Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000582752
Ethics application status
Approved
Date submitted
28/02/2022
Date registered
20/04/2022
Date last updated
26/05/2024
Date data sharing statement initially provided
20/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM26/T4 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - SNDX5613
Scientific title
AMLM26/T4- 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 - SNDX5613
Secondary ID [1] 306551 0
AMLM26/T4
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 investigational agent included on the platform - SNDX5613

Health condition
Health condition(s) or problem(s) studied:
acute myeloid leukaemia 325443 0
Condition category
Condition code
Cancer 322824 322824 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 SNDX5613. This will have 1 treatment arm - SNDX5613 alone.

SNDX5613 is a capsule that will be administered orally twice a day. Taken on an empty stomach at least 2 hours after a meal or 1 hour before the next meal. Administered days 1-28 of a 28 days cycle for 12 cycles.

As this agent has not yet been tested in patients with MRD progression, we will confirm the dose for patients with MRD progression in a pilot safety run-in phase. The first dose level explored will be 276mg twice a day. If not tolerable 226mg twice a day will be investigated, and if that is not tolerable 163mg twice a day will be investigated.

Once the optimal dose is determined in the pilot phase for MRD progressors, enrolment onto a proof of concept phase will commence using the dose level deemed tolerable.

Patients in the morphologic relapse will immediately be enrolled into the POC phase at a dose of 276mg twice a day SNDX-5613 from days 1-28 of a 28-day cycle (utilising the recommended phase 2 dose determined by the SNDX- 5613 sponsored phase 1b/II study (NCT04065399) to be most tolerable and effective).

