Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000082505
Ethics application status
Approved
Date submitted
31/10/2023
Date registered
30/01/2024
Date last updated
26/05/2024
Date data sharing statement initially provided
30/01/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM26/T1 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - Gilteritinib+ Venetoclax
Scientific title
AMLM26/T1- 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 - Gilteritinib+ Venetoclax
Secondary ID [1] 307317 0
AMLM26/T1- 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 MRD or early morphologic relapse. These treatment arms described in this registration form are for one investigational combination included on the platform - Gilteritinib+ Venetoclax

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia 326607 0
Condition category
Condition code
Cancer 323850 323850 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 gilteritinib in combination with venetoclax .

Gilteritinib in tablet form will be administered orally with or without food. Venetoclax also in tablet form will be administered orally after food.

A pilot safety run-in phase will be undertaken to verify the tolerability of gilteritinib in combination with venetoclax and to identify the appropriate dose for expansion of the proof-of-concept phase in patients. The first dose level explored will be level 4, if this is not tolerable lower dose levels will be studied.

The dose levels explored will be,
Level 4: Gilteritinib 120mg daily. Administered days 1-28 of a 28-day cycle for 12 cycles.
If the patient is in morphological remission,
Venetoclax 400mg daily. Administered days 2-28 inclusive. No dose ramp-up is required. Venetoclax continues at 400mg daily on days 1- 28 from cycle 2 onwards.
If the bone marrow blasts at screening > 5%, a 3-day dose ramp-up is required for cycle 1. Venetoclax 100mg on day 2, then 200mg on day 3, then 400mg daily on days 4-28. Venetoclax continues at 400mg daily on days 1-28 from cycle 2 onwards.

Level 3: Gilteritinib 120mg daily. Administered days 1-28 of a 28-day cycle for 12 cycles.
If in morphological remission,
venetoclax will be dosed at 400mg daily days 2-21 inclusive. No dose ramp-up is required. Venetoclax continues at 400mg daily on days 1- 21 from cycle 2 onwards.
If bone marrow blasts at screening >5%, a 3-day dose ramp-up is required.
Venetoclax 100mg on day 2, then 200mg on day 3, then 400mg daily on days 4-21. Venetoclax continues daily at 400mg on days 1- 21 from cycle 2 onwards.

Level 2: Gilteritinib 120mg daily. Administered days 1-28 of a 28-day cycle for 12 cycles.
If in morphological remission,
venetoclax will be dosed at 400mg daily days 2-14 inclusive. No dose ramp-up is required. Venetoclax continues at 400mg on days 1-14 from cycle 2 onwards.
If bone marrow blasts at screening >5%, a 2-day dose ramp-up is required.
Venetoclax 100mg on day 2, then 200mg on day 3, then 400mg daily on days 4-14. Venetoclax continues at 400mg on days 1-14 from cycle 2 onwards.

Level 1: Gilteritinib 80mg daily. Administered days 1-28 of a 28-day cycle for 12 cycles.
If in morphological remission, venetoclax will be dosed at 200mg daily days 2-14 inclusive. No dose ramp-up is required. Venetoclax continues at 200mg on days 1-14 from cycle 2 onwards.
If bone marrow blasts at screening >5%, a 2-day dose ramp-up is required.
Venetoclax 100mg on day 2, then 200mg on days 3-14. Venetoclax continues at 200mg on days 1-14 from cycle 2 onwards.

