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)

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.

Asciminib is a potent allosteric inhibitor of BCR-ABL1 oncogene that confers resistance to tyrosine kinase inhibitors (TKIs). Asciminib has potential to combine with TKIs to prevent the emergence of BCR-ABL1 mutations, increasing the depth of molecular response in CML-CP patients. Anticipated enrollment is 50 subjects across sites.

Primary Objective:

To estimate the proportion of patients with previously untreated CML-CP who attain BCR::ABL1 <0.01% (MR4.0) IS by RQ-PCR with single agent asciminib therapy.

Secondary Objectives:

1. To estimate the proportion of patients achieving molecular response at specific time points
2. To estimate the time to molecular response
3. To evaluate the duration of hematologic and molecular response to asciminib
4. To define the time to progression and overall survival for patients with CML in early CP treated with asciminib
5. To evaluate the safety profile of asciminib in patients with CML-CP
6. To evaluate the development of ABL mutations for patients with CML in early CP treated with asciminib
7. To analyze differences in response rates and in prognosis within different risk groups and patient characteristics
8. To evaluate patient-reported outcomes in patients with CML receiving asciminib
9. To investigate treatment-free remission after at least 2 years of sustained deep molecular remission for patients receiving single agent asciminib or combination (asciminib + low TKI)

Exploratory objectives:

1. To evaluate the safety and efficacy of concomitant use of low TKI with asciminib in patients who have not achieved MR4.5.
2. To evaluate the rate of successful treatment discontinuation for patients using the combination of asciminib and low TKI
3. To evaluate the safety and efficacy of concomitant use of lowTKI with asciminib in patients who experience treatment failure at any time with single agent asciminib
4. To evaluate the safety and efficacy of concomitant use of lowTKI with asciminib in patients who have not achieved an optimal response after 12 months of single agent asciminib
5. Evaluate the role of Digital droplet PCR (ddPCR) in predicting TFR
6. Evaluating the correlation between the gene expression signature of patients and the chances of achieving MMR and DMR
7. 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.

Subjects must meet all inclusion criteria and none of the exclusion criteria of the study. No enrollment waivers will be granted. After successful screening, subjects will be enrolled and treatment will start within 7 days of enrollment. Eligible subjects will begin asciminib on cycle 1 day 1 of the trial. After 2 years (but no later than 3 years), subjects will be offered the addition of taking nilotinib, dasatinib, or imatinib with asciminib if a molecular response is not met (PCR blood test).

Duration of each participant is expected to take approximately 5 years on treatment and up to a total of 8 years if attempting treatment free remission.

Regimen Description

Asciminib 80 mg Oral Once a day 4 weeks (28 days) Nilotinib 300 mg* Oral Once a day 4 weeks (28 days) Dasatinib 50 mg* Oral Once a day 4 weeks (28 days) Imatinib 300 mg* Oral Once a day 4 weeks (28 days)

*Nilotinib, dasatinib, or imatinib will be taken if indicated.

Dose levels and dose modifications of the study drugs will be made per protocol.

Inclusion Criteria:

1. Age ≥18 years old

2. Willing and able to give informed consent

3. 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.

4. 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.

5. ECOG performance status 0-2 (appendix 1)

6. 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)

7. Adequately controlled blood pressure, defined as systolic blood pressure of <140 mmHq and diastolic of <90 mmHg, at the time of enrollment.

8. 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.

9. Creatine phosphokinase < 2.5 x ULN

10. Female patients must meet one of the following:

    1. Postmenopausal for at least one year before the screening visit,
    2. Surgically sterile
    3. 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,
    4. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
    5. 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.)

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

    1. Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose
    2. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
    3. 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 Criteria:

1. Patients with accelerated or blast phase CML (refer to appendix 4)

2. Active second malignancy requiring active treatment

3. History of recent (within 12 months) acute pancreatitis or chronic pancreatitis

4. Subjects who have previously received treatment with asciminib.

5. Subjects with PLT count < 50,000 mm3 or ANC of < 500 mm3 or Hemoglobin < 8 g/dL

6. Cardiac or cardiac repolarization abnormality, including any of the following:

   1. History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
   2. 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)
   3. 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
   4. 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

7. Pregnant or lactating

8. Taking a strong inhibitors or inducers of CYP3A4 or CYP3A4 substrates with narrow therapeutic index (refer to appendix 6) at time of enrollment

9. Unable to comply with lab appointment schedule and PRO assessments

10. Another investigational drug within 4 weeks of enrollment

11. Any serious medical or psychiatric illness that could, in the investigator's opinion, interfere with the completion of treatment according to this protocol

12. Patient has undergone a prior allogeneic stem cell transplant

13. Known clinical history of active HBV infection