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Trial registered on ANZCTR


Registration number
ACTRN12624000141549
Ethics application status
Approved
Date submitted
31/10/2023
Date registered
15/02/2024
Date last updated
26/05/2024
Date data sharing statement initially provided
15/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM26/T2 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - Ivosidenib + Venetoclax
Scientific title
AMLM26/T2- 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 - Ivosidenib + Venetoclax
Secondary ID [1] 310866 0
AMLM26/T2
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 - Ivosidenib + Venetoclax

Health condition
Health condition(s) or problem(s) studied:
acute myeloid leukaemia 331905 0
Condition category
Condition code
Cancer 328639 328639 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 combination - Ivosidenib + Venetoclax.

Ivosidenib and Venetoclax are both tablets that will be administered orally once a day up to 12 cycles, each 28 days in duration. Ivosidenib is taken with or without food and Venetoclax is taken after food. Ivosidenib is started on day 15 of the first cycle and taken continuously. Venetoclax is given days 1-14.

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 500mg daily ivosidenib day 15 onwards, and 800mg Venetoclax daily days 1 to 14. If not tolerable 500mg daily ivosidenib day 15 onwards, and 600mg Venetoclax daily days 1 to 14 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 500mg daily ivosidenib day 15 onwards, and 800mg Venetoclax daily days 1 to 14 (utilising the recommended phase 2 dose determined by the sponsored phase 1b/II study (NCT03471260) to be most tolerable and effective).Patients with morphologic disease will undertake a dose ramp up of Venetoclax in cycle 1 only 100mg on Day 1, 200mg on day 2, 400mg on day 3 and 800mg on days 4to 14.

Patients will be asked to complete a dose diary to confirm the tablets were taken. Patients will also be asked to return the ivosidenib and venetoclax bottles (with unused tablets or empty containers) to the hospital. This is to monitor compliance with the treatment.
Intervention code [1] 327285 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336438 0
To determine the response of patients with IDH1 mutated AML in the MRD failure stratum to their first-exposure to decision rule guided therapy with venetoclax and ivosidenib
Timepoint [1] 336438 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] 428405 0
To determine the durability of the response of patients with AML to decision-rule guided therapy to Ivosidenib and Venetoclax.
Timepoint [1] 428405 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] 428406 0
To investigate the dynamics of MRD response combined with the duration of clinical benefit in the morphologic and MRD failure strata.
Timepoint [2] 428406 0
Time from cycle 1 Day 1 until time of MRD response
Secondary outcome [3] 428407 0
To investigate the duration of MRD response in patients treated at MRD versus morphologic failure
Timepoint [3] 428407 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 [4] 428408 0
To characterize the safety and tolerability of Ivosidenib + Venetoclax
Timepoint [4] 428408 0
at any time in the first 100 days post cycle 1 day 1 on therapy
Secondary outcome [5] 428409 0
Quality of Life
Timepoint [5] 428409 0
Day 1 of cycles 1-3.
Secondary outcome [6] 428410 0
To investigate the efficacy of distinct treatment sequences in AML patients who fail one or more lines of therapy on study.
Timepoint [6] 428410 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 [7] 428411 0
To determine the overall efficacy of the platform as an evolving system for managing patients with AML.
Timepoint [7] 428411 0
Overall survival as measured from the date of first dose of study drug until the date of last contact or death

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 an IDH1 mutation in a bone marrow or peripheral blood sample taken no more than 28 days prior to cycle 1 day 1 of 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) greater than 450ms (except for right bundle branch block)
3. Prior allogeneic stem cell transplant within 30 days of post-transplant conditioning, or on immunosuppression for graft vs host disease (GVHD) (other than less than or equal to 10mg/day of prednisolone which 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, or greater than 10mg/day prednisolone for graft versus host disease
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 pilot 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 5a)
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%.

