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
Chronic Myeloid Leukaemia (CML)
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.
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).
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).
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).
Australasian Leukaemia & Lymphoma Group
CML14 ASCENDANCE
ACTRN12623001338651p