Once the optimal dose is determined in the safety run-in phase enrolment onto a proof-of-concept phase will commence using the dose level deemed tolerable.
Patients will be asked to complete a dose diary to confirm the tablets were taken. In order to monitor adherence to the interventions patients will be asked to return the gilteritinib and venetoclax containers (with unused tablets or empty containers) to the hospital.
Intervention code [1] 323763 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331665 0
To determine the MRD response of patients with FLT3-mutated AML in the MRD failure stratum to their first exposure to decision rule guided therapy with Venetoclax and Gilteritinib. To do this blood and bone marrow samples will be collected to assess your disease levels.
Timepoint [1] 331665 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] 410676 0
To determine the durability of the response of AML patients to Gilteritinib+ Venetoclax. 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 the blood and bone marrow samples.
Timepoint [1] 410676 0
Relapse-free survival (RFS): Measured from the date of response (morphological or molecular) to the earliest date of progression or the date of death without prior progression.
Secondary outcome [2] 410680 0
To investigate the dynamics of MRD response and the duration of clinical benefit in the morphologic and MRD failure strata as a combined outcome. This is assessed by bone marrow and peripheral. blood at screening, and end of cycle 1, 2,3,6,12, end of months 18 and 24 post treatment commencement.
Timepoint [2] 410680 0
Time from cycle 1 Day 1 to MRD response
Secondary outcome [3] 410682 0
To investigate the duration of MRD response in patients treated at MRD failure versus morphologic relapse assessed by MRD in bone marrow.
Timepoint [3] 410682 0
Duration of MRD response measured from the date of MRD response to the earliest date of MRD failure or the date of the death without prior progression.
Secondary outcome [4] 410686 0
To characterize the safety and tolerability of the combination Gilteritinib + venetoclax. This information will be gathered from patient self-reporting to the clinician, patient's medical records, adverse events of the treatment updated in the trial database for the patient, clinician physical exam, letters to clinician from GPs.
Timepoint [4] 410686 0
Occurrence of newly occurring or worsening
related CTCAE grade 3-5 non-hematologic adverse events at any time in the first 100 days post-Cycle 1 Day 1
related CTCAE grade 4-5 neutropenia or thrombocytopenia or grade 3-5 febrile neutropenia at any time in the first 100 days post-Cycle 1 Day 1
Secondary outcome [5] 411580 0
To investigate the efficacy of distinct treatment sequences in AML patients who fail one or more lines of therapy on study.
Timepoint [5] 411580 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 for up to a maximum of 5 years post-enrolment.
Secondary outcome [6] 411581 0
To determine the overall efficacy of the platform as an evolving system for managing patients with AML.
Timepoint [6] 411581 0
Overall survival as measured from the date of first dose of study drug until the date of last contact or death.
Secondary outcome [7] 411582 0
Quality of Life. this is measured together via the use of 2 quality of life tools.
Timepoint [7] 411582 0
Quality of Life (QoL) measured using QLQ- C30 and EQ-5D day 1 of cycle 1, day 1 of cycle 2, 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 a FLT3 (ITD and/or TKD) or CBL mutation in a bone marrow or peripheral blood sample taken no more than 42-days prior to cycle 1 day 1 if treatment on this treatment arm.
3. ECOG 0-2
4. 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,
5. 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)
6. 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
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) >450ms (except for right bundle branch block)
3. 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 less than or equal to 10mg/day for GVHD management is permitted)
4. Subject is HIV positive
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. 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 cycle 1 of the safety run-in phase and 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 6a).
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 radiation therapy within 4 weeks prior to the first study dose.
12. 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%.
13. Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject, which will require approval from the chief investigator.

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
Pilot Phase – Safety Run-In
A Bayesian optimal interval (BOIN) design will be used to verify the feasible doses for the combination therapy. The BOIN design is implemented in a way that is similar to the traditional 3+3 design. The target toxicity rate for the feasible expansion dose is Phi equal to 0.33 and the maximum sample size is 12. Patients will be enrolled and treated in cohorts of size 3. After the safety run-in is completed, selection of the dose level for expansion will be guided by isotonic regression as specified in Liu and Yuan (2015). This computation will be performed using the shiny app “BOIN” available at http://www.trialdesign.org.

