Asciminib Combinations for Chronic Myeloid Leukemia
(ALERTCML Trial)
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Augusta University
Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers
Disqualifiers: Accelerated CML, Active malignancy, Pancreatitis, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 2 Jurisdictions
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.12345
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.12467
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.12345
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.
See 5 more
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.
See 10 more
Trial 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 (Tyrosine Kinase Inhibitor)
- Nilotinib (Tyrosine Kinase Inhibitor)
Trial OverviewThe 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
1Treatment groups
Experimental Treatment
Group I: AsciminibExperimental Treatment4 Interventions
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.
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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Froedtert Moorland Reserve Health CenterNew Berlin, WI
Memorial Sloan Kettering Cancer CenterNew York, NY
Froedtert Hospital & the Medical College of WisconsinMilwaukee, WI
Roswell Park Comprehensive Cancer CenterBuffalo, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Augusta UniversityLead Sponsor
H. Jean Khoury Cure CML ConsortiumCollaborator
References
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]Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53-32.95; two-sided p = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.
[Pharmacological and clinical profile of asciminib hydrochloride, a novel first-in-class tyrosine kinase inhibitor specifically targeting ABL myristoyl pocket]. [2023]On March 28th, 2022, asciminib hydrochloride (Scemblix® Tablets 20 ‍mg/40 ‍mg), the world's first tyrosine kinase inhibitor (TKI) specifically targeting the ABL myristoyl pocket (STAMP inhibitor), was approved for chronic myeloid leukemia (CML) resistant or intolerant to prior therapy. Asciminib specifically binds to the myristoyl pocket, an allosteric site of BCR::ABL1, and inhibits the ABL1 family molecules. In vitro and in vivo pharmacology studies demonstrated cell growth inhibition and antitumor effects of asciminib. The international phase I study for patients with chronic or accelerated phase CML investigated the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of asciminib monotherapy. However, the MTD was not reached, so and RDE was determined based on tolerability, safety, pharmacokinetics (PK) and preliminary efficacy data obtained by the time of the study. RDE was determined to be 40 ‍mg twice daily in chronic or accelerated phase CML without T315I mutation, and 200 ‍mg twice daily in chronic or accelerated phase CML with T315I mutation. The international phase III study for patients with chronic phase CML who were previously treated with ≥2 TKIs and resistant or intolerant to the recent treatment demonstrated the superiority of asciminib over bosutinib in achieving the primary endpoint of a major molecular response (MMR) at week 24. Regarding safety, the most common treatment-related adverse event in asciminib arm was thrombocytopenia, and others included neutropenia. Asciminib is expected to be a new treatment option for CML patients who have limited choices due to resistance or intolerance to previous therapies.
An evaluation of asciminib for patients with chronic myeloid leukemia previously treated with ≥2 tyrosine kinase inhibitors. [2022]To date, five tyrosine kinase inhibitors (TKIs) are available for treating chronic myeloid leukemia (CML) patients in clinical practice. Despite this, a significant proportion of patients will ultimately develop failure to approved TKIs due to intolerance or resistance. Consequently, new treatment approaches are still required in this unmet clinical need. Asciminib, a first-in-class BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to prior TKI treatment.
Asciminib monotherapy for newly diagnosed chronic myeloid leukemia in chronic phase: the ASC4FIRST phase III trial. [2023]Asciminib is the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). Asciminib has shown favorable efficacy and safety in patients with chronic myeloid leukemia in chronic phase without the T315I mutation who have received ≥2 prior tyrosine kinase inhibitors (TKIs) in phase I and III clinical trials and in patients with the T315I mutation who have received ≥1 prior TKI in phase I. ASC4FIRST (NCT04971226) is a phase III, multicenter, open-label, randomized study of asciminib versus investigator-selected TKI in patients with newly diagnosed chronic myeloid leukemia in chronic phase. The primary end point is major molecular response at week 48. Secondary end points include responses at and by scheduled time points, safety, pharmacokinetics and patient-reported outcomes. Clinical Trial Registration: NCT04971226 (ClinicalTrials.gov).
Asciminib: First Approval. [2022]Asciminib (Scemblix®) is an orally administered, small molecule, selective allosteric inhibitor that targets the myristoyl pocket of the BCR-ABL1 tyrosine kinase and is being developed by Novartis for the treatment of haematological malignancies, including Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML). The drug is active against a number of the single catalytic-site mutations, such as T315I, that confer resistance to conventional tyrosine kinase inhibitors (TKIs) that bind to the ATP-binding site of BCR-ABL1. In October 2021, asciminib monotherapy was granted accelerated approval for the treatment of adults with Ph+ CML in chronic phase (CML-CP), previously treated with ≥ 2 TKIs, and full approval for the treatment of adults with Ph+ CML-CP with the T315I mutation. The drug is under regulatory review for use as monotherapy in CML in the EU, and is in phase 1-3 development exploring its potential in first-line, later-line and paediatric patients with CML. This article summarizes the milestones in the development of asciminib leading to this first approval for the treatment of adults with Ph+ CML-CP, previously treated with ≥ 2 TKIs, and Ph+ CML-CP with the T315I mutation.
Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. [2023](1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs.
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]Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.