Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001338651p
Ethics application status
Not yet submitted
Date submitted
28/11/2023
Date registered
19/12/2023
Date last updated
19/12/2023
Date data sharing statement initially provided
19/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
CML14 (ASCENDANCE) - A study to assess efficacy of combination therapy with asciminib plus low dose dasatinib in newly diagnosed chronic phase Chronic Myeloid Leukaemia (CML) with high risk genetics
Scientific title
CML14 (ASCENDANCE) - ASCiminib Evaluation in Newly diagnosed CML with Dasatinib to Augment response in Complex genomic Etiology
Secondary ID [1] 311041 0
None
Universal Trial Number (UTN)
Trial acronym
CML14 ASCENDANCE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Myeloid Leukaemia (CML)
 332156 0
Condition category
Condition code
Cancer 328878 328878 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Asciminib is an oral-tablet available in capsule strengths of 20mg or 40mg. Both capsule strengths will be used interchangeably depending on the patient's condition.

All patients will receive treatment with asciminib monotherapy at 80mg daily for the first 4 weeks.

• At the end of this period, New Generation Sequencing (NGS) and cytogenetic results will be available from the central and local labs. The presence of additional genomic abnormalities (AGA) will be defined by the central lab for each case as per predefined criteria. The presence of high risk Additional Cytogenetic Abnormalities (ACAs) are defined in this protocol as” duplication of Ph-positive chromosome, trisomy 8, trisomy 19, i(17q), and chromosome 3q26 abnormalities.

• Patients with evidence of AGAs and high risk ACAs will be assigned to the high risk cohort, and will receive asciminib 80mg plus dasatinib 50mg daily via oral tablet.
- All patients with high risk will receive combination therapy from month 2 . High risk patients are assessed for BCR-ABL1 by cytogenetics at 3, 6 and 12 months.
- Patients who achieved Molecular Response 4 (MR4) at the 3 month timepoint or afterwards will de-escalate to asciminib monotherapy. Those that do not achieve MR4 at the 3 or 6 month timepoint will continue on asciminib plus dasatinib.
- Patients without MR4 at month 12 will de-escalate to asciminib monotherapy. An extension of combination therapy to the 18th month timepoint is permitted at the discretion of the investigator
- Patients with intolerance to combination therapy, despite maximal supportive therapy for the same, will deescalate to asciminib monotherapy at any time

• All other patients will be assigned to the standard risk cohort and will continue to receive asciminib 80mg daily monotherapy.
- AGA negative patients will then have to achieve predetermined targets: BCR::ABL1 of less than or equal to 10 percent, at 3 & 6 months, and less than or equal to 1percent, at 12 and 18 months. Patients failing to achieve these responses will have dasatinib 50mg daily added to asciminib 80mg daily. Patients with “warning” under ELN2020 will be offered, at investigator discretion, asciminib dose escalation to 80mg twice a day (for responses of BCR::ABL1 of less than or equal to 10percent but less than 1percent at 6 months, less than or equal to 1percent but greater than 0.1percent at 12 months, and no MR4, but achieved Major Molecular Response [MMR] at 18 months).

Overall treatment duration is 2 years post-enrollment. All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.
Intervention code [1] 327484 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336684 0
Early Molecular Response (EMR)
Timepoint [1] 336684 0
At 3 months after starting study treatment.
Primary outcome [2] 336685 0
Molecular Response 4 (MR4) at 12 months
Timepoint [2] 336685 0
At 12 months after starting study treatment.
Secondary outcome [1] 429328 0
Safety and tolerability of asciminib (as a composite secondary outcome)
Timepoint [1] 429328 0
At all scheduled timepoints of trial treatment: baseline, days 8, 29 & 57, then every 3 months until End of Study (EOS) (2 years of study treatment, 3 years of follow up).
Secondary outcome [2] 429329 0
Overall survival (OS), progression free survival (PFS), event free survival (EFS) and failure free survival (FFS) in patients with AGAs and without.
All measures will be assessed together as a composite secondary outcome
Timepoint [2] 429329 0
OS: time from enrolment to death from any cause.
PFS: time from enrolment to first of Accelerated Phase (AP), Blast Crisis (BC) or death from any cause.
FFS: time from enrolment to first of AP, BC, death from any cause, loss of response (confirmed MR4, MMR, MR2, clinically relevant mutations, failure to achieve BCR::ABL1 less than or equal to 1percent after 12 months),
EFS: as per FFS, but including withdrawal due to treatment resistance or intolerance.
Final end point: At end of trial.
Secondary outcome [3] 429330 0
Proportion of MR2, MMR, MR4 and MR4.5 at various timepoints, as stratified for additional genomic abnormalities at baseline.
All measures will be assessed together as a composite secondary outcome.
Timepoint [3] 429330 0
At 12, 24, 36, 48 and 60 months from the start of the treatment..
Secondary outcome [4] 429331 0
Rate of treatment failure and their mechanisms
Timepoint [4] 429331 0
At all scheduled timepoints of trial treatment: baseline, days 8, 29 & 57, then every 3 months until End of Study (EOS) (2 years of study treatment, 3 years of follow up).
Secondary outcome [5] 429332 0
Effect of salvage therapies in patients who have not met their treatment targets.
Timepoint [5] 429332 0
At 6 and 12 months from the start of the treatment
Secondary outcome [6] 429333 0
Changes in Quality of Life (QOL) through patient reported outcomes (PROs)
Timepoint [6] 429333 0
At screening, months 3, 6, 12, 18, 24 after starting study treatment and at End of Study (5 years after starting study treatment, EOS) or early withdrawal

