Asciminib as Initial Therapy with Addition of Lower Dose Tyrosine Kinase Inhibitors for Patients with Chronic Myeloid Leukemia who do not Achieve a Deep Molecular Remission (ALERT CML)

Cancer Categories

Karmanos Trial ID

NCT ID

Age Group

Scope

Phase

Principal Investigator

Primary Objective:

To estimate the proportion of patients with previously untreated CML-CP attaining deep molecular response. DMR defined as BCR-ABL1 < 0.0032% (MR4.5) by RQ-PCR.

Secondary Objective:

To estimate the proportion of patients achieving molecular response at specific time points
To estimate the time to molecular response
To evaluate the duration of hematologic and molecular response to asciminib
To define the time to progression and overall survival for patients with CML in early CP treated with asciminib
To evaluate the safety profile of asciminib in patients with CML-CP
To evaluate the development of ABL mutations for patients with CML in early CP treated with asciminib
To analyze differences in response rates and in prognosis within different risk groups and patient characteristics
To evaluate patient-reported outcomes in patients with CML receiving asciminib
To investigate treatment-free remission after at least 2 years of sustained deep molecular remission for patients receiving single agent asciminib

Exploratory:

To evaluate the safety and efficacy of concomitant use of nilotinib with asciminib in patients who have not achieved MR4.5.
To evaluate the rate of successful treatment discontinuation for patients using the combination of asciminib and nilotinib
Evaluate the role of Digital droplet PCR (ddPCR) in predicting TFR
Evaluating the correlation between the gene expression signature of patients and the chances of achieving MMR and DMR
Evaluate whether B, NK and T cells DNA mutation and RNA expression are relevant and whether they can predict response in patients with CML using single cell analysis.

Eligibility

Inclusion Criteria:

Age ≥18 years old
Willing and able to give informed consent
Newly diagnosed with CML in chronic phase within 6 months from confirmed diagnosis and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR::ABL1 protein. Subtype classification whether b3a2 (e14a2) or b2a2 (e13a2) is not required for study eligibility.
Minimal prior CML therapy with a TKI for less than or equal to 30 days. Treatment with hydroxyurea, busulfan, anagrelide or other non-specific chemotherapy agents is allowed with no time restrictions within the eligible time from diagnosis.
ECOG performance status 0-2 (appendix 1)
Adequate organ function:

AST and ALT < 3 times the institutional upper limit of normal (ULN)
Creatinine < 1.5 times the institutional upper limit of normal
Total bilirubin < 1.5 times the institutional ULN or < 3.0 x the institutional ULN with Gilbert Syndrome (unless direct bilirubin is within normal limits)

Adequately controlled blood pressure, defined as systolic blood pressure of <140 mmHq and diastolic of <90 mmHg, at the time of enrollment.
Serum lipase less than or equal to 1.5 x ULN. For serum lipase > ULN - less than or equal to 1.5 x ULN, value should be considered not clinically significant and not associated with risk factors for acute pancreatitis.
Female patients must meet one of the following:

Postmenopausal for at least one year before the screening visit,
Surgically sterile
If they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug,
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable contraception methods.)

Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:

Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

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 greater than or equal to 450 msec (male patients), greater than or equal to 460 msec (female patients) unless patient has a pacemaker
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 ii. Concomitant medication(s) with a "Known risk of Torsades de Pointes" per wwwcrediblemeds.org/ that cannot be discontinued or replace 7 days prior to starting study drug by safe alternative medication. iii. Inability to determine the QTcF interval

Pregnant or lactating
Taking a strong inhibitors or inducers of CYP3A4 or CYP3A4 substrates with narrow therapeutic index (refer to appendix 6) at time of enrollment
Unable to comply with lab appointment schedule and PRO assessments
Another investigational drug within 4 weeks of enrollment
Any serious medical or psychiatric illness that could, in the investigator's opinion, interfere with the completion of treatment according to this protocol
Patient has undergone a prior allogeneic stem cell transplant
Known clinical history of active HBV infection

Locations

4100 John R
Detroit, MI 48201
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Phone: 800-527-6266

31995 Northwestern Hwy
Farmington Hills, MI 48334
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Phone: 800-527-6266

Applicable Disease Site

Therapies, Drugs, Devices