Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000824460p
Ethics application status
Submitted, not yet approved
Date submitted
6/06/2025
Date registered
1/08/2025
Date last updated
1/08/2025
Date data sharing statement initially provided
1/08/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM26/T9 INTERCEPT A multi-arm trial for patients with acute myeloid leukemia investigating new treatments which target early relapse and changes in disease characteristics - PHI-101
Scientific title
AMLM26/T9 - 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- PHI-101
Secondary ID [1] 314602 0
AMLM26/T9
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 an investigational combination included on the platform - PHI-101

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia 337731 0
Condition category
Condition code
Cancer 334057 334057 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 monotherapy using PHI-101.

PHI-101 is available in tablet form and will be administered orally once daily for up to 12 cycles, with each cycle lasting 28 days. The tablet should be taken on an empty stomach and must be administered at least two hours after a meal, preferably following an overnight fast. After taking the dose, participants must continue fasting for another two hours.

Patients will enrol directly into a proof-of-concept (POC) phase, where the safety and efficacy of the recommended dose selected for expansion is 160mg once daily or days 1-28 of a 28-day cycle.
No further dose exploration will be undertaken, as PHI-101 has previously been evaluated in a first-in-human, open-label phase 1a/1b trial (NCT04842370). That study included a dose-escalation phase ranging from 40 mg to 200 mg daily and identified 160 mg once daily as the recommended Phase 2 dose.

This proposed arm aims to assess the safety, tolerability, and efficacy of PHI-101 in patients with FLT3-mutated AML who have experienced measurable residual disease (MRD) failure.

Patients will be provided with a dosing schedule diary to complete at home. The pharmacy will perform drug accountability upon return of the empty bottles.
Intervention code [1] 331226 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 341719 0
To determine the rates of MRD clearance of patients with FLT3-ITD -mutated AML, to their first or second decision rule guided therapy with PHI-101 monotherapy.
Timepoint [1] 341719 0
Achievement of complete Remission (CR) MRD- (based on the primary response marker assigned by the MRD Reference Committee (MRC) whilst receiving AMLM26 treatment). The duration may vary depending on the patient's response to treatment, but assessments occur at screening and post-cycles 1, 2, 3, 6, 8, 10, and 12, followed by every two months until disease progression or withdrawal. Final analysis of CRMRD- will be conducted once all patients on treatment have either completed the EOC6 assessment, withdrawn beforehand, or achieved CRMRD- prior to EOC6.
Secondary outcome [1] 448508 0
To determine the MRD response of patients with AML to decision-rule guided therapy.
Timepoint [1] 448508 0
Based on the primary response marker assigned by the MRC whilst receiving AMLM26 treatment, complete remission with (a) molecular MRD response requiring at least 1 log reduction, or (b) flow MRD response requiring multiparameter flow cytometry (MFC) < 0.1%, within 100 days of commencing specific study therapy.
Secondary outcome [2] 449266 0
To determine the durability of the response of patients with AML to decision-rule guided therapy.
Timepoint [2] 449266 0
Relapse-free survival (RFS) and relapse-free survival MRD (RFSMRD): Measurements are based on the patient’s stratification at entry to the treatment arm and their response during treatment from earliest date of response to the specific therapy (morphologic or MRD) to the date of morphologic or MRD relapse (included as an event in RFSMRD) or date of death AND Event-free survival MRD (EFSMRD): Measured based on the patient’s stratification at entry. Events will be defined as no response within 100 days, hematologic relapse, MRD relapse or death.
Secondary outcome [3] 449268 0
A key scientific objective of the study is to investigate the dynamics of MRD response and the duration of clinical benefit in the morphologic and MRD failure strata
Timepoint [3] 449268 0
Time to MRD response is measured from commencement of specific study therapy to achievement of CR MRD- based on the primary response marker assigned by the MRC whilst receiving AMLM26 treatment
Secondary outcome [4] 449269 0
To investigate if duration of MRD response is longer for patients treated at MRD vs morphologic failure
Timepoint [4] 449269 0
Duration of MRD response measured from the date of achievement of CR MRD- (based on the primary response marker assigned by the MRC whilst receiving AMLM26 treatment) to the earliest date of MRD relapse or the date of death.