Eligibility
Key inclusion criteria
1. Newly diagnosed Ph-positive Chronic Phase (CP)-CML patients aged 18 or older
a) No prior (Tyrosine Kinase Inhibitor) TKI exposure of more than 14 days. (Hydroxyurea, anagrelide, leukapheresis allowed prior, and up to 1 week after starting study treatment)
b) Must be 6 months or less from diagnosis to screening
c) Must have e13a2 (b2a2) and/or e14a2 (b3a2) or e1a2 transcript on screening
d) Must have bone marrow aspirate confirming chronic phase as per ELN (not WHO) criteria. Additional cytogenetic abnormalities at baseline or diagnosis do not classify a patient as accelerated phase for the purpose of this study.
2. Willingly provide informed consent and agree to comply with study protocol
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
4. Based on known medical history, expected to have a life expectancy of 12 months or more
5. Eligible for a reimbursed treatment with imatinib or dasatinib under the Pharmaceutical Benefit Scheme (PBS) complex drug program in Australia, the Pharmac system in New Zealand or through other arrangements with regulatory and funding authorities (compassionate supply or hospital funded supply).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Abnormal clinical laboratory results
a) Total bilirubin greater than 1.5 times Upper Limit of Normal (ULN) (in patients with Gilbert’s syndrome, total bilirubin greater than 3 times ULN, or direct bilirubin greater than 1.5 times ULN)
b) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 times ULN.
c) Alkaline phosphatase greater than 2.5 times the ULN unless considered to be not of hepatic origin
d) Creatinine greater than 1.5 times ULN
e) Amylase or Lipase values greater than 1.5 times institutional ULN
2. Treatment with strong inducers of CYP3A4 or CYP3A5, CYP2C8 and CYP2C9 (Consumption of grapefruit, Seville oranges, star fruit and their juice or derivatives or products is not permitted whilst a patient is taking study medication).
3. Active, uncontrolled infection requiring systemic therapy at the time of screening
4. History of significant congenital or acquired bleeding disorder unrelated to cancer.
5. Known human immunodeficiency virus (HIV) positive (testing to exclude infection is not required in the absence of suggestive history)
6. Serious medical or psychiatric illness likely to interfere with safety and efficacy monitoring or otherwise jeopardising the participant’s health within this clinical study.
7. Corrected QT interval (QTc) of greater than 480 milliseconds (ms) on baseline electrocardiogram (ECG) (using corrected QT interval using Fridericia [QTcF]).
8. Uncontrolled cardiovascular condition, including ongoing cardiac arrhythmias (e.g. ventricular arrhythmias or Torsades de Pointe, or third degree heart block without pace maker insertion); congestive heart failure, angina, or myocardial infarction within the past 3 months prior to screening.
9. Other concurrent uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infections, acute or chronic renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol.
10. A history of concomitant primary malignant disease that requires active cytotoxic treatment and / or a life limiting illness expected to have a life expectancy greater than 5 years.
11. History of acute pancreatitis within 1 year of study entry, chronic pancreatitis, or any ongoing pancreatic disease.
12. Acute or chronic active liver disease. (HBV core antibody positivity is not an automatic exclusion.)
13. Subjects unable to comply with requirements for contraception as per study requirements.
14. Reproductive status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU per L or equivalent units of HCG) within 24 hours prior to the start of study drug.
b) Women must not be breastfeeding.
c) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug, plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion.
d) Men who are sexually active with Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion.
e) Azoospermic males are exempt from contraceptive requirements.
15. Current participation in another therapeutic clinical trial (participation in clinical trials that do not involve active interventions is not an exclusion for the study).

