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Asciminib 80mg taken orally once a day starting cycle 1 day 1 for up to 24 months during the single agent asciminib phase.

Patients who have not achieved MR4.5 after 24 months will be given a low dose tyrosine kinase inhibitor (low-TKI). There will be three options of low-TKIs to be given at the investigator's discretion.

Potent tyrosine kinase inhibitor that displays anti-tumor activity by specifically targeting the ABL myristate-binding pocket (STAMP).

For subjects that do not achieve MR4.5 (molecular response) after 24 months of single-agent asciminib will be offered the addition of nilotinib 300mg, once daily, with the goal of attaining MR4.5.

Ascimininb + Nilotinib

For subjects that do not achieve MR4.5 (molecular response) after 24 months of single-agent asciminib will be offered the addition of imatinib 300mg, once daily, with the goal of attaining MR4.5.

Asciminib + Imatinib

For subjects that do not achieve MR4.5 (molecular response) after 24 months of single-agent asciminib will be offered the addition of dasatinib 50mg, once daily, with the goal of attaining MR4.5.

Asciminib + Dasatinib

Kelly Jenkins, MSN, RN

GCC Clinical Trials Office

Jorge E. Cortes, MD

Sharon Prokop, RN, BSN

Michael Mauro, MD

Additional Contact Information

Braxton Smith

Ehab Atallah, MD

Jorge Cortes, MD

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 a deep molecular response (DMR) with asciminib therapy (PCR blood test).

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. Evaluate the role of Digital droplet PCR (ddPCR) in predicting TFR
4. Evaluating the correlation between the gene expression signature of patients and the chances of achieving MMR and DMR
5. 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.

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 a Deep Molecular Remission (ALERT CML)

This measure is the number of subjects in deep molecular response (DMR) defined as breakpoint cluster region ABL proto-oncogene 1 (BCR-ABL1) \<0.0032% International Standard (IS) by real-time quantitative polymerase chain reaction (RT-PCR).

H. Jean Khoury Cure CML Consortium

Augusta University

Leukemia, Myeloid, Chronic-Phase

All eligible patients will begin a combination of asciminib in combination with a TKI cycle 1 day 1 in the combination treatment phase. They will continue combination therapy for a total of 12 cycles (minimum of 12 months). At the end of 12 cycles asciminib will be discontinued and any patient who has met the criteria for the treatment free remission (TFR) screening phase will enter into the TFR phase. Once in the TFR phase, patients will discontinue their TKI and be monitored off treatment.

40 mg by mouth (PO) when used with imatinib.

Asciminib 40 MG

40 mg twice daily when used with nilotinib.

Asciminib 40 MG Twice Daily

Asciminib 80 MG daily

Imatinib

Medical College of Wisconsin Cancer Center Clinical Trials Office

Sharon Prokop

Jay Yang, MD

Srinivas Tantravahi, MBBS

Michael J. Mauro, MD

This is a single arm phase II study that will enroll a minimum of 47 subjects with a maximum of 51. All patients will have a confirmed diagnosis of chronic phase chronic myeloid Leukemia and must have previously attempted to discontinue Tyrosine Kinase inhibitors (TKI). All patients must have restarted the same TKI they were on prior to discontinuation at the time of relapse in order to be eligible for this trial.

All eligible patients will begin asciminib in combination with a TKI on cycle 1 day 1 of the combination phase. They will continue combination therapy for a total of 12 cycles (minimum of 12 months). Each cycle will be \~28 days. At the end of 12 cycles asciminib will be discontinued and any patient who has met the criteria for the treatment free remission (TFR) screening phase will enter into the TFR phase. Once in the TFR phase, patients will also discontinue their TKI and be monitored off treatment. The primary endpoint of this study is the 12-month 'second' TFR rate after completion of 12 cycles of combination therapy. Patients will remain in the TFR phase of the study for up to three years and will have central PCR testing during the first two years. Therefore, the total duration of the subject participation trial will be approximately five years (one year on combination treatment phase plus three years in the TFR phase plus one year of long-term follow-up post TFR or early discontinuation.

Protocol Number: HJKC3-0003. Treatment Free Remission After Combination Therapy With Asciminib (ABL001) Plus Tyrosine Kinase Inhibitors (TKI) in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed After a Prior Attempt at TKI Discontinuation

This will be measured by the number of subjects who achieve one-year treatment-free remission after 12 months of combination therapy with TKI plus asciminib. These subjects have previously failed a first treatment free remission attempt.

Medical College of Wisconsin

Professor

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase	NCT05143840	Chronic Myeloid... Adult CML Leukemia, Myelo... Leukemia,Myeloi...	Asciminib Ascimininb + Ni... Asciminib + Ima... Asciminib + Das...	18 Years -	Augusta University
Protocol Number: HJKC3-0003. Treatment Free Remission After Combination Therapy With Asciminib (ABL001) Plus Tyrosine Kinase Inhibitors (TKI) in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed After a Prior Attempt at TKI Discontinuation	NCT04838041	Chronic Phase C...	Asciminib 40 MG Asciminib 40 MG... Asciminib 80 MG... Imatinib Nilotinib Dasatinib	18 Years -	Medical College of Wisconsin
Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase	NCT05143840	Chronic Myeloid... Adult CML Leukemia, Myelo... Leukemia,Myeloi...	Asciminib Ascimininb + Ni... Asciminib + Ima... Asciminib + Das...	18 Years -	Augusta University
Protocol Number: HJKC3-0003. Treatment Free Remission After Combination Therapy With Asciminib (ABL001) Plus Tyrosine Kinase Inhibitors (TKI) in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed After a Prior Attempt at TKI Discontinuation	NCT04838041	Chronic Phase C...	Asciminib 40 MG Asciminib 40 MG... Asciminib 80 MG... Imatinib Nilotinib Dasatinib	18 Years -	Medical College of Wisconsin

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