Asciminib Combinations for Chronic Myeloid Leukemia

(ALERTCML Trial)

Recruiting at 6 trial locations

Overseen By James Sonnenberg

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Augusta University

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Accelerated CML, Active malignancy, Pancreatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests the effectiveness and safety of a medication called asciminib in patients newly diagnosed with Chronic Myeloid Leukemia in the Chronic Phase. Patients will take asciminib daily, and if they do not respond after a few years, they may also take another low-dose medication. Asciminib works by blocking a protein that helps cancer cells grow.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot take strong inhibitors or inducers of CYP3A4 or certain medications with a known risk of heart rhythm issues. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Asciminib for treating chronic myeloid leukemia?

Research shows that Asciminib is effective for patients with chronic myeloid leukemia who have been treated with at least two other drugs but still need help. In a study, Asciminib was better at helping patients reach a major molecular response (a key measure of treatment success) compared to another drug, bosutinib, and had fewer serious side effects. ^{1 2 3 4 5}

Is asciminib safe for humans?

Asciminib has shown a good safety profile in clinical trials for chronic myeloid leukemia, with common side effects including fatigue, low platelet count (thrombocytopenia), and low white blood cell count (neutropenia). Serious side effects were less common, and the risk of new side effects decreased over time. ^{1 2 4 6 7}

How is the drug asciminib unique in treating chronic myeloid leukemia?

Asciminib is unique because it is the first drug to specifically target the ABL myristoyl pocket, a different site on the BCR-ABL1 protein than other treatments, which helps it overcome resistance to conventional therapies. It is taken orally and has shown better efficacy and safety compared to some existing treatments for patients who have tried at least two other drugs. ^{1 2 3 4 5}

Research Team

Jorge Cortes, MD

Principal Investigator

Augusta University

Eligibility Criteria

Adults over 18 with newly diagnosed Chronic Myeloid Leukemia in chronic phase, who have not been treated for more than 30 days. They must have normal organ function and agree to effective contraception. Excluded are those with advanced CML stages, other active cancers, recent pancreatitis, certain blood disorders or taking strong CYP3A4 inhibitors/inducers.

Inclusion Criteria

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.

I agree to use effective contraception or practice true abstinence during and up to 90 days after the study.

I've had limited CML treatment with a TKI for 30 days or less.

Exclusion Criteria

I have had a stem cell transplant from a donor.

My CML is in the accelerated or blast phase.

I have been treated with asciminib before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment - Asciminib

Participants receive asciminib 80 mg orally once daily for up to 24 months

24 months

Regular visits for monitoring (frequency not specified)

Treatment - Combination Therapy

Participants who do not achieve a deep molecular response after 24 months may receive a low dose tyrosine kinase inhibitor (dasatinib, imatinib, or nilotinib) in addition to asciminib

12 months

Regular visits for monitoring (frequency not specified)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Periodic visits (frequency not specified)

Treatment Details

Interventions

• Asciminib
• Nilotinib

Trial Overview The trial is testing the safety and effectiveness of asciminib as an initial oral treatment for new Chronic Myeloid Leukemia patients. If no response after up to 36 months, a low dose of dasatinib, imatinib or nilotinib may be added at the doctor's choice.

Participant Groups

Group I: Single Agent Asciminib Arm Experimental Treatment 1 Intervention

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

Group II: Elective treatment free remission arm: Experimental Treatment 1 Intervention

.Elective treatment free remission arm: Once central eligibility has been obtained the patient should discontinue asciminib and if applicable lowTKI within 14 days.

Group III: Adding Low TKI Experimental Treatment 1 Intervention

TKI should begin within 28-days of obtaining central eligibility confirmation. This phase II trial will use single agent asciminib 80 mg PO daily during the single agent asciminib phase. All eligible subjects will begin asciminib on cycle 1 day 1 of this trial. 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.

Asciminib is already approved in United States, European Union for the following indications:

Approved in United States as Scemblix for:

• Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) in adults previously treated with ≥2 tyrosine kinase inhibitors (TKIs)
• Ph+ CML in CP with the T315I mutation
• newly diagnosed Ph+ CML in CP

Approved in European Union as Scemblix for:

• Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) in adults previously treated with ≥2 tyrosine kinase inhibitors (TKIs)
• Ph+ CML in CP with the T315I mutation

Who Is Running the Clinical Trial?