Eligibility
Key inclusion criteria
A patient will be eligible for study participation to these PHI-101 treatment arm if he/she meets the following criteria:
1. Meets inclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol (ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842)
2. ECOG 0-2
3. Subject must have adequate renal function as demonstrated by a creatinine clearance greater than 40 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:
a. aspartate aminotransferase (AST) less than 2.5 × ULN
b. alanine aminotransferase (ALT) less than 2.5 × ULN
c. bilirubin less than 1.5 × ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
5. Agrees to follow the recommended contraception procedures for this treatment domain
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A subject will not be eligible for participation on these PHI-101-containing treatment arms if any of the following criteria apply:
1. Presence of any general exclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol (ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842)
2. Prior allogeneic stem cell transplantation within 30 days of stem cell infusion or has clinically significant graft-versus-host disease requiring treatment, or has persistent greater than or equal to grade 2 non-haematologic toxicity related to transplant
3. QT-interval corrected according to Fridericia’s formula (QTcF) greather than 450ms (except for right bundle branch block)
4. Presence of hypokalemia (defined as serum potassium less than 3.5 mmol/L) and hypomagnesaemia (defined as serum magnesium less than 0.7 mmol/L) at the time of screening for this treatment arm. Supplementation is permitted during the screening window to establish values above the defined thresholds above.
5. Subject is HIV positive
6. 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. 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 resolved HBV infection may participate.
7. Chronic systemic chronic corticosteroid therapy (greater than or equal to 10 mg/day prednisone or equivalent) or any immunosuppressive therapy within the last 7 days prior to Day 1 of study drug. Topical, inhaled, nasal and ophthalmic steroids are allowed.
8. History of or current drug-induced interstitial lung disease or pneumonitis
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. Use of any live vaccines against infectious diseases (i.e. Influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment
12. 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 45%, uncontrolled hypertension or clinically significant arrhythmia
• Acute myocardial infarction or unstable angina pectoris less than 3 months prior to study entry
13. Use of medications, herbal products or foods known to be moderate or potent inhibitors of P glycoprotein (P-gp) within the last 7 days prior to Day 1 or known to be moderate or potent inducers of P-gp within the last 14 days prior to Day 1
14. Patients unable to swallow oral medications, or with gastrointestinal issues which might affect oral drug absorption or ingestion (i.e, gastroparesis, etc).
15. Prior treatment with cytotoxic/anti-leukaemic agents (apart from hydroxyurea, thioguanine, or single dose of cytarabine infusion for control of leucocytosis) within 2 weeks prior to first dose of study agent, or within 5 half-lives prior to study drug administration.

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
Bayesian proof-of-concept approach will be adopted for the statistical analysis and reporting of the primary outcome in each treatment arm.

