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Trial registered on ANZCTR


Registration number
ACTRN12621000439842p
Ethics application status
Submitted, not yet approved
Date submitted
7/12/2020
Date registered
16/04/2021
Date last updated
16/04/2021
Date data sharing statement initially provided
16/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM26 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - The Master Protocol
Scientific title
AMLM26- INTERCEPT (Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in AML): A Multi-arm, Precision-based, Recursive, Platform Trial - The Master Protocol
Secondary ID [1] 303382 0
nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia (AML) 319994 0
Condition category
Condition code
Cancer 317930 317930 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The INTERCEPT study is a multi-domain, multi-arm, platform trial. This master protocol will govern the development and management of an adaptive clinical trial platform that will screen novel therapeutic combinations to demonstrate recurrent and sequential anti-leukaemic activity using MRD (minimal residual disease) technologies to provide proof of concept. This protocol allows patients to rotate from one treatment arm to another, when there is evidence of MRD progression.
Patients enter the study in first or second morphologic remission(CR or CRi) with known and trackable MRD marker(s). The relevant MRD marker(s) will be monitored as per standard practice until evidence of MRD failure and/or morphological relapse. MRD monitoring could be performed every 1-3 months for approximately 2-3 years. For some MRD markers, it may be more appropriate to monitor bone marrow e.g. every 3 months for at least 12 months. Monitoring will occur as per standard practice at the site. They will then be allocated to the best available treatment option at the time.
As a platform trial, new treatment arms may be added, as well as the removal of futile therapeutic options. New targeted treatment domains may be created when there is sufficient evidence available to enable biomarker-driven enrichment cohorts to be accrued to more rapidly.
In domains with a single treatment arm, proof of concept analyses of the primary efficacy endpoint will commence after the first 10 patients have had the required assessments or withdrawn earlier. In domains with more than one treatment arm and with a pre-planned comparison of the arms, the timing of the first analysis will be determined when these arms are added to the trial and information included in the specific treatment arm's linked ANZCTR entry. Treatment arms that commence with an EffTox design during a run-in period will have the timing of the first analysis and the frequency of subsequent analyses specified in the specific treatment arm's linked ANZCTR entry. Unless a domain or a treatment arm within a domain is stopped early for futility or overwhelming evidence of efficacy, the main analysis of the primary endpoint in a domain will usually occur when 50 patients have had the required assessments or have withdrawn early. Continuation of an efficacious treatment arm may be assessed if either new or rotated patients are likely to benefit from continued access to it.

