, or less than 0.1% aberrant disease by flow cytometry. This is measured by bone marrow and blood samples. Your disease will continue to be followed until the study is completed (this may be for longer than 5years).
Secondary outcome [2] 428550 0
To investigate the dynamics of MRD response and the duration of clinical benefit as a composite outcome in the morphologic and MRD failure strata
Timepoint [2] 428550 0
Time to MRD response will be assessed at end of cycle 1,2,3, and 12, end of months 18 and 24 post treatment commencement.
Secondary outcome [3] 428552 0
To investigate duration of MRD response in patients treated at MRD failure versus morphologic relapse.
Timepoint [3] 428552 0
Duration of MRD response measured from the date of MRD response to the earliest date of MRD failure or the date of death without prior progression
Secondary outcome [4] 428553 0
To investigate the efficacy of distinct treatment sequences in AML patients who fail one or more lines of therapy on study.
Timepoint [4] 428553 0
For each patient, relapse-free periods will be calculated using the same definitions of response and relapse as for the primary and key-secondary endpoints. Patients will continue to have their disease status followed until the end of the trial, (this may be for longer than 5 years)
Secondary outcome [5] 428554 0
To determine the overall efficacy of the platform as an evolving system for managing patients with AML
Timepoint [5] 428554 0
Overall survival as measured from the date of first dose of study drug until the date of last contact or death. Patients will continue to have their survival status followed until the end of the trial under the Master Protocol
Secondary outcome [6] 428555 0
Quality of Life will be measured as a composite outcome via the use of 2 quality of life tools.
Timepoint [6] 428555 0
Quality of Life (QoL) measured using QLQ-C30 & EQ-5D Day 1 of cycle 1, day 1 of cycle 2 and day 1 of cycle 3.

Eligibility
Key inclusion criteria
1. Meets inclusion criteria outlined in the AMLM26 Master Protocol (see ACTRN12621000439842 for details on the master protocol)
2. ECOG 0-2
3. 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
4. Subject must have adequate liver function as demonstrated by below, unless considered to be due to leukemic organ involvement
a. aspartate aminotransferase (AST) less than or equal to 3.0 × Upper Limit Normal (ULN)
b. alanine aminotransferase (ALT) less than or equal to 3.0 × ULN
c. bilirubin less than or equal to 1.5 × ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
5. Female subjects must be either postmenopausal defined as:
a. Age greater than 55 years with no menses for 12 or more months without an alternative medical cause.
b. Age less than or equal to 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level greater than 40 IU/L.
OR
c. Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
OR
d. A Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control starting at Study Day 1 through at least 180 days after the last dose of study drug.
6. Male subjects who are sexually active with a WOCBP, even if the male subject has undergone a successful vasectomy, must agree from Study Day 1 through at least 180 days after the last dose of study drug to use condoms and his female partner(s) must use at least one of the contraceptive measures (as defined in the protocol for female study subjects of childbearing potential). Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 180 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 AMLM26 INTERCEPT Master Protocol (see ACTRN12621000439842 for details on the master protocol)
2. Prior use of venetoclax with LDAC/HMA is allowed unless demonstrated to be refractory to this combination. Prior venetoclax monotherapy is allowed.
3. Subject is HIV positive
4. Prior allogeneic stem cell transplantation within 30 days of post-conditioning or on immunosuppression for graft vs host disease (GVHD) (except for sole immunosuppression with prednisolone of <10mg/day for GVHD management which is permitted)
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: 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) or patients who have past exposure to HepB (HBs antigen negative but HBc antibody positive and DNA negative) who do not require treatment 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 days prior to cycle 1 day 1. They are prohibited during venetoclax dose ramp-up in all phases. At other times they may be used if required with caution and with appropriate dose modifications for venetoclax
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 (except steroids see exclusion 5a)
9. Subject has been diagnosed with another malignancy, unless disease-free for at least 2 years and not needing active treatment. Subjects with fully excised BCC/SCC/CIN or other minor malignancy are not excluded.
10. Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation
11. Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject 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 45%.

