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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a new treatment called asciminib (Scemblix) for individuals recently diagnosed with Chronic Myeloid Leukemia in the chronic phase, a type of blood cancer. Participants will take asciminib daily, and if it proves insufficient after 24 months, another medicine may be added. Ideal candidates are those diagnosed with this leukemia type within the last six months and who have received minimal prior treatment. The study aims to determine if asciminib alone or with additional medication can effectively manage the condition. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in leukemia treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that asciminib is generally safe for people with Chronic Myeloid Leukemia (CML). Studies have found it to be well-tolerated, even with long-term use. The most common side effect is a decrease in blood platelets, known as thrombocytopenia, which can sometimes cause easy bruising or bleeding but can be managed.

For those considering asciminib with low-dose tyrosine kinase inhibitors (TKIs) like dasatinib, imatinib, or nilotinib, research suggests this combination offers new treatment options with acceptable safety. Each of these TKIs has been used for CML and is generally considered safe, although they can have their own side effects.

In summary, while some side effects may occur, asciminib and its combinations are usually tolerated well enough to be considered safe for clinical use in CML. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about asciminib for chronic myeloid leukemia (CML) because it offers a new way to fight the disease. Unlike traditional treatments like imatinib, dasatinib, or nilotinib, which target the whole BCR-ABL protein, asciminib specifically targets the ABL myristoyl pocket, providing a more precise mechanism of action. This unique approach could potentially result in fewer side effects and improved effectiveness, especially for patients who haven’t responded well to existing therapies. Additionally, the trial explores combining asciminib with lower doses of traditional drugs, which might enhance treatment outcomes and allow some patients to achieve treatment-free remission.

What evidence suggests that this trial's treatments could be effective for Chronic Myeloid Leukemia?

Research has shown that asciminib effectively treats chronic myeloid leukemia (CML) in its early stages. Studies have found that asciminib often works better and causes fewer side effects than traditional treatments, such as other similar drugs. One major benefit is its ability to significantly reduce cancer cells in the blood. In this trial, some participants will receive asciminib as a single agent, while others may have a low dose of a tyrosine kinase inhibitor (such as nilotinib) added to their treatment if certain criteria are met. When combined with other drugs like nilotinib, asciminib acts quickly, but some people may find it harder to tolerate. Overall, asciminib is a promising option for managing CML, especially for those who are newly diagnosed. ^{2 5 6 7 8}

Who Is on the Research Team?

Jorge Cortes, MD

Principal Investigator

Augusta University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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, 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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12064212/

Real‐World Efficacy Profile of Compassionate Use ... This retrospective Italian analysis reports the efficacy and safety outcomes of asciminib in treating 77 CML patients in chronic phase (CML‐CP) ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2400858

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia Here we report the primary results of ASC4FIRST, a pivotal phase 3, randomized trial assessing the efficacy and safety of asciminib as compared ...

3. novartis.com novartis.com/news/media-releases/novartis-scemblix-phase-iii-data-first-show-superior-efficacy-favorable-safety-and-tolerability-profile-vs-standard-care-tkis-adults-newly-diagnosed-cml

Novartis Scemblix® Phase III data first to show superior ... Scemblix is the first CML treatment to show significantly better efficacy compared to investigator-selected standard-of-care TKIs.

4. onclive.com onclive.com/view/meta-analysis-highlights-efficacy-safety-benefits-with-asciminib-in-chronic-myeloid-leukemia

Meta-Analysis Highlights Efficacy, Safety Benefits With ... Asciminib shows superior efficacy and lower adverse effects compared to other TKIs in CP-CML patients, with improved major molecular response ...

5. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/479/530697/Efficacy-and-Safety-of-Asciminib-in-Chronic

Efficacy and Safety of Asciminib in Chronic Myeloid Leukemia ... Results: This interim analysis included 43 pts with CML-CP in 2L who enrolled and received ≥1 dose of asciminib on or before the data cutoff ( ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40510784/

The efficacy and safety of asciminib treatment in patients ... Asciminib is effective in the treatment of patients with CML, and the most common AE during treatment is thrombocytopenia.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04216563

ABL001 for the Treatment of Chronic Myeloid Leukemia in ... This phase II trial studies how well ABL001 works in treating patients with chronic myeloid leukemia who are on therapy with tyrosine kinase inhibitor.

8. novartis.com novartis.com/us-en/news/media-releases/longer-term-data-novartis-scemblix-reinforce-superior-efficacy-favorable-safety-and-tolerability-profile-adults-newly-diagnosed-cml

Longer-term data for Novartis Scemblix® reinforce superior ... Asciminib Continues to Provide Superior Efficacy and Favorable Safety and Tolerability vs Tyrosine Kinase Inhibitors In Newly Diagnosed Chronic ...