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 in the MRD progression treatment failure stratum. 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 = 0.33 and provision will be made to enroll 9 patients in the safety run-in. 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.
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 IDH 1 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 therapy in the MRD failure stratum for IDH1 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).
Based on expected rates of MRD salvage with Azacitidine or intensive chemotherapy, an approximate 50% response rate, a therapy with an observed ORR of greater than or equal to 40% is considered to be a viable alternative to intensive salvage chemotherapy, more so if there is a high chance that the true ORR is greater than 30%.
Monitoring of the dual criteria for PoC will commence when the first 10 MRD failure patients with IDH1 mutated AML are evaluable for response. Patients in the MRD failure stratum who received the feasible dose of ivosidenib + venetoclax combination during the pilot phase will be included in the analyses of response. A decision will be made whether to expand to at least 60 patients if approved by the TMC, trial coordinating centre and pharmaceutical company. It is envisaged that these criteria will be assessed whenever data become available for every 5 evaluable patients up to 30 evaluable patients. It is further envisaged that PoC can be declared (and published) at any time after the evaluation of 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 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 MRD failure patients 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 failure stratum. It is expected that PoC would be declared in the first 3 “looks” at the accumulating response data in a stratum and the 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.
As expected, for true response rates in the neighbourhood of the futility rate cut-off (30%) the probability of an indeterminate outcome can be higher than 50%.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2024
Actual
Date of last participant enrolment
Anticipated
1/08/2027
Actual
Date of last data collection
Anticipated
1/08/2028
Actual
Sample size
Target
69
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 25930 0
New Zealand
State/province [1] 25930 0

Funding & Sponsors
Funding source category [1] 315126 0
Other Collaborative groups
Name [1] 315126 0
Australasian Leukaemia & Lymphoma Group
Country [1] 315126 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] 317140 0
None
Name [1] 317140 0
Address [1] 317140 0
Country [1] 317140 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314062 0
the Alfred Hospital Ethics Committee
Ethics committee address [1] 314062 0
55 Commercial Road Melbourne, VIC 3004
Ethics committee country [1] 314062 0
Australia
Date submitted for ethics approval [1] 314062 0
12/02/2024
Approval date [1] 314062 0
Ethics approval number [1] 314062 0
Ethics committee name [2] 314065 0
Bellberry Limited
Ethics committee address [2] 314065 0
123 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [2] 314065 0
Australia
Date submitted for ethics approval [2] 314065 0
20/02/2024
Approval date [2] 314065 0
Ethics approval number [2] 314065 0
Ethics committee name [3] 314066 0
Central Adelaide Local Health Network HREC
Ethics committee address [3] 314066 0
Level 3 Roma Mitchell Building 136 North Terrace, Adelaide SA 5000
Ethics committee country [3] 314066 0
Australia
Date submitted for ethics approval [3] 314066 0
19/12/2023
Approval date [3] 314066 0
20/12/2023
Ethics approval number [3] 314066 0

Summary
Brief summary
This is an investigational combination treatment arm within the ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842. This treatment arm (Ivosidenib + 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
Ivosidenib and Venetoclax are given orally. Ivosidenib 500mg once a day commencing day 15 of cycle one and taken continuously and Venetoclax administered days 1-14 of a 28 day cycle for 12 cycles. Patients with minimal residual disease will have a pilot safety run-in phase to confirm dose - investigating Venetoclax doses 800mg or 600mg daily. Once a tolerable dose is determined that dose will be used in a proof of concept phase.. Patients with morphologic relapse will enter directly into a proof of concept phase using a Venetoclax dose of 800mg daily with a dose ramp up in cycle 1.

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 Ivosidenib 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 130278 0
Prof Andrew Wei
Address 130278 0
Peter MacCallum Cancer Centre 305 Grattan Street Melbourne VIC 3000
Country 130278 0
Australia
Phone 130278 0
+61 3 8559 7915
Fax 130278 0
Email 130278 0
[email protected]
Contact person for public queries
Name 130279 0
Delaine Smith
Address 130279 0
Australasian Leukaemia & Lymphoma Group 35 Elizabeth St, Richmond VIC 3121
Country 130279 0
Australia
Phone 130279 0
+61 383739702
Fax 130279 0
Email 130279 0
[email protected]
Contact person for scientific queries
Name 130280 0
Delaine Smith
Address 130280 0
Australasian Leukaemia & Lymphoma Group 35 Elizabeth St, Richmond VIC 3121
Country 130280 0
Australia
Phone 130280 0
+61 383739702
Fax 130280 0
Email 130280 0
[email protected]

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.