Asciminib + Imatinib for Chronic Myeloid Leukemia

Recruiting at 3 trial locations

Overseen By Chadi Zakaria, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Sarit Assouline

Must be taking: Imatinib

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Cardiac disease, Other malignancy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

164 Participants Needed

Trial Summary

What is the purpose of this trial?

The aim of this study is to establish if consolidation of imatinib-treated patients in stable DMR through the addition of asciminib, can lead to superior rates of TFR1, compared to imatinib alone in Chronic Phase-Chronic Myelogenous Leukemia patients.

Will I have to stop taking my current medications?

The trial requires that you continue taking imatinib, as it is part of the study treatment. The protocol does not specify if you need to stop other medications, but you should discuss this with the study team.

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

Research shows that Imatinib, a key component of the combination, has been highly effective in treating chronic myeloid leukemia by blocking cancer cell growth and inducing cell death. However, some patients develop resistance, and combining Imatinib with other agents like Asciminib may help overcome this resistance and improve treatment outcomes. ^{1 2 3 4 5}

Is the combination of Asciminib and Imatinib safe for treating chronic myeloid leukemia?

Imatinib, one of the drugs in the combination, has been used for many years to treat chronic myeloid leukemia and is generally considered safe, though some patients may experience side effects like changes in blood cell counts or other non-blood-related effects. There is no specific safety data available for the combination of Asciminib and Imatinib, but Imatinib alone has a well-documented safety profile. ^{6 7 8 9 10}

What makes the drug combination of Asciminib and Imatinib unique for treating chronic myeloid leukemia?

The combination of Asciminib and Imatinib is unique because Asciminib is a novel drug that targets a different part of the BCR-ABL1 protein than traditional treatments, making it effective for patients who have developed resistance to other therapies. This combination offers a new approach for those who have not responded well to previous treatments. ^{11 12 13 14 15}

Research Team

Sarit E Assouline, MD, MSc

Principal Investigator

SMBD Jewish General Hospital CIUSSS West Central Montreal

Eligibility Criteria

Adults diagnosed with Chronic Phase-Chronic Myelogenous Leukemia (CML-CP) who have been treated with imatinib for over 4 years and are in deep molecular response for at least a year. They must be able to conceive and agree to use effective contraception, have good organ function, no history of certain severe diseases or conditions that could affect trial participation, and not be on conflicting medications.

Inclusion Criteria

I am able to get out of my bed or chair and move around.

I am 18 or older with confirmed chronic myeloid leukemia in the chronic phase.

My organs are working well.

Exclusion Criteria

My CML has returned to a chronic phase after worsening.

I have not had major surgery in the last 2 weeks.

I am not taking medication that strongly affects liver enzyme CYP3A4.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Asciminib (60 mg PO daily) added to standard of care Imatinib (300 or 400 mg PO daily) for 52 weeks

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including time to molecular relapse and adverse events

6 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Asciminib
• Imatinib

Trial Overview The study is testing if adding asciminib to the current imatinib treatment leads to better rates of Treatment-Free Remission (TFR) compared to using imatinib alone in patients with CML-CP who are already responding well to treatment.

Participant Groups

Group I: Imatinib and Asciminib Experimental Treatment 2 Interventions

Asciminib (60 mg PO daily for 52 weeks) will be added to standard of care imatinib (300 or 400 mg PO daily for 52 weeks)

Group II: Imatinib Active Control 1 Intervention

Standard of care imatinib at 300 or 400 mg PO daily for 52 weeks

Imatinib is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in United States as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Canada as Glivec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Japan as Glivec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Switzerland as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Who Is Running the Clinical Trial?

Sarit Assouline

Lead Sponsor

Trials

3

Recruited

230+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Findings from Research

Imatinib mesylate has shown remarkable efficacy and safety in treating chronic myelogenous leukemia (CML), particularly in patients in the chronic phase, but there is a risk of relapse in those who are Philadelphia chromosome positive after failing interferon alpha treatment.

