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Trial registered on ANZCTR


Registration number
ACTRN12624000738527
Ethics application status
Approved
Date submitted
9/05/2024
Date registered
14/06/2024
Date last updated
6/07/2024
Date data sharing statement initially provided
14/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
AMLM22/D4: The International AML Platform Consortium (IAPC) trial – Combining Oral Azacitidine and Dendritic Cell Vaccination Vididencel in maintenance (CADENCE)
Scientific title
AMLM22/D4: The International AML Platform Consortium (IAPC) trial – is a randomised, 2-arm trial that will investigate the efficacy of oral Azacitidine combined with an allogeneic dendritic cell vaccine vididencel, compared with oral Azacitidine alone, in maintaining or inducing negativity for measurable residual disease (MRD) in AML patients in first complete remission (CR1) following intensive chemotherapy.
Secondary ID [1] 312109 0
Nil known
Universal Trial Number (UTN)
Trial acronym
AMLM22 D4 CADENCE
Linked study record
ACTRN12619000248167and ACTRN12619000280101 are linked to this study as these are sub-studies of the main platform study

Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia (AML) 333749 0
Condition category
Condition code
Cancer 330433 330433 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This domain of the AMLM22 platform trial (ACTRN12619000248167) is a randomised, 2-arm trial that will investigate the efficacy of oral azacitidine combined with an allogeneic dendritic cell vaccine vididencel, compared with oral azacitidine alone, in maintaining or inducing negativity for measurable residual disease (MRD) in AML patients in first complete remission (CR1) following intensive chemotherapy, not planned for alloSCT.

Oral tablet -Aza 300mg is administered orally daily on days 1-14 of repeated 28-day cycles, continued until progression to more than 15% blasts or unacceptable adverse events. Patients with low level AML relapse with 5-15% blasts in blood or bone marrow can have the dosing regimen increased to 21 days per cycle at the discretion of the treating investigator.

Vididencel is administered as an intradermal vaccine. A primary course of vididencel will be administered intradermally by a trained clinician on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 15 (totaling 4 injections) at a dose of 25 x 106 cells/vc, followed by a booster course of 3 additional injections on Day 1 of cycle 4, Day 1 of cycle 5 and Day 1 of cycle 6 at a dose of 10 x 106 cells/vc. The intervention will be administered as inpatient, and administration and visit details will be captured in a electronic database.

Patient will receive 24 cycles of treatment but the vididencel will be only administered according to the previous paragraph. Disease progression with greater than or equal to 15% blasts in bone marrow and/or peripheral blood, Unacceptable toxicity or Adverse event are considered sufficient reasons for discontinuing a patient from the trial treatment.

Trial has 2 stages:
1. Stage 1: Pilot Phase, n = 40
2. Stage 2: Proof of concept, n = 100

The two participant groups will have separate recruitment. The first (pilot) stage will consist of 40 patients. Patients will be randomized 1:1 in each age stratum until a total of 40 patients has been randomized. If there are no adverse safety signals the second (proof of concept) stage will open and an additional 100 patients will be randomized. Both stage patient will have the same the same dosing. A pause in recruitment after stage 1 completes enrolment may be required for Trial management committee's (TMC) decision making. TMC will review the safety data from stage 1 patients and decide on the continuation of the trial to stage 2.
Intervention code [1] 328552 0
Treatment: Drugs
Comparator / control treatment
Control group will have Oral Azacitidine, a film coated tablet. Oral-Aza for this indication became available on the Pharmaceutical Benefits Scheme (PBS) in Australia on 1st September, 2023.
Control arm patients will have Oral Azacitidine: 300 mg Day 1-14 of 24 continuous 28-day cycles.

Control group
Active

Outcomes
Primary outcome [1] 338183 0
The primary objective of the pilot phase is to investigate safety based on rates of newly occurring or worsening toxicities in the experimental (combination) arm and the control (oral-Aza only) arm within the first 2 cycles of study drug.
Timepoint [1] 338183 0
Safety assessments will include evaluating adverse events and serious adverse events and concomitant medication / therapies used to treat them, daily for the first 2, 28-day cycles.
Primary outcome [2] 338265 0
The primary endpoint in Stage 2 of the study is leukaemia event free survival (LFS).
Timepoint [2] 338265 0
This is measured from the date of randomization to the date of the earliest occurrence of one of the following three events:

•MRD relapse or progression [defined as

1) conversion of MRD negativity to MRD positivity by centralised multiparameter flow
cytometry or ‘validated molecular test’ OR

2) increase of MRD greater than or equal to 1 log10 between any 2 positive samples measured in the same tissue
(peripheral blood (PB) or bone marrow (BM)) in patients who have detectable MRD or for NPM1
mutated AML, low level MRD (MRD-LL) , confirmed on greater than or equal to 2 consecutive tests AND a change in
treatment occurred as a result of the MRD relapse or progression.

