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Trial registered on ANZCTR


Registration number
ACTRN12621001265864p
Ethics application status
Not yet submitted
Date submitted
15/06/2021
Date registered
20/09/2021
Date last updated
20/09/2021
Date data sharing statement initially provided
20/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM26/T5 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - MBG453 OR MBG453 and Azacitidine
Scientific title
AMLM26/T5- 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 - MBG453 OR MBG453 and Azacitidine
Secondary ID [1] 304488 0
AMLM26/T5
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 MRD or early morphologic relapse. These treatment arms described in this registration form are for one investigational agent included on the platform - MBG453.

Health condition
Health condition(s) or problem(s) studied:
acute myeloid leukaemia 322332 0
Condition category
Condition code
Cancer 320004 320004 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 investigational agent MBG453. This will have 2 treatment arms - arm A MBG453 alone and arm B MBG453 in combination with azacitidine. Eligible patients will be randomly allocated to one of the two treatment arms.

MBG453 will be administered via intravenous infusion over 30minutes or up to 2hrs if clinically indicated.

Treatment arm A - MBG453 on its own will be given at a dose of 800mg on day 1 of a 28 day cycle by intravenous infusion.
Treatment arm B - MBG453 and azacitidine. Azacitidine 75mg/m2 days 1-7, MBG453 800mg on day 8 by intravenous infusion. Azacitidine will be given subcutaneously (sc) or intravenously (IV) for 7 days from days 1-7 or using the 5-2-2 schedule (administered for 5 consecutive days on days 1-5, followed by a two-day break, then administered for two consecutive days on days 8-9), with MBG453 infusion on day 8 out of a 28-day cycle. Whether azacitidine is given via IT or SC is per the hospital's standard clinical practice.

Both treatment arms will be given for 12 cycles. Patients will attend hospital to receive treatment. If there is poor compliance with protocol procedures patients may be removed from the trial.