To address resistance and improve treatment outcomes, ongoing clinical studies are exploring combination therapies with imatinib and other novel antileukemic agents, based on promising pre-clinical evaluations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective. La Rosée, P., O'Dwyer, ME., Druker, BJ.[2015]

Imatinib has significantly improved the treatment of chronic myeloid leukemia (CML), but 10%-15% of patients may develop resistance or experience adverse effects, necessitating alternative therapies.

Second-generation tyrosine kinase inhibitors like nilotinib and dasatinib have shown superior efficacy compared to imatinib in frontline therapy, with nilotinib demonstrating higher major molecular response rates and better tolerability, particularly in the ENESTnd trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical appraisal of nilotinib in frontline treatment of chronic myeloid leukemia. Deremer, DL., Katsanevas, K., Ustun, C.[2023]

Imatinib mesylate (Glivec) is a targeted therapy that effectively inhibits the BCR-ABL tyrosine kinase, leading to significant responses in chronic myeloid leukemia (CML) patients, with 88% of interferon-alpha-resistant or intolerant patients achieving complete hematologic responses.

The treatment also resulted in major cytogenetic responses in 50% of chronic-phase CML patients and notable responses in accelerated (21%) and blastic (13.5%) phases, indicating improved outcomes for patients who previously had poor prognoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A new drug in the therapy of chronic myeloid leukemia: ST1571]. Salesi, N., Bossone, G., Della Longa, G., et al.[2015]

The BCR/ABL tyrosine kinase is identified as a key factor in chronic myeloid leukemia (CML), leading to the development of STI571 (imatinib mesylate) as a targeted treatment.

Phase I and II trials have demonstrated the efficacy of STI571 in treating CML, and the authors propose algorithms to assist in personalized treatment decisions for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[How I treat...chronic myeloid leukemia]. Hafraoui, K., Humblet-Baron, S., Baron, F., et al.[2015]

Imatinib mesylate (Gleevec) is highly effective in treating chronic myeloid leukemia (CML) due to its specificity, although some patients may develop resistance.

Combining imatinib with other chemotherapeutic agents or inhibitors targeting key signaling pathways in CML may help prevent resistance and improve treatment outcomes, as suggested by various in vitro studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in combination with other chemotherapeutic drugs: in vitro studies. Tipping, AJ., Melo, JV.[2015]

In a study of 81 patients with chronic myeloid leukemia (CML) treated with imatinib over two years, 326 adverse drug reactions (ADRs) were reported, with hematological toxicities being the most common, particularly thrombocytopenia at 21.17%.

Most ADRs were classified as mild to moderate, indicating that while imatinib can cause significant side effects, they are generally manageable, highlighting the need for careful monitoring to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions of imatinib in patients with chronic myeloid leukemia: A single-center surveillance study. Francis, J., Palaniappan, M., Dubashi, B., et al.[2020]

In a study of 200 patients with chronic myeloid leukemia (CML), imatinib mesylate was found to be a safe and well-tolerated treatment, with no deaths due to toxicity reported.

The most common side effects included grade 2 anemia (12.5%) and fluid retention (51.5%), both of which were manageable with supportive care, indicating that while side effects occur, they can be effectively treated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the safety of imatinib mesylate in 200 iraqi patients with chronic myeloid leukemia in the chronic phase: single-center study. Matti, BF., Alwan, AF., Alwan, AF.[2022]

Imatinib Mesylate has significantly improved outcomes for chronic myeloid leukemia (CML) patients in the chronic phase, leading to high rates of complete hematologic and cytogenetic responses.

Long-term studies indicate that while Imatinib is effective, there is a need for early molecular markers to identify which patients will benefit most from this treatment, especially with the availability of generic options and newer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes. Stagno, F., Stella, S., Spitaleri, A., et al.[2016]

In a long-term study with a median follow-up of 10.9 years, imatinib demonstrated a high overall survival rate of 83.3% in patients with chronic myeloid leukemia (CML), indicating its sustained efficacy as an initial treatment.