•Conventional relapse (blasts >5% in bone marrow or peripheral blood)

•Death
Secondary outcome [1] 434851 0
The secondary endpoint of the pilot phase is:

- Confirmed MRD conversion to negative (in patients who are MRD+ at screening) by established MRD methods (such as NPM1 qPCR, or multiparameter flow cytometry);
- Achievement of CR without MRD (CRMRD-).

The cumulative incidence of confirmed MRD conversion from positive to negative and achievement of CRMRD- will be monitored and assessed together by the TMC.
Timepoint [1] 434851 0
End of cycles 2, 4 and 6 to determine remission status
Secondary outcome [2] 435200 0
The secondary endpoints of stage 2:
Overall survival (OS)
Timepoint [2] 435200 0
Time from the date of randomisation to 24 months post-treatment cycle 24
Secondary outcome [3] 435672 0
The secondary endpoints of stage 2:
Confirmed MRD conversion to negative (in patients who are MRD+ at screening) by established MRD methods (such as NPM1 qPCR or multiparameter flow cytometry);
Timepoint [3] 435672 0
Time from the date of randomisation to 24 months of treatment
Secondary outcome [4] 435673 0
The secondary endpoints of stage 2:
Duration of MRD negativity and Achievement of CR without MRD (CRMRD-)
Timepoint [4] 435673 0
Time from the date of randomisation to 24 months of treatment
Secondary outcome [5] 435677 0
The secondary endpoints of stage 2:
Quality of life (QOL)
Timepoint [5] 435677 0
At baseline (date of Randomisation), 6, 12, 18 and 24 months of treatment

Eligibility
Key inclusion criteria
A patient will be eligible for trial participation to this domain if they additionally meet the following criteria:

1. Is within 180 days of first CR / CRh / CRi.
2. Has undergone induction therapy with intensive chemotherapy, with or without consolidation therapy. Prior gemtuzumab ozogamicin, CPX-351 (Vyxeos), midostaurin or venetoclax used within the context of intensive induction are permitted.
3. Is not planned for alloSCT.
4. Has adequate bone marrow function, based on
- Platelets greater than or equal 50 x 109/L
- Neutrophils greater than or equal 0.5 x 109/L
5. Has an ECOG performance status of 0-3.
6. Has adequate organ function, defined as
- Serum bilirubin less than or equal to 1.5 times the upper limit of normal (ULN);
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 times the ULN;
- Serum creatinine less than or equal to 2.5 times the ULN;
7. Agrees to follow the recommended contraception procedures for this treatment arm from Study Day 1 to 180 days after the last dose of study drug
8. Is able to adhere to the trial visit schedule and other protocol requirements;
9. Is able to swallow study medication.
10. Understands and voluntarily signs the consent form prior to any study related assessments/procedures are conducted.
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A patient will not be eligible for trial participation to this domain if they meet any of the following exclusion criteria:
1. Presence of any exclusion criteria noted in the AMLM22 Master Protocol.
2. AML associated with inv(16), t(8;21), t(16;16) or molecular evidence of such translocations (ie. RUNX1::RUNX1T1, CBFB::MYH11)
3. There is an intent to undertake a stem cell transplant procedure in CR1.
4. Prior hypomethylating agents used in induction of AML. (Hypomethylating agents for a prior myelodysplastic syndrome (MDS) are permitted).
5. Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure;
6. Subject is HIV positive;
7. Evidence of other clinically significant, uncontrolled conditions(s) including, but not limited to
a) Uncontrolled and/or active systemic infection (viral, bacterial or fungal) (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment)
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) may participate.
8. Requirement for ongoing systemic immunosuppressive therapy equivalent to an average dose of greater than or equal to 10 mg of prednisone / day to avoid impairing the immune response to study therapy.
9. Active autoimmune disease, except for well controlled diabetes
10. Major surgical procedure (including open biopsy) within 28 days prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment.
11. Known or suspected hypersensitivity to azacitidine and/or vididencel (or its excipients)
12. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study;
13. Pregnant or lactating women
14. Any condition that would impair absorption of the study medication (i.e. short gut, malabsorption syndrome).