If patients have not responded to treatment within 100days of commencing MBG453 alone patients will be able to crossover to receive MBG453 + Azacitidine, if they undergo screening procedures and meet eligibility to go onto this combined treatment arm.
Intervention code [1] 320850 0
Treatment: Drugs
Comparator / control treatment
This is a randomised non-comparator trial. Patients are randomly allocated to either MBG453 alone or MBG453 + azacitidine. There is no inclusion in the protocol currently to compare the efficacies of the treatment arms. However this may be re-assessed by the trial management committee after availability of sufficient data from the proof of concept phase prior to completing the expansion phases.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327875 0
To determine the response of AML patients in the “Other” domain to their therapy (on study) with investigational agent MBG453 monotherapy or MBG453 + Azacitidine. Response is assessed using bone marrow and/or peripheral blood samples.
Timepoint [1] 327875 0
The primary endpoint in patients enrolled to this drug-specific “Other” domain 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] 396826 0
To determine the durability of the response of AML patients to MBG453 +/- azacitidine. Response is assessed using blood and bone marrow samples. The time is measured from the date of the response to the date of progression or death.
Timepoint [1] 396826 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] 396827 0
To characterize the safety and tolerability of MBG453 and MBG453 + Azacitidine . This is one secondary outcome assessing adverse events that occur on the treatment arms.
Timepoint [2] 396827 0
Occurrence of newly occurring or worsening related CTCAE grade 3-5 non-hematologic adverse events (AEs) 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. This information will be gathered from patient self-reporting to the clinician, patient's medical records, clinician physical exam, letters to clinician from GPs.
Secondary outcome [3] 396828 0
To investigate the efficacy of distinct treatment sequences in AML patients who fail one or more lines of therapy on study.
Timepoint [3] 396828 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 [4] 396829 0
To determine the overall efficacy of the platform as an evolving system for managing patients with AML.
Timepoint [4] 396829 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, (this may be for longer than 5 years)
Secondary outcome [5] 396830 0
Quality of Life. this is measured together via the use of 2 quality of life tools.
Timepoint [5] 396830 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
Patient must meet eligibility to come onto the Intercept Master Protocol (as detailed in linked entry ACTRN12621000439842).
In order to be eligible to the MBG453 treatment arms inclusion criteria includes:
- meet MRD eligibility for INTERCEPT therapy based on a screening sample taken no more than 28 days prior to cycle 1 of day 1 of treatment on this treatment arm. (An increase of MRD greater than or equal to 1 log from nadir to at least 0.01%, confirmed with a repeat central sample.) Eligibility will be confirmed by the MRD review committee.
- ECOG0-2
- Patients entering this arm post-allogeneic stem cell transplantation will need to have an absolute lymphocyte count of greater than or equal to 0.2 x 109/L and no evidence of active acute graft-versus-host disease (GVHD)
- 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
-Subject must have adequate liver function as demonstrated by:
- aspartate aminotransferase (AST) less than or equal to 3.0 × ULN
- alanine aminotransferase (ALT) less than or equal to 3.0 × ULN
- bilirubin less than or equal to 1.5 × ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
- agree to follow the recommended contraception procedures
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patient must meet eligibility to come onto the Intercept Master Protocol (as detailed in linked entry ACTRN12621000439842).
In order to be eligible to the MBG453 treatment arms exclusion criteria includes:
- 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
- QT-interval corrected according to Fridericia’s formula (QTcF) greater than 470ms (except for right bundle branch block)
- Subject is HIV positive
- Patients with greater than or equal to 5% myeloblasts in bone marrow on morphologic assessment
- 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. Acute/Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
- Systemic chronic corticosteroid therapy (greater than or equal to 10 mg/day prednisone or equivalent) or any immunosuppressive therapy within 7 days of first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.
- For initial enrolment to INTERCEPT therapy, patients who have received previous TIM3 inhibitor treatment are excluded. This exclusion criteria does not apply to patients crossing-over from MBG453 arm to the combination MBG453 + azacitidine arm, unless MBG453 was ceased due to MBG453-related toxicity.
- Patients with active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur should not be excluded
- History of or current drug-induced interstitial lung disease or pneumonitis grade greater than or equal to 2
- Subject has been diagnosed with another malignancy, unless disease-free for at least 2 years and not needing active treatment. Patients with fully excised BCC/SCC/CIN or other minor malignancy are not excluded
- Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation
- Use of any live vaccines against infectious diseases (i.e. Influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment
- Impaired cardiac function or clinically significant cardiac disease, including any of the following:
• Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade greater than or equal to 2) with an LVEF of less than 40%, uncontrolled hypertension or clinically significant arrhythmia
• Acute myocardial infarction or unstable angina pectoris less than 3 months prior to study entry
- Known hypersensitivity to azacitidine or mannitol.

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)
randomization will be undertaken by the ALLG, sponsor for the trial
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
dynamic randomisation. New treatment arms may be added over the course of the Intercept trial and the randomisation will be updated as required with this additions
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Crossover of patients from the sole agent arm to combination therapy is permitted if there is evidence of “treatment failure” within 100 days after starting MBG453 monotherapy. In this setting, patients who crossover will need to undergo screening procedures and meet eligibility prior to enrolment onto the combination therapy arm.
Crossover does not occur from combination arm to sole agent arm.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A Bayesian proof-of-concept approach will be adopted for the statistical analysis and reporting of the primary outcome in each treatment arm.
Decisions to terminate or expand accrual in a treatment arm within this drug-specific domain will be based on the observed response rate in the treatment arm.
At any time after the initial run-in phase, efficacy of a treatment arm will be claimed if two criteria are met:
1. Observed response rate greater than or equal to 40%.
2. Posterior probability that the true response rate is greater than or equal to 30% (the futility rate), given the data, is greater than or equal to 0.90 (the level of proof).

Monitoring of the dual criteria in each arm will commence when the first 10 patients allocated to each arm are evaluable for response. If an arm is not closed for futility after the run-in phase, it is envisaged that these criteria will be assessed whenever data become available after about every 5 evaluable patients up to a cap of approximately 30 evaluable patients in an arm.
It is further envisaged that an efficacy claim can be made for a treatment arm (and published) at any time after the run-in period of 10 evaluable patients. We also refer to this claim as a PoC claim.

