Study Description
This will be a multicenter Phase II open-label study of asciminib in CML-CP patients who
have been previously treated with one prior ATP- binding site TKI with discontinuation
due to treatment failure, warning or intolerance. (2L patient cohort). In addition, newly
diagnosed CML-CP patients who may have received up to 4 weeks of prior TKI are included
in a separate 1L patient cohort. This trial consists of three periods: screening and baseline for up to 28 days, active
treatment for up to 104 weeks and a safety follow up period for 30 days.
Ninety-two (92) 2L patients with CML-CP without T315I mutation who had 1 prior
ATP-binding site TKI discontinued due to treatment failure, warning or intolerance will
be considered for the current study. Patients will be tested at screening for the T315I
mutation and excluded if the mutation is found.
To gain additional insights into the effect of asciminib in the 1L setting, an additional
cohort of newly diagnosed CML-CP patients will be enrolled in the study. Based on the
number of participating sites, it is approximated that between 60 and 90 patients could
be enrolled. Enrollment of the 1L cohort will be stopped when a maximum of 90 patients
have been enrolled or when approximately 60 patients have been enrolled and the 2L cohort
is fully recruited, whichever comes first.
Informed consent will be obtained before any procedures are performed for the study
including eligibility assessments.
All eligible patients will be initially treated with asciminib at 80 mg QD. At 6 months
of study treatment, patients who have achieved BCR-ABL1IS ≤1% will continue on the same
dose whereas those who have not will increase dose to 200mg QD.
At 12 months of study treatment, patients will be evaluated for the primary endpoint of
the study (MMR at 12 month in 2L patient cohort) and will pursue one of the following:
- Continue on the current dose of asciminib if MMR is achieved
- Increase dose to 200 mg QD if on 80 mg QD dosing and MMR is not achieved
- Increase dose to 200 mg BID if on 200 mg QD dosing and MMR is not achieved
- Take the patient off the study and switch to Investigator's agent of choice if MMR
is not achieved and it is in the interest of the patient based on investigator's
clinical judgment of prospect treatment benefit.
Interventions
asciminib
Eligibility Criteria
Key Inclusion Criteria:
Participants eligible for inclusion in this study must meet the following criteria:
Criteria #1-5 are common to both patient cohorts (2L and 1L):
1. Signed informed consent must be obtained prior to participation in the study
2. CML-CP, no previous AP or BC
3. ≥ 18 years of age
4. ECOG performance status of 0, 1 or 2
5. Adequate end organ function within 14 days before the first dose of asciminib
treatment.
Patients with mild to moderate renal and hepatic impairment are eligible if:
- Total bilirubin ≤ 3.0 x ULN without AST/ALT increase
- Aspartate transaminase (AST) ≤ 5.0 x ULN
- Alanine transaminase (ALT) ≤ 5.0 x ULN
- Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN and ≤ 1.5 x ULN, value should be
considered not clinically significant and not associated with risk factors for acute
pancreatitis
- Alkaline phosphatase ≤ 2.5 x ULN
- Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft- Gault formula
Criteria #6 and 7 are specific to the 2L patient cohort 6. Warning or failure
(according to 2020 ELN Recommendations; Hochhaus et al) to 1L TKI therapy at the
time of screening a. Warning is defined as: i. Six months after the initiation of
treatment: BCR- ABL1IS >1-10% ii. Twelve months after the initiation of treatment:
BCR- ABL1IS >0.1-1% b. Treatment failure/resistance to 1L TKI is defined as: i.
BCR-ABL1IS >10% if 1L treatment duration between 6 and 12 months ii. BCR-ABL1IS >1%
if 1L treatment longer than 12 months treatment: loss of MMR 7. Beyond 12 months
after the initiation of to 1L TKI, a. BCR-ABL1IS > 0.1% at screening b. Intolerance
is defined as: i. Non-hematologic intolerance: Patients with grade 3 or 4 toxicity
while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal
management, including dose adjustments (unless dose reduction is not considered in
the best interest of the patient if response is already suboptimal) ii. Hematologic
intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or
platelets) while on therapy that is recurrent after dose reduction to the lowest
doses recommended by manufacturer Criteria #8 is specific to the 1L patient cohort
8. Patients with newly diagnosed CML-CP (treatment with a prior TKI (imatinib, or
nilotinib, or dasatinib or bosutinib) for ≤ 4 weeks is allowed)
Key Exclusion Criteria:
1. Previous treatment
1. With 2 or more ATP-binding site TKIs (for 2L patient cohort)
2. More than 4 weeks with 1-ATP-binding site TKIs (for 1L patient cohort)
2. Previous treatment with asciminib
3. Known presence of the T315I mutation at any time prior to study entry
4. Known second chronic phase of CML after previous progression to AP/BC
5. Previous treatment with a hematopoietic stem-cell transplantation
6. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
7. Cardiac or cardiac repolarization abnormality, including any of the following:
- History within 6 months prior to starting study treatment of myocardial
infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),
complete left bundle branch block, high-grade AV block (e.g., bifascicular
block, Mobitz type II and third degree AV block)
- QTcF at screening ≥450 msec (male patients), ≥450 msec (female patients)
- Long QT syndrome, family history of idiopathic sudden death or congenital long
QT syndrome, or any of the following:
- Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or
hypomagnesemia, history of cardiac failure, or history of clinically
significant/symptomatic bradycardia
- Concomitant medication(s) with a "Known risk of Torsades de Pointes" per
www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to
starting study drug by safe alternative medication
- Inability to determine the QTcF interval
8. History of acute pancreatitis within 1 year of study entry or past medical history
of chronic pancreatitis
9. Participation in a prior investigational study within 30 days prior to randomization
or within 5 half-lives of the investigational product, whichever is longer
10. Treatment with medications that meet one of the following criteria is not allowed
and should be switched to an alternative at least one week prior to the start of
treatment with study treatment:
- Strong inducers of CYP3A for patients on the dose of 80 mg QD and 200mg QD
- Strong inducers and inhibitors of CYP3A for patients on the dose of 200 mg BID
11. Pregnant or nursing (lactating) women
12. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception.
Highly effective contraception for women should be maintained throughout the study
and for at least 7 days after the last dose.
13. Sexually active males unwilling to use a condom during intercourse while taking
study treatment and for 7 days after stopping study (only for patients treated with
asciminib).
14. Severe and/or uncontrolled concurrent medical disease that in the opinion of the
Investigator could cause unacceptable safety risks or compromise compliance with the
protocol (e.g. uncontrolled diabetes, active or uncontrolled infection; uncontrolled
arterial or pulmonary hypertension, uncontrolled clinically significant
hyperlipidemia).
15. History of other active malignancy within 3 years prior to study entry with the
exception of previous or concomitant basal cell skin cancer and previous carcinoma
in situ treated curatively.
16. Known hypersensitivity to the study treatment.
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