Augusta University

Lead Sponsor

Trials

219

Recruited

85,900+

H. Jean Khoury Cure CML Consortium

Collaborator

Trials

3

Recruited

80+

Findings from Research

Asciminib, a new treatment for chronic myeloid leukemia (CML), showed superior efficacy compared to bosutinib, with a major molecular response rate of 37.6% versus 15.8% after 96 weeks in patients who had previously been treated with two or more tyrosine kinase inhibitors.

Patients taking asciminib experienced fewer severe adverse events and were more likely to continue treatment without discontinuation, indicating better safety and tolerability compared to bosutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Hochhaus, A., Réa, D., Boquimpani, C., et al.[2023]

Asciminib hydrochloride, the first tyrosine kinase inhibitor targeting the ABL myristoyl pocket, was approved for chronic myeloid leukemia (CML) patients who are resistant or intolerant to prior therapies, showing significant antitumor effects in both lab and animal studies.

In a phase III study, asciminib demonstrated superior efficacy compared to bosutinib in achieving a major molecular response at week 24 for patients with chronic phase CML previously treated with multiple TKIs, with the most common side effect being thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological and clinical profile of asciminib hydrochloride, a novel first-in-class tyrosine kinase inhibitor specifically targeting ABL myristoyl pocket]. Chung, J., Ariyoshi, T., Yoneda, T., et al.[2023]

Asciminib is a first-in-class BCR::ABL1 inhibitor that specifically targets the ABL myristoyl pocket, showing promise in overcoming resistance or intolerance to existing tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients.

Clinical data indicate that asciminib has considerable efficacy in CML patients who have failed at least two prior TKIs, with a favorable safety profile and low cross-intolerance with other TKIs, making it a significant advancement in CML treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of asciminib for patients with chronic myeloid leukemia previously treated with ≥2 tyrosine kinase inhibitors. García-Gutiérrez, V., Hernandez-Boluda, JC.[2022]

Asciminib is the first drug that specifically targets the ABL myristoyl pocket, showing promising efficacy and safety in patients with chronic myeloid leukemia (CML) who have previously been treated with multiple tyrosine kinase inhibitors (TKIs).

The ongoing phase III trial (ASC4FIRST) is comparing asciminib to standard TKIs in newly diagnosed CML patients, with the primary goal of achieving a major molecular response by week 48, highlighting its potential as a new treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asciminib monotherapy for newly diagnosed chronic myeloid leukemia in chronic phase: the ASC4FIRST phase III trial. Cortes, JE., Hochhaus, A., Takahashi, N., et al.[2023]

Asciminib (Scemblix®) is an innovative oral medication that selectively inhibits the BCR-ABL1 tyrosine kinase, specifically targeting the myristoyl pocket, making it effective against certain mutations like T315I that resist traditional treatments.

In October 2021, asciminib received accelerated approval for adults with Philadelphia chromosome-positive chronic myeloid leukaemia (CML) who have previously been treated with at least two other tyrosine kinase inhibitors, highlighting its efficacy in difficult-to-treat cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asciminib: First Approval. Deeks, ED.[2022]

Asciminib, a new treatment for chronic myeloid leukemia (CML), shows a good safety profile with a lower rate of adverse effects compared to previous tyrosine kinase inhibitors (TKIs), with 55% of patients reporting side effects and only 18% experiencing severe effects.

Despite its unique mechanism of action, asciminib does carry a risk of cross-toxicity with traditional TKIs, particularly for side effects like thrombocytopenia and anemia, indicating careful monitoring is still necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. Pérez-Lamas, L., Luna, A., Boque, C., et al.[2023]

In a phase 1 trial involving 115 patients with chronic myeloid leukemia (CML-CP), asciminib demonstrated long-term efficacy, with 61.3% of patients achieving a major molecular response (MMR) after approximately 4 years of treatment.

While asciminib was generally well-tolerated, common grade ≥3 adverse events included increased pancreatic enzymes (22.6%) and thrombocytopenia (13.9%), but most adverse events occurred in the first year, indicating a manageable safety profile over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results. Mauro, MJ., Hughes, TP., Kim, DW., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. [2023]

2. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological and clinical profile of asciminib hydrochloride, a novel first-in-class tyrosine kinase inhibitor specifically targeting ABL myristoyl pocket]. [2023]

3. England pubmed.ncbi.nlm.nih.gov

An evaluation of asciminib for patients with chronic myeloid leukemia previously treated with ≥2 tyrosine kinase inhibitors. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Asciminib monotherapy for newly diagnosed chronic myeloid leukemia in chronic phase: the ASC4FIRST phase III trial. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Asciminib: First Approval. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results. [2023]