In addition to early declaration of PoC, the TMC has the discretion to terminate a treatment arm early if there is evidence of futility. The dual criteria for (non-binding) early stopping for futility are:
1. Observed response rate less than 40%.
2. Posterior probability that the true response rate is less than 30%, given the data, is greater than or equal to 0.90 (the level of proof).
Monitoring of the dual criteria for futility will also commence when the first 10 patients in a treatment arm are evaluable for response.

When the true response rate is 46% the probability that PoC is declared is 80% (and the probabilities of a futility stop and an indeterminate outcome are 2.5% and 17.5% respectively) when provision is made to evaluate up to 30 patients in a treatment arm. It is expected that PoC would be declared in the first 3 “looks” at the accumulating response data in an arm and the required sample size would be 17 or less.

When the true response rate is 21% the probability that PoC is declared is 5% i.e. the “false positive rate” is controlled when the true response rate is low.
If recurrent mutations associated with a promising response rate, e.g. greater or equal to 50% in greater or equal to 6 cases, are identified a decision will be made whether to promote the mutation into a targeted domain to enrich for recruitment. After 10 evaluable patients with the mutation have been enrolled, efficacy will be re-assessed. Based on this assessment, a decision will be made whether to expand to at least 20 patients. The trial management committee (TMC) will recommend which mutation biomarkers should be promoted for cohort enrichment and expansion.

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] 23785 0
New Zealand
State/province [1] 23785 0

Funding & Sponsors
Funding source category [1] 308848 0
Other Collaborative groups
Name [1] 308848 0
Australasian Leukaemia & Lymphoma Group
Address [1] 308848 0
Ground Floor, 35 Elizabeth St, Richmond VIC 3121
Country [1] 308848 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] 309767 0
None
Name [1] 309767 0
Address [1] 309767 0
Country [1] 309767 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 308757 0
the Alfred Hospital Ethics Committee
Ethics committee address [1] 308757 0
55 Commercial Road
Melbourne, VIC 3004
Ethics committee country [1] 308757 0
Australia
Date submitted for ethics approval [1] 308757 0
26/07/2021
Approval date [1] 308757 0
Ethics approval number [1] 308757 0

Summary
Brief summary
This is an investigational agent within the ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842. This investigational agent (MBG453 - a new treatment) will be evaluated for its activity alone and in combination with azacitidine 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 minimal residual disease (very small amounts of disease) is rising. The trial management committee will review your disease characteristics and determine your best treatment option(s) available on the trial.

Study details
Participants who choose to enrol in this study may be randomly allocated by chance (similar to flipping a coin), to receive either MBG453 alone or MBG453 with azacitidine or another available treatment option within the Intercept platform which the TMC has indicated are your best treatment options.

MBG453 is given intravenously by itself (treatment A) or in combination with azacitidine therapy administered either intravenously or subcutaneously (injections under the skin, Treatment B). Participants who receive Treatment A will have MBG453 administered as a single 800mg intravenous dose on day 1 of a 28 day treatment cycle for 12 cycles. Participants who receive Treatment B will have daily 75mg doses of azacitidine during the first week of a 28 day treatment cycle and 800mg of MBG453 on day 8. This treatment will also continue for 12 cycles. After 100 days on therapy, participants in Treatment A who are not responding to the single therapy may be re-allocated to Treatment B for another 12 cycles (after rescreening for eligibility). Participants will undergo a disease assessment at screening after cycle 1, cycle 3, cycle 6 and then 3 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 MBG453 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 111782 0
A/Prof Andrew Wei
Address 111782 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 111782 0
Australia
Phone 111782 0
+61 3 9076 3392
Fax 111782 0
Email 111782 0
andrew.wei@monash.edu
Contact person for public queries
Name 111783 0
A/Prof Andrew Wei
Address 111783 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 111783 0
Australia
Phone 111783 0
+61 3 9076 3392
Fax 111783 0
Email 111783 0
andrew.wei@monash.edu
Contact person for scientific queries
Name 111784 0
A/Prof Andrew Wei
Address 111784 0
The Alfred Hospital
55 Commercial Rd
Melbourne, VIC 3004
Country 111784 0
Australia
Phone 111784 0
+61 3 9076 3392
Fax 111784 0
Email 111784 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