Patients will be asked to complete a dose diary to confirm the tablets were taken. Patients will also be asked to return the SNDX5613 bottles (with unused tablets or empty containers) to the hospital. This is to monitor compliance with the treatment.
Intervention code [1] 322977 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330608 0
To determine the response of patients with either MLL-r mutated or NPM1 mutated AML in the MRD failure stratum to decision rule guided therapy with SNDX-5613
To do this blood and bone marrow samples will be collected to assess your disease levels.
Timepoint [1] 330608 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] 406929 0
To determine the durability of the response of AML patients to SNDX5613. Response is assessed using blood and bone marrow samples. 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. Haematologic response is determined by the amount of bone marrow blasts, blasts in your blood, extramedullary disease and neutrophil and platelet counts. These are assessed from your blood and bone marrow samples. The time is measured from the date of the response to the date of progression or death
Timepoint [1] 406929 0
Relapse-free survival (RFS): Measured from the date of response (morphologic or molecular) to the earlier of the date of progression or the date of death without prior progression.
Secondary outcome [2] 406930 0
To characterize the safety and tolerability of SNDX5613 . This is one secondary outcome assessing adverse events that occur on this treatment arm.
Timepoint [2] 406930 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] 406931 0
To investigate time to MRD response in patients treated at MRD failure versus morphologic relapse assessed by MRD in bone marrow.
Timepoint [3] 406931 0
Time to MRD response will be compared in the Morphologic relapse stratum against the MRD failure stratum.
Secondary outcome [4] 406932 0
To investigate duration of MRD response in patients treated at MRD failure versus morphologic relapse. The duration of MRD response will be assessed using bone marrow and peripheral blood samples.
Timepoint [4] 406932 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 [5] 406933 0
To investigate the efficacy of distinct treatment sequences in AML patients who fail one or more lines of therapy on study.
Timepoint [5] 406933 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 [6] 406934 0
To determine the overall efficacy of the platform as an evolving system for managing patients with AML
Timepoint [6] 406934 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 [7] 406935 0
Quality of Life. this is measured together via the use of 2 quality of life tools.
Timepoint [7] 406935 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 INTERCEPT Master Protocol (see ACTRN12621000439842 for details on the master protocol)
2. Presence of MLL-r or PTD, or NPM1 mutation in a bone marrow or peripheral blood sample taken no more than 28 days prior to cycle 1 of day 1 of treatment on this treatment arm. Patients with MLL-r with mixed-phenotype acute leukaemia (MPAL) will also be considered eligible for this study
3. ECOG 0-2
4. Confirmation of serum potassium greater than or equal to 3.6 mmol/L and serum magnesium greater than or equal to 0.66 mmol/L within one week before first dose of study drug, at which time oral supplementation can be started to maintain potassium greater than or equal to 4.0 and magnesium greater than or equal to 0.82 to meet electrolyte thresholds for SNDX5613 dosing. Subject must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 60 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hours urine collection
6. Adequate cardiac function defined as left ventricular ejection fraction (EF) of greater than 50% by echocardiogram or multi-gated acquisition (MUGA) scan.
7. Subject must have adequate liver function as demonstrated by:
a. aspartate aminotransferase (AST) less than or equal to 3.0 × 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)
8. Agrees to follow the recommended contraception procedures for this treatment arm
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. QT-interval corrected according to Fridericia’s formula (QTcF) greater than 450ms on triplicate ECGs (each separated by 2 minutes with average of 3 ECGs used to calculate QTcF interval).
3. Subject is HIV positive and has detectable HIV viral PCR and/or with signs of active/uncontrolled infection. Patients who are HIV-positive with undetectable viral load are eligible provided that anti-retroviral used is not a prohibited medication on study.
4. Prior allogeneic stem cell transplantation within 60 days of post-conditioning or on immunosuppression or greater than 10mg/day prednisolone for graft vs host disease (GVHD). Patients must have been off systemic immunosuppressive therapy (apart from stated prednisolone dose above) for at least 4 weeks prior to enrolment.
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 (HepB Surface Antigen negative but core antibody positive and DNA negative) who do not require treatment may participate.
6. Patients who have ingested seville oranges, grapefruit or grapefruit juice and/or kumquats, pomegranate or pomegranate juice, pomelos, exotic citrus fruit (i.e., star fruit, bitter melon), grapefruit hybrids or fruit juices, or other foods and juices known to inhibit CYP3A4 within three days prior to initiation of study treatment, and are not willing to cease their ingestion for the duration of the study.
7. Treatment with any of the following within 7 days prior to the first dose of study drug:
a. Steroid therapy for anti-neoplastic intent or on greater than 10mg/day prednisolone for graft versus host disease
b. Moderate or strong CYP3A inducers
c. CYP3A inhibitors:
• SAFETY RUN-IN PHASE PATIENTS: Moderate and strong cytochrome CYP3A inhibitors are prohibited 7 days prior to cycle 1 day 1 and during cycle 1 of the safety run-in phase.
• PROOF OF CONCEPT (POC) AND EXPANSION PHASE PATIENTS: Moderate and strong cytochrome CYP3A4 inhibitors with the exception of posaconazole, voriconazole, itraconazole or ketoconazole are prohibited 7 days prior to cycle 1 day 1. Patients on azole antifungals should have been on it for greater than or equal to 7 days prior to first dose of SNDX-5613.
8. Treatment with prior anti-leukemic therapy within 5 half-lives or 14 days (whichever is shorter) prior to the first dose of study drug (except steroids see exclusion 7a).
9. 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.
10. Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation
11. Subject has had any of the following within 6 months prior to screening: myocardial infarction, uncontrolled/unstable angina, congestive heart failure New York Heart Association (NYHA) class 3 or 4, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
12. Patients unable to swallow oral medications, or with gastrointestinal issues which might affect oral drug absorption or ingestion (i.e, gastroparesis, etc).

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
Response rates in each domain will be calculated as percentages within the MRD failure treatment failure stratum (excluding patients with MLL-PTD mutated AML). 95% credible intervals will be calculated and will utilise a minimally informative prior for the response rate.
A Bayesian proof-of-concept approach will be adopted for the statistical analysis and reporting of the primary outcome.
Decisions to terminate or expand accrual in a treatment arm within a domain will be based primarily on the observed response rate calculated for the MRD “treatment failure” stratum (noting for the MLL-x domain, patients MLL-PTD mutated AML will be not be included in this determination).
Proof-of-concept (PoC) for the efficacy of this treatment arm for each domain will be inferred 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 for futility, in each domain, will also commence when the first 10 MRD failure patients are evaluable for response (excluding patients with MLL-PTD mutated AML).