A treatment arm will close due to the following reasons-
• Inadequate recruitment once a consistent accrual rate has been established
• The treatment arm is determined by the Trial Management Committee(TMC) and Safety Data Monitoring Committee (SDMC) to be excessively toxic.
• In treatment arms without a safety run-in and after at least 10 patients have commenced therapy in the treatment arm, greater than or equal to 33% incidence of adverse events that are either grade 3+ non-haematological toxicities considered drug related and not resolving to grade 2 within 14 days, or, grade 4 neutropenia and/or thrombocytopenia lasting greater than 21 days after drug cessation and not related to myeloid disease e.g. AML/MDS. If the pilot or phase 2/3 recruitment has been completed and there is a low likelihood that the experimental therapy will improve outcomes (futility)
• If the pilot or phase 2/3 recruitment has been completed and there is evidence of overwhelming efficacy (superiority)
• If the pilot or phase 2/3 recruitment has been completed and the pharmaceutical collaborator wishes to graduate the experimental therapy into an independent clinical trial
• There is mutual agreement to close the study arm by the TMC and the pharmaceutical collaborator
• Evidence becomes available during the accrual phase of the treatment arm, which clearly demonstrates that it is unethical to continue to treat patients on the trial arm.
• There is evidence at interim analysis of inferiority of the treatment arm
Intervention code [1] 319248 0
Early detection / Screening
Comparator / control treatment
no control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325933 0
To determine the response of AML patients to their first-line of targeted therapy on study. In patients with marrow blasts greater than or equal to 5% prior to the start of therapy, morphologic response (CR, CRi, CRh or MLFS).
In patients with rising minimal residual disease prior to the start of therapy a reduction = 1-log in the molecular marker, and/or minimal residual disease negativity, or less than 0.1% aberrant disease by flow cytometry.
For either stratum, the response must be achieved within 100 days of the first dose of study therapy.
Timepoint [1] 325933 0
response must be achieved within 100days of the first dose of study therapy. Once treatment has commenced, response will be assessed at minimum at the end of months 1, 3, 6 and 3monthly thereafter.
Secondary outcome [1] 389589 0
to determine the durability of the response of AML patients to their first-line of targeted therapy on study
Timepoint [1] 389589 0
relapse free survival (RFS): measured from the date of response to the earliest date of progression or date of death without prior progression. Patients will be monitored until date of death. Due to the nature of arms being added and removed from the study platform the timeline for the trial is ongoing, we anticipate the study to continue whilst funding is maintained.
Secondary outcome [2] 389590 0
to characterize the safety and tolerability of targeted therapies
Timepoint [2] 389590 0
occurrence of newly occurring or worsening related CTCAE grade 3-5 non hematologic adverse events and related CTCAE grade 4-5 neutropenia or thrombocytopenia or grade 3-5 febrile neutropenia at any time in the first 100 days on therapy.
Secondary outcome [3] 389591 0
to investigate the efficacy of distinct treatment sequences in AML patients who fail one or more lines of therapy on study. Relapse is assessed by a physical exam, bone marrow biopsy and peripheral blood sample to review presence of extramedullary disease, minimal residual disease and blast, neutrophil and platelet counts
Timepoint [3] 389591 0
Relapse free periods will be calculated. (measured from date of response to the earliest date of progression or date of death without prior progression). Once patients have completed treatment and enter follow up, their disease status will be assessed every 3 months until death. Due to the nature of arms being added and removed from the study platform the timeline for the trial is ongoing, we anticipate the study to continue whilst funding is maintained.
Secondary outcome [4] 389592 0
To determine the overall efficacy of the platform as an evolving system for managing patients with AML
Timepoint [4] 389592 0
Overall survival measured from the date of first dose of study drug until the date of last contact or death. Once patients have completed treatment and enter follow up, their survival status will be assessed every 3 months until death. Due to the nature of arms being added and removed from the study platform the timeline for the trial is ongoing, we anticipate the study to continue whilst funding is maintained.

Eligibility
Key inclusion criteria
for study entry:
- diagnosis of AML in first or second CR/CRi
- a diagnostic baseline bone marrow and/or blood sample suitable for DNA/RNA-based studies is available
- presence of molecular and/or flow cytometric MRD marker(s) at AML diagnosis

to commence active treatment:
- WBC <25 x 10^9/L (hydroxyurea permitted for WCC control)
- for initial therapy on trial patient must have evidence of morphologic relapse or molecular progression/relapse
- for patients on trial rotating to other therapies - must have evidence of progressive disease, treatment failure or relapse

there will be additional arm specific eligibility criteria which will be specified in the domain-specific protocols
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
for study entry:
-Acute promyelocytic leukaemia
-prior allogeneic stem cell transplantation within 3 months of post-conditioning or on greater than or equal to 10mg/day prednisolone for graft vs host disease

to commence active treatment:
- known active CNS disease
-Within 14-days from receipt of prior anti-leukaemic therapy (except hydroxyurea or 6-thioguanine)

there will be additional arm specific eligibility criteria which will be specified in the domain-specific protocols

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
Other
Other design features
Once a patient is taken off their first treatment on trial, they may be screened for eligibility to another domain or another treatment option within a domain. There is no defined treatment pathway for all patients. Treatment pathways are based on a patient's individual clinical and molecular information to determine the best available treatment for that patient available on the study.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Statistical analyses of endpoints will be of three types:
1. Analyses of first line therapies. These analyses will be conducted separately for each domain. In domains for which there is little information on the recommended dose for relapsing AML patients, a BOP2 design to jointly monitor efficacy (i.e. response) and toxicity (i.e. occurrence of the specified AEs of interest) will be implemented. If some safety information is available, the domain may commence with a pre-specified, formal safety run-in utilising, for example, a BOIN design to provide further evidence regarding the recommended dose. In domains for which a recommended dose is available, toxicity will be informally monitored and efficacy will be investigated using a dual-criteria, Bayesian, Proof-of-Concept (PoC) approach with a minimally informative prior (the amount of prior information being restricted to be equivalent to information from 1, but no more than 2, patients). The prior probability of response will be updated once the first 10 patients have been followed for at least 100 days or have withdrawn prior to that. Efficacy will be based on the percentiles of the posterior distribution for the response rate.
2. Analyses of therapy paths (the dynamic treatment regimens). If the number of distinct observed paths is small, these analyses will be model-based and, of necessity, exploratory. Each patient will be regarded as an n-of-1 trial and analyses will use methods, based on extensions of the Cox Proportional Hazards model, for three types of recurrent events (on-target progression, off-target progression and co-occurrence of both types of progression). If the number of distinct paths is large, then a similar approach, allowing for recurrence of responses and relapses, will be used to investigate models restricted to groups of patients who commence in the same starting domain.
3. Analysis of Overall Survival and Relapse-Free Intervals. These analyses will be conducted for all patients and include subgroup analyses based on initial mutation status. The goal of these analyses is to estimate the overall efficacy of the “system”. Exploratory analyses of relapse-free intervals after 1, 2 or 3 molecular relapses will also be conducted but restricted to patients who achieve a molecular response.

