RecruitingPhase 2NCT05143840

Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase

Asciminib as Initial Therapy With Addition of Lower Dose Tyrosine Kinase Inhibitors for Patients With Chronic Myeloid Leukemia Who do Not Achieve Optimal Response or a Deep Molecular Remission (ALERT CML)

Sponsor

Augusta University

Enrollment

100 participants

Start Date

Apr 22, 2022

Study Type

INTERVENTIONAL

Conditions

Leukemia, Myeloid Chronic Myeloid Leukemia, Chronic Phase Leukemia,Myeloid, Chronic Adult CML

Summary

This study is a multicenter Phase 2, non-randomized, open-label single-group frontline study administering asciminib in patients with newly diagnosed Chronic Myeloid Leukemia-Chronic Phase (CML-CP). The aim of this study is to evaluate the efficacy and safety of asciminib in newly diagnosed CML-CP. Patients will receive asciminib 80 mg orally once daily during the single asciminib phase. Response is determined by PCR (polymerase chain reaction) blood test during the study. Patients who have not achieved a response after 24 months (but no later than 36 months) of single agent asciminib will be offered the addition of a low dose tyrosine kinase inhibitor (low-TKI) namely dasatinib, imatinib, or nilotinib at the investigator's discretion. The following doses of the TKIs will be used: 1. Dasatinib 50 mg daily 2. Imatinib 300 mg daily 3. Nilotinib 300 mg daily Patients will discontinue study treatment if they experience disease progression, or unacceptable toxicity.

Eligibility

Min Age: 18 Years

Inclusion Criteria22

Age ≥18 years old
Willing and able to give informed consent
Newly diagnosed with CML in chronic phase within 6 months from confirmed diagnosis via bone marrow biopsy/aspirate 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)
eGFR ≥ 30 mL/min as calculated using the 2021 chronic kidney disease epidemiology (CKD-EPI) creatinine equation (https://www.kidney.org/professionals/kdoqi/gfr\_calculator)
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.
Lipase ≤ 1.5 x ULN. For lipase \> ULN - ≤ 1.5 x ULN, value should be considered not clinically significant and not associated with risk factors for acute pancreatitis.
Creatine phosphokinase \< 2.5 x ULN
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.)

Exclusion Criteria19

Patients with accelerated or blast phase CML (refer to appendix 4)
Active second malignancy requiring active treatment
History of recent (within 12 months) acute pancreatitis or chronic pancreatitis
Subjects who have previously received treatment with asciminib.
Subjects with PLT count \< 50,000 mm3 or ANC of \< 500 mm3 or Hemoglobin \< 8 g/dL
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 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:
i. 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

Interventions

DRUGSingle Agent Asciminib

taken orally once a day starting cycle 1 day 1 for up to 24 months during the single agent asciminib phase. Asciminib is a potent allosteric inhibitor of BCR::ABL1.

COMBINATION_PRODUCTLow TKI

Low dose tyrosine kinase inhibitor (lowTKI) (dasatinib 50 mg daily or imatinib 300 mg daily or nilotinib 300 mg daily) at investigators discretion, may be added to asciminib in the following situations: * Patients who have treatment failure at any time based on ELN criteria (Appendix 7) * Patients who have a warning response after 12 months of single agent asciminib based on ELN criteria (Appendix 7) * Patients who have not achieved MR4.5 after 24 months, but no later than 36 months, of single agent asciminib.

OTHERElective Free Treatment

Once central eligibility has been obtained the patient should discontinue asciminib and if applicable lowTKI within 14 days.