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/06/2024
Actual
Date of last participant enrolment
Anticipated
3/06/2027
Actual
Date of last data collection
Anticipated
3/06/2028
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 25950 0
New Zealand
State/province [1] 25950 0

Funding & Sponsors
Funding source category [1] 315128 0
Other Collaborative groups
Name [1] 315128 0
Australasian Leukaemia & Lymphoma Group
Country [1] 315128 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia & Lymphoma Group
Address
Ground Floor, 35 Elizabeth St, Richmond VIC, 3121
Country
Australia
Secondary sponsor category [1] 317143 0
None
Name [1] 317143 0
Address [1] 317143 0
Country [1] 317143 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314067 0
the Alfred Hospital Ethics Committee
Ethics committee address [1] 314067 0
55 Commercial Road Melbourne, VIC 3004
Ethics committee country [1] 314067 0
Australia
Date submitted for ethics approval [1] 314067 0
21/07/2022
Approval date [1] 314067 0
29/09/2022
Ethics approval number [1] 314067 0
Ethics committee name [2] 314090 0
Bellberry Limited
Ethics committee address [2] 314090 0
123 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [2] 314090 0
Australia
Date submitted for ethics approval [2] 314090 0
10/11/2022
Approval date [2] 314090 0
13/02/2023
Ethics approval number [2] 314090 0
Ethics committee name [3] 314091 0
Central Adelaide Local Health Network HREC
Ethics committee address [3] 314091 0
Level 3 Roma Mitchell Building 136 North Terrace, Adelaide SA 5000
Ethics committee country [3] 314091 0
Australia
Date submitted for ethics approval [3] 314091 0
04/10/2023
Approval date [3] 314091 0
18/10/2023
Ethics approval number [3] 314091 0

Summary
Brief summary
This is a combination drug treatment arm within the ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842. The combination of Low dose cytarabine (LDAC) and venetoclax will be evaluated for its activity in a population of participants with progressive acute myeloid leukemia (AML).

Who is it for?
You may be eligible for to receive this treatment if you are a part of the AMLM26 Intercept trial which is registered on ANZCTR with ID ACTRN12621000439842 (ie if you are aged 18 or older, you have been diagnosed with progressive acute myeloid leukemia, and are currently in your first or second morphologic remission with a known and trackable minimal residual disease (MRD) marker.). If you are on the AMLM26 Intercept trial you may be eligible for this treatment option if your disease is worsening. The trial management committee will review your disease characteristics and determine your best treatment option(s) available on the trial.

Study details:
Venetoclax will be administered orally once daily (QD) Days 1–28, of a 28-day cycle, with a designated dose of 600 mg daily. Please note that Venetoclax dose ramp-up is required only for patients commencing therapy with bone marrow blasts of greater than or equal to 5%: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3 and 600 mg on day 4 onwards.
LDAC (20 mg/m2) is administered subcutaneously (SC) QD following administration of Venetoclax on Days 1-10 of every cycle

Participants will undergo a disease assessment at screening after cycle 1, cycle 2, cycle 3, cycle 6 and then 2 monthly until progression. This will require blood tests and bone marrow biopsies. Safety and tolerability of treatment will be assessed throughout the trial whilst you are receiving treatment. Health related quality of life during treatment will be assessed on the first treatment day of 3 consecutive cycles.

This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that Low dose cytarabine and Venetoclax will be well tolerated and may improve outcomes for future patients, however, there may be no clear benefit from participation in this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130286 0
Prof Andrew Wei
Address 130286 0
Peter MacCallum Cancer Centre 305 Grattan Street Melbourne VIC 3000
Country 130286 0
Australia
Phone 130286 0
+61 3 8559 7915
Fax 130286 0
Email 130286 0
andrew.wei@petermac.org
Contact person for public queries
Name 130287 0
Ms Delaine Smith
Address 130287 0
Australasian Leukaemia & Lymphoma Group 35 Elizabeth St, Richmond VIC 3121
Country 130287 0
Australia
Phone 130287 0
+61 383739702
Fax 130287 0
Email 130287 0
info@allg.org.au
Contact person for scientific queries
Name 130288 0
Ms Delaine Smith
Address 130288 0
Australasian Leukaemia & Lymphoma Group 35 Elizabeth St, Richmond VIC 3121
Country 130288 0
Australia
Phone 130288 0
+61 383739702
Fax 130288 0
Email 130288 0
info@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.