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] 23281 0
New Zealand
State/province [1] 23281 0

Funding & Sponsors
Funding source category [1] 307020 0
Charities/Societies/Foundations
Name [1] 307020 0
Australasian Leukaemia & Lymphoma Group
Address [1] 307020 0
35 Elizabeth St
Richmond VIC 3121
Country [1] 307020 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Australasian Leukaemia & Lymphoma Group
Address
35 Elizabeth St
Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 307590 0
None
Name [1] 307590 0
Address [1] 307590 0
Country [1] 307590 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307151 0
the Alfred Hospital Ethics Committee
Ethics committee address [1] 307151 0
55 Commercial Road
Melbourne, VIC 3004
Ethics committee country [1] 307151 0
Australia
Date submitted for ethics approval [1] 307151 0
16/11/2020
Approval date [1] 307151 0
Ethics approval number [1] 307151 0

Summary
Brief summary
The aim is to demonstrate that targeting rising minimal residual disease (MRD) in patients with progressive acute myeloid leukemia (AML) may be an effective approach to maintaining patients in remission for longer. The trial will also determine if a range of novel treatments aimed at targeting MRD will result in improved treatment outcomes.

You may be eligible to participate in this study if you are an adult with acute myeloid leukemia and are currently in your first or second morphologic remission with a known and trackable MRD marker.

If you enter the trial your MRD marker(s) will be monitored as per standard practice until evidence of MRD progresssion and/or morphological relapse. When this occurs you will then be allocated to the best available treatment option for your MRD markers. This is determined by a set of clinical decision rules upon discussion with a MRD committee (a group of specialist doctors in AML), If there is no preference for a specific treatment for you, you may be randomly allocated to one.

Once on treatment you will be continue to have your MRD monitored, if you do not respond to treatment or your disease worsens you may be removed from treatment and be reassessed for the next best treatment option for you to receive (either on or off trial). During treatment you will be assessed regularly which will include physical exams, blood tests, ECG (test on your heart), bone marrow biopsies, toxicities to the treatment, quality of life. If responding to the treatment you will continue on treatment for 12months. After treatment your disease will continue to be monitored and if you have MRD progression or morphological relapse you will be assessed for the next best treatment option for you.

It is hoped that the results of this trial will help us understand the natural history of MRD markers in patients during the course of their disease through diagnosis, treatment and relapse as well as making new treatments available to patients with AML at a faster rate using the platform trial design (many treatments teste through one trial) than with current clinical trial practices
Trial website
Trial related presentations / publications
Public notes
This is a master protocol and additional registration records will be completed for each therapy or combination of therapies, and that these will be entered in the 'Linked study record' field as they become available.

Contacts
Principal investigator
Name 106210 0
A/Prof Andrew Wei
Address 106210 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 106210 0
Australia
Phone 106210 0
+61 3 9076 3392
Fax 106210 0
Email 106210 0
andrew.wei@monash.edu
Contact person for public queries
Name 106211 0
A/Prof Andrew Wei
Address 106211 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 106211 0
Australia
Phone 106211 0
+61 3 9076 3392
Fax 106211 0
Email 106211 0
andrew.wei@monash.edu
Contact person for scientific queries
Name 106212 0
A/Prof Andrew Wei
Address 106212 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 106212 0
Australia
Phone 106212 0
+61 3 9076 3392
Fax 106212 0
Email 106212 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 publicly. Aggregate patient data and final results will be presented in the final report
What supporting documents are/will be available?
No other documents available
Summary results
No Results