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
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
1/05/2024
Actual
Date of last participant enrolment
Anticipated
1/05/2026
Actual
Date of last data collection
Anticipated
1/05/2029
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 25995 0
New Zealand
State/province [1] 25995 0

Funding & Sponsors
Funding source category [1] 315300 0
Other Collaborative groups
Name [1] 315300 0
Australasian Leukaemia and Lymphoma Group (ALLG)
Country [1] 315300 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Ground Floor, 35 Elizabeth St, Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 317346 0
None
Name [1] 317346 0
Address [1] 317346 0
Country [1] 317346 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 314224 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 314224 0
Port Road, Adelaide, SA 5000
Ethics committee country [1] 314224 0
Australia
Date submitted for ethics approval [1] 314224 0
01/03/2024
Approval date [1] 314224 0
Ethics approval number [1] 314224 0

Summary
Brief summary
The purpose of this trial is to assess efficacy of an induction phase of combination therapy with asciminib plus low dose dasatinib in newly diagnosed chronic phase CML (CP-CML) with high-risk genetics, with respect to achievement of major and deep molecular response.

CML14 (ASCENDANCE) is a successor trial to the ALLG-sponsored CML13 (ASCEND-CML, ACTRN12620000851965). CML14 aims to further improve outcomes through the use of our NGS panel to identify AGAs, and offer these patients with AGAs frontline treatment with combination asciminib / dasatinib therapy.

Who is it for?
You may be eligible for this study if you are aged 18 and above and have been newly diagnosed with CP-CML.

Study details
Participants who choose to participate in this trial will receive treatment with asciminib monotherapy at 80mg daily for the first 4 weeks.
At the end of this period, New Generation Sequencing (NGS) and cytogenetic results will be available from the central and local labs. The presence of additional genomic abnormalities (AGA) will be defined by the central lab for each case as per predefined criteria.
Patients with evidence of AGAs and high risk ACAs will be assigned to the high risk cohort, and will receive combination treatment of asciminib 80mg plus dasatinib 50mg daily
- All patients with high risk will receive combination therapy between months 2 to 12.
- Patients who achieved Molecular Response 4 (MR4), and confirmed at a timepoint 3 months afterwards, will de-escalate to asciminib monotherapy.
- Patients without MR4 at month 12 will de-escalate to asciminib monotherapy. An extension of combination therapy to the 18th month timepoint is permitted at the discretion of the investigator
- Patients with intolerance to combination therapy, despite maximal supportive therapy for the same, will deescalate to asciminib monotherapy at any time

All other patients (without evidence of AGAs and high risk ACAs) will be assigned to the standard risk cohort and will continue to receive asciminib 80mg daily monotherapy.
- AGA negative patients will then have to achieve predetermined targets: BCR::ABL1 of less than or equal to 10 percent, at 3 & 6 months, and less than or equal to 1percent, at 12 and 18 months to continue with asciminib 80mg daily.
- Patients failing to achieve these responses will have dasatinib 50mg daily added to asciminib 80mg daily.
- Patients with “warning” under ELN2020 will be offered, at investigator discretion, asciminib dose escalation to 80mg twice a day.
Overall treatment duration is 2 years post-enrolment. All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.

It is hoped this research will improve overall survival and molecular response achievement and minimise treatment related morbidity and mortality for CP-CML patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130846 0
A/Prof David Yeung
Address 130846 0
Royal Adelaide Hospital, Port Rd, Adelaide SA 5000
Country 130846 0
Australia
Phone 130846 0
+6 18 7074 0000
Fax 130846 0
Email 130846 0
david.yeung@adelaide.edu.au
Contact person for public queries
Name 130847 0
Ms Delaine Smith
Address 130847 0
ALLG, 35 Elizabeth St, Richmond, VIC 3121
Country 130847 0
Australia
Phone 130847 0
+61 3 8373 9701
Fax 130847 0
Email 130847 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 130848 0
Ms Delaine Smith
Address 130848 0
ALLG, 35 Elizabeth St, Richmond, VIC 3121
Country 130848 0
Australia
Phone 130848 0
+61 3 8373 9701
Fax 130848 0
Email 130848 0
delaine.smith@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.