Asciminib + Imatinib for Chronic Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Medical College of Wisconsin
Must be taking: Tyrosine kinase inhibitors
Must not be taking: Asciminib
Disqualifiers: Accelerated CML, Second malignancy, Pancreatitis, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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.
Do I need to stop my current medications for the trial?
The trial requires that you continue taking the same Tyrosine Kinase Inhibitor (TKI) you were on before your first attempt to stop treatment. You will need to stay on this medication for at least 12 months during the trial.
What data supports the effectiveness of the drug combination Asciminib and Imatinib for treating Chronic Myeloid Leukemia?
Asciminib has shown strong effectiveness in treating chronic myeloid leukemia, especially in patients who have not responded well to other treatments. In clinical trials, it demonstrated better results and fewer side effects compared to another drug, bosutinib, making it a promising option for patients with limited treatment choices.
12345Is the combination of Asciminib and Imatinib safe for treating chronic myeloid leukemia?
Asciminib has shown a good safety profile in clinical trials for chronic myeloid leukemia, with common side effects including fatigue, low platelet counts, and anemia. It has fewer severe side effects compared to some other treatments, and no cardiovascular events were reported in one study.
12567How is the drug Asciminib + Imatinib unique for treating chronic myeloid leukemia?
Asciminib is a novel drug that targets a specific part of the BCR::ABL1 protein, known as the ABL myristoyl pocket, which is different from other treatments that target the ATP-binding site. This unique mechanism allows it to be effective in patients who have developed resistance or intolerance to other tyrosine kinase inhibitors, offering a new option for those with limited treatment choices.
12458Eligibility Criteria
Adults diagnosed with chronic phase chronic myeloid leukemia (CP-CML) who have tried to stop taking imatinib once before but relapsed. They must be on imatinib again, agree to use two contraception methods if of childbearing potential, and meet specific health criteria including a stable molecular response for over two years and an ECOG performance status of 0-3.Inclusion Criteria
Must have met all the following criteria prior to first attempt to discontinue their imatinib:
I have chronic phase CML with a specific protein variant.
- If they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug
+17 more
Exclusion Criteria
I can care for myself but may not be able to do heavy physical work.
Any serious medical or psychiatric illness that could, in the investigator's opinion, interfere with the completion of treatment according to this protocol
I have completed 12 cycles of combination therapy.
+17 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Combination Treatment
Participants receive asciminib in combination with a TKI for 12 cycles
12 months
Monthly visits for each cycle
Treatment-Free Remission (TFR)
Participants discontinue TKI and are monitored off treatment
3 years
Regular central PCR testing during the first two years
Follow-up
Participants are monitored for safety and effectiveness after TFR phase
1 year
Participant Groups
The trial is testing the combination therapy of Asciminib plus Imatinib in patients with CP-CML who previously relapsed after stopping treatment. It's a single-arm phase II study aiming for 41-51 participants to see if this combo can allow them to achieve treatment-free remission.
3Treatment groups
Experimental Treatment
Group I: Asciminib 80 mg daily plus dasatinib (maximum dose of 100 mg PO once daily)Experimental Treatment2 Interventions
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.
Group II: Asciminib 40 mg twice daily plus nilotinib (maximum dose of 300 mg twice daily)Experimental Treatment2 Interventions
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.
Group III: Asciminib 40 mg PO daily plus imatinib (maximum dose of 400 mg PO once daily)Experimental Treatment2 Interventions
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.
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:
Huntsman Cancer InstituteSalt Lake City, UT
Froedtert Hospital & the Medical College of WisconsinMilwaukee, WI
The Barbara Ann Karmanos Cancer InstituteDetroit, MI
Memorial Sloan Kettering Cancer CenterNew York, NY
Loading ...
Who Is Running the Clinical Trial?
Medical College of WisconsinLead Sponsor
H. Jean Khoury Cure CML ConsortiumCollaborator
References
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 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.
Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase. [2023]The prognosis of patients with chronic phase (CP) chronic myeloid leukemia (CML) has significantly improved due to the development of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs). However, approximately 15‒20% of patients ultimately experience treatment failure due to resistance or intolerance to TKI therapy. As the prognosis of patients in whom multiple TKIs fail remains poor, an optimal therapeutic approach is required to treat the condition. Asciminib, an allosteric inhibitor that targets ABL1 myristoyl pocket, has been approved by the Food and Drug Administration for use in patients with CP-CML resistant or intolerant to ≥2 prior TKIs or those with T315I mutation. In a phase 1 trial, asciminib monotherapy showed a relatively favorable safety profile and potent efficacy in patients with and without the T315I mutation. In a subsequent phase 3 trial, asciminib treatment was associated with a significantly higher major molecular response rate and lower discontinuation rate than bosutinib in patients with CP-CML for whom two previous TKIs failed. Several clinical trials are being performed in various clinical settings to evaluate the role of asciminib as a frontline treatment for newly diagnosed CP-CML, either as a single agent or in combination with other TKIs as a second-line or additive treatment to improve treatment-free or deep remission. This review summarizes the incidence, available therapies, and outcomes of patients with CP-CML who experienced treatment failure, the mechanism of action, preclinical and clinical data, and ongoing trials for asciminib.
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.
[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.
Asciminib vs bosutinib in CML patients pretreated with ≥2 tyrosine kinase inhibitors: Results from the Japanese subgroup analysis of ASCEMBL study. [2023]Asciminib, a first-in-class, allosteric inhibitor of BCR-ABL1 that acts by STAMP (Specifically Targeting the ABL Myristoyl Pocket), is a novel therapeutic option for patients with chronic myeloid leukemia (CML). In the global, phase 3, open-label ASCEMBL study in patients with CML in chronic phase (CML-CP) pretreated with ≥2 tyrosine kinase inhibitors (TKIs) (NCT03106779), asciminib (40 mg twice-daily) demonstrated significant superiority over the ATP-competitive TKI bosutinib (500 mg once daily) for the primary endpoint of major molecular response (MMR; BCR::ABL1 transcript levels on the international scale [BCR::ABL1IS ] ≤0.1%) at week 24. Here, we report results from a descriptive subgroup analysis of Japanese patients enrolled in ASCEMBL study (data cut-off: May 25, 2020). Overall, 16 Japanese patients were randomized (asciminib, n = 13; bosutinib, n = 3). At week 24, the MMR rate with asciminib was 30.8% (4/13; 95% confidence interval [CI], 9.09-61.43). BCR::ABL1IS ≤1% and complete cytogenic response (CCyR) at week 24 were 61.5% (8/13 patients) and 50.0% (4/8 patients), respectively. In the bosutinib group, no patient achieved MMR, CCyR, or BCR::ABL1IS ≤1%, but results were limited by the low number of patients. The safety profile of asciminib was comparable to that previously observed in the overall study population. Findings from this Japanese subgroup analysis of the ASCEMBL study support the use of asciminib for the treatment of Japanese patients with CML-CP previously treated with ≥2 TKIs. ClinicalTrials.gov Identifier: NCT03106779.
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: a new therapeutic option in chronic-phase CML with treatment failure. [2022]Asciminib, a first-in-class allosteric inhibitor of BCR::ABL1 kinase activity, is now approved for the treatment of patients with chronic-phase chronic myeloid leukemia who failed 2 lines of therapy or in patients with the T315I mutation. Promising attributes include high specificity and potency against BCR::ABL1, activity against most kinase domain mutations, and potential for combination therapy with ATP-competitive tyrosine kinase inhibitors. Clinicians now have expanded third-line options, which in most cases will involve a choice between asciminib and ponatinib.