Statistical Analysis of the Primary Endpoint
Response rates will be calculated as percentages within the MRD “treatment failure” stratum. 95% credible intervals will be calculated and will utilise a minimally informative prior for the response rate (median response rate equal to 35%).
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 the FLT3/CBL domain will be based primarily on the observed response rate calculated for the MRD “treatment failure” response stratum
Proof-of-concept (PoC) for the efficacy of the gilteritinib/venetoclax therapy in the MRD failure stratum for FLT3 mutated patients 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 will commence when the first 10 MRD failure patients with FLT3 mutated AML enrolled at the confirmed feasible dose are evaluable for response. Patients in the MRD failure stratum with FLT3-mutated AML who received the feasible dose during the pilot phase will be included in the analyses of 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, for MRD failure FLT3-mutated patients, can be declared (and published) at any time after evaluation of the first 10 patients.
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 guidelines for (non-binding) early stopping for futility are:
1. Observed response rate less than 40%.
2. Posterior probability that the true response rate is greater than or equal to 30%, given the data, is less than or equal to 0.10.
Monitoring of the dual criteria for futility will also commence when the first 10 patients with FLT3- mutated AML in the MRD failure stratum are evaluable for response.

When the true response rate is less than 21% the probability that PoC is declared is 5% or less and so the “false positive rate” is controlled below the conventional 5% level .

For true response rates in the vicinity of the futility rate (30%) the probability of an indeterminate outcome can be as high as 53% and the expected sample size is more than 22 patients when the planned number of patients enrolled at the confirmed feasible dose is 30.

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] 24877 0
New Zealand
State/province [1] 24877 0
Auckland

Funding & Sponsors
Funding source category [1] 311610 0
Other Collaborative groups
Name [1] 311610 0
Australasian Leukaemia and Lymphoma Group
Country [1] 311610 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Ground Floor, 35 Elizabeth Street, Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 313043 0
None
Name [1] 313043 0
Address [1] 313043 0
Country [1] 313043 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311052 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 311052 0
55 Commercial Road Melbourne, VIC 3004
Ethics committee country [1] 311052 0
Australia
Date submitted for ethics approval [1] 311052 0
06/12/2021
Approval date [1] 311052 0
18/05/2022
Ethics approval number [1] 311052 0
Ethics committee name [2] 313247 0
Bellberry Ltd
Ethics committee address [2] 313247 0
123 Glen Osmond RoadEastwoodSouth Australia 5063
Ethics committee country [2] 313247 0
Australia
Date submitted for ethics approval [2] 313247 0
30/11/2022
Approval date [2] 313247 0
13/02/2023
Ethics approval number [2] 313247 0
2022/ETH0392
Ethics committee name [3] 313248 0
Central Adelaide Local Health Network
Ethics committee address [3] 313248 0
Level 3 Roma Mitchell Building136 North Terrace,Adelaide SA 5000
Ethics committee country [3] 313248 0
Australia
Date submitted for ethics approval [3] 313248 0
06/12/2022
Approval date [3] 313248 0
15/12/2022
Ethics approval number [3] 313248 0
2022/HREC00129

Summary
Brief summary
This is a combined drug treatment arm within the ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842. The combination of gilteritinib 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:

The trial will commence with a safety run to determine the optimal dosing. Gilteritinib is given orally with or without food. Venetoclax is given orally after food. Venetoclax dose ramp-up is required only for patients commencing therapy with bone marrow blasts of greater than or equal to 5%. Each cycle will be 28-days in length

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 Gilteritinib 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 119826 0
Prof Andrew Wei
Address 119826 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000
Country 119826 0
Australia
Phone 119826 0
+61 3 8559 7915
Fax 119826 0
Email 119826 0
andrew.wei@petermac.org
Contact person for public queries
Name 119827 0
Ms Deliane Smith
Address 119827 0
Australasian Leukaemia & Lymphoma Group35 Elizabeth St, Richmond VIC 3121
Country 119827 0
Australia
Phone 119827 0
+6138373 9702
Fax 119827 0
Email 119827 0
info@allg.org.au
Contact person for scientific queries
Name 119828 0
Ms Deliane Smith
Address 119828 0
Australasian Leukaemia & Lymphoma Group35 Elizabeth St, Richmond VIC 3121
Country 119828 0
Australia
Phone 119828 0
+6138373 9702
Fax 119828 0
Email 119828 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.

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