Proof-of-concept (PoC) for the efficacy of this treatment arm will be inferred if two criteria are met:
1. Observed CRMRD- response rate greater than or equal to 15%.
2. Posterior probability that the true response rate is greater than or equal to 10% (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 will commence when the first 10 patients are evaluable for response. It is envisaged that these criteria will be assessed whenever data become available for every 5 patients thereafter up to 30 patients. It is further envisaged that PoC can be declared (and published) at any time after evaluation of the first 10 patients.
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 0.10 (a equal 0.30103, b equal 1).
In addition to early declaration of PoC, the Trial management committee (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 PHI-101 treatment arm are:
1. Observed response rate less than 10%.
2. Posterior probability that the true response rate is less than 10%, given the data, is greater than or equal to 0.80 (the level of proof).
The operating characteristics of the PHI-101 treatment arm are illustrated in the following table for five scenarios each of which have been simulated 100,000 times using R code adapted from Sverdlov et al 2015.13
When the true CRMRD- response rate exceeds 24.0% the probability that PoC is declared is greater than 80% (and the probabilities of a futility stop and an indeterminate outcome are 7.7% and 12.2% respectively) when provision is made to evaluate up to 30 FLT3-mutated and to check the dual PoC criteria after every 5 patients become evaluable.
When the true response rate is less than 7% the probability that PoC is declared is 5% or less and the “false positive rate” is controlled below the conventional 5% level.
For true response rates in the vicinity of the futility rate (10%) the probability of an indeterminate outcome can be as high as 39% and the expected sample size is more than 20 patients when the planned number of patients to be enrolled at the confirmed feasible dose is 30.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/09/2025
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 28012 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 28013 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 28014 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 28015 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [5] 28016 0
The Alfred - Melbourne
Recruitment hospital [6] 28017 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [7] 28018 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [8] 28019 0
Gold Coast University Hospital - Southport
Recruitment hospital [9] 28020 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [10] 28021 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [11] 28022 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [12] 28023 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [13] 28024 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [14] 28025 0
Westmead Hospital - Westmead
Recruitment hospital [15] 28026 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [16] 28027 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 44216 0
3000 - Melbourne
Recruitment postcode(s) [2] 44217 0
3050 - Parkville
Recruitment postcode(s) [3] 44218 0
3168 - Clayton
Recruitment postcode(s) [4] 44219 0
3220 - Geelong
Recruitment postcode(s) [5] 44220 0
6009 - Nedlands
Recruitment postcode(s) [6] 44221 0
6150 - Murdoch
Recruitment postcode(s) [7] 44222 0
4215 - Southport
Recruitment postcode(s) [8] 44223 0
4102 - Woolloongabba
Recruitment postcode(s) [9] 44224 0
4029 - Herston
Recruitment postcode(s) [10] 44225 0
5000 - Adelaide
Recruitment postcode(s) [11] 44226 0
2050 - Camperdown
Recruitment postcode(s) [12] 44227 0
2065 - St Leonards
Recruitment postcode(s) [13] 44228 0
2145 - Westmead
Recruitment postcode(s) [14] 44229 0
2298 - Waratah
Recruitment postcode(s) [15] 44230 0
2139 - Concord

Funding & Sponsors
Funding source category [1] 319161 0
Other Collaborative groups
Name [1] 319161 0
Australasian Leukaemia & Lymphoma Group
Country [1] 319161 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia & Lymphoma Group
Address
Country
Australia
Secondary sponsor category [1] 321617 0
None
Name [1] 321617 0
Address [1] 321617 0
Country [1] 321617 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 317740 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 317740 0
Ethics committee country [1] 317740 0
Australia
Date submitted for ethics approval [1] 317740 0
24/07/2025
Approval date [1] 317740 0
Ethics approval number [1] 317740 0
Ethics committee name [2] 317748 0
Bellberry Human Research Ethics Committee A
Ethics committee address [2] 317748 0
Ethics committee country [2] 317748 0
Australia
Date submitted for ethics approval [2] 317748 0
28/07/2025
Approval date [2] 317748 0
Ethics approval number [2] 317748 0
Ethics committee name [3] 317749 0
Central Adelaide Local Health Network HREC
Ethics committee address [3] 317749 0
Ethics committee country [3] 317749 0
Australia
Date submitted for ethics approval [3] 317749 0
28/07/2025
Approval date [3] 317749 0
Ethics approval number [3] 317749 0

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

Contacts
Principal investigator
Name 141998 0
Prof Andrew Wei
Address 141998 0
Peter MacCallum Cancer Centre 305 Grattan Street, Melbourne VIC 3000
Country 141998 0
Australia
Phone 141998 0
+61 385597915
Fax 141998 0
Email 141998 0
[email protected]
Contact person for public queries
Name 141999 0
Delaine Smith
Address 141999 0
Australasian Leukaemia & Lymphoma Group 35 Elizabeth Street, Richmond Victoria 3121
Country 141999 0
Australia
Phone 141999 0
+61 383739702
Fax 141999 0
Email 141999 0
[email protected]
Contact person for scientific queries
Name 142000 0
Delaine Smith
Address 142000 0
Australasian Leukaemia & Lymphoma Group 35 Elizabeth Street, Richmond Victoria 3121
Country 142000 0
Australia
Phone 142000 0
+61 383739702
Fax 142000 0
Email 142000 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No


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.