A minimally informative prior distribution for the true response rate has been selected with a median between the threshold rates specified in the dual PoC criteria, namely a Beta distribution with median equal to 0.35 (a equal to 0.660252, b equal to 1).

Separately in each domain, monitoring of the dual criteria for PoC in this treatment arm will commence when the first 10 MRD failure patients are evaluable for response, (excluding patients with MLL-PTD mutated AML). Patients in this treatment arm who received the feasible dose of SNDX-5613 monotherapy during the pilot phase will be included in the analyses of response. It is envisaged that PoC can be declared (and published) at any time after evaluation of the first 10 MRD failure patients within a domain, (excluding patients with MLL-PTD mutated AML).
In the primary analysis of the MLL-x domain, patients with MLL-PTD mutated AML will be excluded. These patients are be included in an exploratory analysis.
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 for each domain 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 or equal to 0.90 (the level of proof).

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 domain. It is expected that PoC would be declared in the first 3 “looks” at the accumulating response data in a domain 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 at the conventional level when the true response rate is low.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
22/07/2022
Actual
17/03/2023
Date of last participant enrolment
Anticipated
17/03/2026
Actual
Date of last data collection
Anticipated
17/03/2027
Actual
Sample size
Target
92
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 25093 0
The Alfred - Melbourne
Recruitment hospital [2] 25094 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 40763 0
3004 - Melbourne
Recruitment postcode(s) [2] 40764 0
4102 - Woolloongabba
Recruitment outside Australia
Country [1] 24624 0
New Zealand
State/province [1] 24624 0

Funding & Sponsors
Funding source category [1] 310886 0
Other Collaborative groups
Name [1] 310886 0
Australasian Leukaemia & Lymphoma Group
Country [1] 310886 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] 312163 0
None
Name [1] 312163 0
Address [1] 312163 0
Country [1] 312163 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310446 0
the Alfred Hospital Ethics Committee
Ethics committee address [1] 310446 0
Ethics committee country [1] 310446 0
Australia
Date submitted for ethics approval [1] 310446 0
06/12/2021
Approval date [1] 310446 0
06/04/2022
Ethics approval number [1] 310446 0
HREC/70097/Alfred-2020
Ethics committee name [2] 313368 0
Bellberry Limited
Ethics committee address [2] 313368 0
Ethics committee country [2] 313368 0
Australia
Date submitted for ethics approval [2] 313368 0
30/06/2022
Approval date [2] 313368 0
13/02/2023
Ethics approval number [2] 313368 0
2022/ETH02392
Ethics committee name [3] 313369 0
Bellberry Limited
Ethics committee address [3] 313369 0
Ethics committee country [3] 313369 0
Australia
Date submitted for ethics approval [3] 313369 0
30/06/2022
Approval date [3] 313369 0
13/02/2023
Ethics approval number [3] 313369 0
2022/ETH02392
Ethics committee name [4] 313370 0
Central Adelaide Local Health Network HREC
Ethics committee address [4] 313370 0
Ethics committee country [4] 313370 0
Australia
Date submitted for ethics approval [4] 313370 0
06/12/2022
Approval date [4] 313370 0
15/12/2022
Ethics approval number [4] 313370 0
2022/HREC00129

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117698 0
Prof Andrew Wei
Address 117698 0
Peter MacCallum Cancer Centre
305 Grattan Street Melbourne VIC 3000
Country 117698 0
Australia
Phone 117698 0
+61 3 8559 7915
Fax 117698 0
Email 117698 0
andrew.wei@petermac.org
Contact person for public queries
Name 117699 0
Delaine Smith
Address 117699 0
Australasian Leukaemia & Lymphoma Group
35 Elizabeth St, Richmond VIC 3121
Country 117699 0
Australia
Phone 117699 0
+61383739702
Fax 117699 0
Email 117699 0
info@allg.org.au
Contact person for scientific queries
Name 117700 0
Andrew Wei
Address 117700 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 117700 0
Australia
Phone 117700 0
+61383739702
Fax 117700 0
Email 117700 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.