Serious adverse events related to imatinib were rare and mostly occurred within the first year of treatment, suggesting that long-term use of imatinib is safe and does not lead to unacceptable cumulative toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. Hochhaus, A., Larson, RA., Guilhot, F., et al.[2022]

In a study of 310 chronic myeloid leukemia (CML) patients treated with imatinib mesylate (400 mg/day), the most common adverse drug reactions (ADRs) were mild to moderate, with anemia being the most frequent hematological ADR and hyperpigmentation and nausea as the most common non-hematological ADRs.

The findings suggest that imatinib mesylate is a well-tolerated treatment for CML, with very few severe ADRs reported among patients in the chronic stable phase of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of adverse drug reactions of imatinib in chronic myeloid leukemia patients: An Eastern Indian experience. Swain, TR., Goutam, S., Jena, RK., et al.[2023]

Asciminib is an allosteric inhibitor specifically designed for patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to at least two prior tyrosine kinase inhibitors (TKIs), showing a favorable safety profile and strong efficacy in clinical trials.

In a phase 3 trial, asciminib demonstrated a significantly higher major molecular response rate and lower discontinuation rate compared to bosutinib in patients with CP-CML who had previously failed two TKIs, indicating its potential as a more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase. Choi, EJ.[2023]

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, 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 is a newly approved BCR-ABL1 inhibitor specifically targeting the ABL myristoyl pocket, offering a potent treatment option for chronic myeloid leukaemia (CML) patients who have not responded to at least two prior therapies or have the T315I mutation.

The drug is noted for its high potency and good tolerability due to limited off-target effects, but further research is needed to determine its optimal use compared to other tyrosine kinase inhibitors like ponatinib, especially in first- and second-line treatments and combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asciminib for chronic myeloid leukaemia: Next questions. Shanmuganathan, N., Hughes, TP.[2022]

Asciminib is an investigational drug that offers a new treatment approach for chronic myeloid leukemia (CML) by allosterically targeting the BCR-ABL1 oncoprotein, which is different from the traditional ATP-competitive tyrosine kinase inhibitors (TKIs).

Clinical trials suggest that asciminib is effective against many mutations that cause resistance to existing TKIs, including the challenging T315I mutation, making it a promising option for patients who have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of asciminib, a novel allosteric inhibitor of BCR-ABL1. Réa, D., Hughes, TP.[2022]

References

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

Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective. [2015]

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

Critical appraisal of nilotinib in frontline treatment of chronic myeloid leukemia. [2023]

3. Italy pubmed.ncbi.nlm.nih.gov

[A new drug in the therapy of chronic myeloid leukemia: ST1571]. [2015]

4. Belgium pubmed.ncbi.nlm.nih.gov

[How I treat...chronic myeloid leukemia]. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in combination with other chemotherapeutic drugs: in vitro studies. [2015]

6. India pubmed.ncbi.nlm.nih.gov

Adverse drug reactions of imatinib in patients with chronic myeloid leukemia: A single-center surveillance study. [2020]

7. Turkey pubmed.ncbi.nlm.nih.gov

Evaluation of the safety of imatinib mesylate in 200 iraqi patients with chronic myeloid leukemia in the chronic phase: single-center study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes. [2016]

9. United States pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. [2022]

10. India pubmed.ncbi.nlm.nih.gov

Analysis of adverse drug reactions of imatinib in chronic myeloid leukemia patients: An Eastern Indian experience. [2023]

11. Korea (South) pubmed.ncbi.nlm.nih.gov

Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase. [2023]

12. England pubmed.ncbi.nlm.nih.gov

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

13. 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]

14. England pubmed.ncbi.nlm.nih.gov

Asciminib for chronic myeloid leukaemia: Next questions. [2022]

15. Netherlands pubmed.ncbi.nlm.nih.gov

Development of asciminib, a novel allosteric inhibitor of BCR-ABL1. [2022]