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)
Randomisation will occur by a central randomization procedure, in a 2-step process.
Participants will first be randomised to an eligible domain based on physical and disease characteristics. They will then be randomised to a treatment arm within that domain.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A stratified randomisation schedule, based on permuted blocks of variable size, will be implemented. Subjects will be stratified by: age at time of induction therapy ( less than 55 years and greater than/equal to 55 years) and cytogenetic risk category at time of induction therapy (Favourable risk / non-favourable risk)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
28/06/2024
Actual
Date of last participant enrolment
Anticipated
30/05/2026
Actual
Date of last data collection
Anticipated
30/05/2028
Actual
Sample size
Target
140
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC

Funding & Sponsors
Funding source category [1] 316467 0
Charities/Societies/Foundations
Name [1] 316467 0
Australian Leukaemia and Lymphoma Group (ALLG)
Country [1] 316467 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Australian Leukaemia and Lymphoma Group (ALLG)
Address
Country
Australia
Secondary sponsor category [1] 318641 0
Commercial sector/Industry
Name [1] 318641 0
Mendus
Address [1] 318641 0
Country [1] 318641 0
Sweden

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315256 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315256 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 315256 0
Australia
Date submitted for ethics approval [1] 315256 0
22/12/2023
Approval date [1] 315256 0
17/03/2024
Ethics approval number [1] 315256 0
HREC/48451/Alfred-2018

Summary
Brief summary
This study will evaluate the safety and efficacy of Combining Oral Azacitidine and Dendritic Cell Vaccination Vididencel in maintenance for Acute Myeloid Leukemia.

Who is it for?
You may be eligible to join this study if you are aged 16 and above and have Acute Myeloid Leukemia in first complete remission following intensive chemotherapy, not planned for allogeneic stem cell transplant

Study details:
This study is part of the International AML Platform Consortium. Participants in this study will be randomly allocated (by chance) to one of two treatment groups. Participants in one group will receive the oral drug Azacitidine daily on Days 1-14 of each 28 day cycle and a course of vididencel will be administered intradermally on cycle 1 (Day 1, Day 15), Cycle 2 (Day 1, Day 15), Cycle 4 day 1, Cycle 5 day 1, and Cycle 6 day 1. Oral-Aza 300mg will continued until progression to >15% blasts or unacceptable adverse events. Participants in the other group will receive the oral drug Azacitidine daily on Days 1-14 of each 28 day cycle, continued until progression to >15% blasts or unacceptable adverse events. Patient with low blast count (5-15%) can have oral Aza dosing regimen increased to 21 days per cycle, if Investigators finds that beneficial for the patient.

As part of the study, participants will have blood tests at the start of each cycle (every 28 days) and measurable residual disease testing on bone marrow samples at the end of each second cycle until cycle 6 and then end of every 3 cycles.

We hope that the results from this trial will be used to help these new treatments which may be better for people with AML than what is currently available become accessible to the general population at faster than the normal process.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134150 0
Prof Andrew Wei
Address 134150 0
Peter MacCallum Cancer Centre Grattan St Parkville, Victoria, Australia 3000
Country 134150 0
Australia
Phone 134150 0
+61 4 0389 9052
Fax 134150 0
Email 134150 0
[email protected]
Contact person for public queries
Name 134151 0
Delaine Smith
Address 134151 0
Australasian Leukaemia and Lymphoma Group Ground Floor, 35 Elizabeth Street, Richmond VIC 3121
Country 134151 0
Australia
Phone 134151 0
+61 3 8373 9701
Fax 134151 0
Email 134151 0
[email protected]
Contact person for scientific queries
Name 134152 0
Delaine Smith
Address 134152 0
Australasian Leukaemia and Lymphoma Group Ground Floor, 35 Elizabeth Street, Richmond VIC 3121
Country 134152 0
Australia
Phone 134152 0
+61 3 8373 9701
Fax 134152 0
Email 134152 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.