Asciminib as Initial Therapy With Addition of Lower Dose Tyrosine Kinase Inhibitors for Patients With Chronic Myeloid Leukemia Who do Not Achieve Optimal Response or a Deep Molecular Remission (ALERT CML)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 100
- 试验地点
- 8
- 主要终点
- Primary Outcome Measure 1: Deep Molecular Response
研究概览
简要总结
This study is a multicenter Phase 2, non-randomized, open-label single-group frontline study administering asciminib in patients with newly diagnosed Chronic Myeloid Leukemia-Chronic Phase (CML-CP). The aim of this study is to evaluate the efficacy and safety of asciminib in newly diagnosed CML-CP. Patients will receive asciminib 80 mg orally once daily during the single asciminib phase. Response is determined by PCR (polymerase chain reaction) blood test during the study. Patients who have not achieved a response after 24 months (but no later than 36 months) of single agent asciminib will be offered the addition of a low dose tyrosine kinase inhibitor (low-TKI) namely dasatinib, imatinib, or nilotinib at the investigator's discretion. The following doses of the TKIs will be used:
- Dasatinib 50 mg daily
- Imatinib 300 mg daily
- Nilotinib 300 mg daily
Patients will discontinue study treatment if they experience disease progression, or unacceptable toxicity.
详细描述
Asciminib is a potent allosteric inhibitor of BCR-ABL1 oncogene that confers resistance to tyrosine kinase inhibitors (TKIs). Asciminib has potential to combine with TKIs to prevent the emergence of BCR-ABL1 mutations, increasing the depth of molecular response in CML-CP patients. Anticipated enrollment is 50 subjects across sites.
Primary Objective:
To estimate the proportion of patients with previously untreated CML-CP who attain BCR::ABL1 <0.01% (MR4.0) IS by RQ-PCR with single agent asciminib therapy.
Secondary Objectives:
- To estimate the proportion of patients achieving molecular response at specific time points
- To estimate the time to molecular response
- To evaluate the duration of hematologic and molecular response to asciminib
- To define the time to progression and overall survival for patients with CML in early CP treated with asciminib
- To evaluate the safety profile of asciminib in patients with CML-CP
- To evaluate the development of ABL mutations for patients with CML in early CP treated with asciminib
- To analyze differences in response rates and in prognosis within different risk groups and patient characteristics
- To evaluate patient-reported outcomes in patients with CML receiving asciminib
- To investigate treatment-free remission after at least 2 years of sustained deep molecular remission for patients receiving single agent asciminib or combination (asciminib + low TKI)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years old
- •Willing and able to give informed consent
- •Newly diagnosed with CML in chronic phase within 6 months from confirmed diagnosis via bone marrow biopsy/aspirate and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR::ABL1 protein. Subtype classification whether b3a2 (e14a2) or b2a2 (e13a2) is not required for study eligibility.
- •Minimal prior CML therapy with a TKI for less than or equal to 30 days. Treatment with hydroxyurea, busulfan, anagrelide or other non-specific chemotherapy agents is allowed with no time restrictions within the eligible time from diagnosis.
- •ECOG performance status 0-2 (appendix 1)
- •Adequate organ function:
- •AST and ALT < 3 times the institutional upper limit of normal (ULN)
- •eGFR ≥ 30 mL/min as calculated using the 2021 chronic kidney disease epidemiology (CKD-EPI) creatinine equation (https://www.kidney.org/professionals/kdoqi/gfr_calculator)
- •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.
- •Lipase ≤ 1.5 x ULN. For lipase > ULN - ≤ 1.5 x ULN, value should be considered not clinically significant and not associated with risk factors for acute pancreatitis.
- •Creatine phosphokinase < 2.5 x ULN
- •Female patients must meet one of the following:
- •Postmenopausal for at least one year before the screening visit,
- •Surgically sterile
- •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,
- •Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
- •Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable contraception methods.)
- •Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:
- •Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose
- •Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
- •Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
排除标准
- •Patients with accelerated or blast phase CML (refer to appendix 4)
- •Active second malignancy requiring active treatment
- •History of recent (within 12 months) acute pancreatitis or chronic pancreatitis
- •Subjects who have previously received treatment with asciminib.
- •Subjects with PLT count < 50,000 mm3 or ANC of < 500 mm3 or Hemoglobin < 8 g/dL
- •Cardiac or cardiac repolarization abnormality, including any of the following:
- •History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
- •Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
- •QTcF at screening greater than or equal to 450 msec (male patients), greater than or equal to 460 msec (female patients) unless patient has a pacemaker
- •Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
- •i. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ii. Concomitant medication(s) with a "Known risk of Torsades de Pointes" per wwwcrediblemeds.org/ that cannot be discontinued or replace 7 days prior to starting study drug by safe alternative medication.
- •iii. Inability to determine the QTcF interval
- •Pregnant or lactating
- •Taking a strong inhibitors or inducers of CYP3A4 or CYP3A4 substrates with narrow therapeutic index (refer to appendix 6) at time of enrollment
- •Unable to comply with lab appointment schedule and PRO assessments
- •Another investigational drug within 4 weeks of enrollment
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, interfere with the completion of treatment according to this protocol
- •Patient has undergone a prior allogeneic stem cell transplant
- •Known clinical history of active HBV infection
研究组 & 干预措施
Elective treatment free remission arm:
.Elective treatment free remission arm: Once central eligibility has been obtained the patient should discontinue asciminib and if applicable lowTKI within 14 days.
干预措施: Elective Free Treatment (Other)
Single Agent Asciminib Arm
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.
干预措施: Single Agent Asciminib (Drug)
Adding Low TKI
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.
干预措施: Low TKI (Combination Product)
结局指标
主要结局
Primary Outcome Measure 1: Deep Molecular Response
时间窗: 24 months
The proportion of patients achieving BCR::ABL1 \<0.01% IS (MR4.0) within 12 months of treatment with single agent asciminib
Digital Droplet PCR
时间窗: 2 years
Digital droplet PCR (ddPCR). Our Consortium work in the LAST study showed that ddPCR is more sensitive than conventional PCR and is very important in predicting TFR in detecting BCR::ABL1 in cases without detectable disease by conventional PCR29. Thus, samples taken for BCR::ABL1 monitoring in this trial will also be tested by ddPCR using the Bio-Rad platform. This will allow for a head to head comparison of these two methods.
次要结局
- Duration of MR1, MR2, MMR, MR4.0, MR4.5, and undetectable BCR::ABL1.(2 years)
- Adverse Events(2 years)
- ABL1 sequencing at the time of primary resistance(2 years)
- Clonal evolution and Sokal risk score(2 years)
- Patient Reported Outcomes(2 years)
- Rate of MMR loss(2 years)
- The rates of BCR::ABL1 IS ≤10%, ≤1% (MR2), ≤0.1% (MMR), ≤0.01% (MR4), and ≤0.0032% MR4.5(2 years)
- Time to complete hematological response.(2 years)
- FFS, TFS, EFS, and OS(2 years)
研究者
Omer Jamy
Associate Professor
University of Alabama at Birmingham