Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase

Study Overview
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Brief Summary
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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 orally once daily. 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.

Detailed Description
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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 a deep molecular response (DMR) with asciminib therapy (PCR blood test). 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) Exploratory objectives: To evaluate the safety and efficacy of concomitant use of low TKI with asciminib in patients who have not achieved MR4.5. To evaluate the rate of successful treatment discontinuation for patients using the combination of asciminib and low TKI Evaluate the role of Digital droplet PCR (ddPCR) in predicting TFR Evaluating the correlation between the gene expression signature of patients and the chances of achieving MMR and DMR Evaluate whether B, NK and T cells DNA mutation and RNA expression are relevant and whether they can predict response in patients with CML using single cell analysis. Subjects must meet all inclusion criteria and none of the exclusion criteria of the study. No enrollment waivers will be granted. After successful screening, subjects will be enrolled and treatment will start within 7 days of enrollment. Eligible subjects will begin asciminib on cycle 1 day 1 of the trial. After 2 years (but no later than 3 years), subjects will be offered the addition of taking nilotinib, dasatinib, or imatinib with asciminib if a molecular response is not met (PCR blood test). Duration of each participant is expected to take approximately 5 years on treatment and up to a total of 8 years if attempting treatment free remission. Regimen Description Asciminib 80 mg Oral Once a day 4 weeks (28 days) Nilotinib 300 mg* Oral Once a day 4 weeks (28 days) Dasatinib 50 mg* Oral Once a day 4 weeks (28 days) Imatinib 300 mg* Oral Once a day 4 weeks (28 days) *Nilotinib, dasatinib, or imatinib will be taken if indicated. Dose levels and dose modifications of the study drugs will be made per protocol.

Official Title
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Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase With Addition of Lower Dose Tyrosine Kinas Inhibitors for Patients With Chronic Myeloid Leukemia Who do Not Achieve a Deep Molecular Remission

Conditions
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Chronic Myeloid Leukemia, Chronic Phase, Adult CML, Leukemia, Myeloid, Leukemia,Myeloid, Chronic

Intervention / Treatment
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* Drug: Asciminib
* Drug: Ascimininb + Nilotinib
* Drug: Asciminib + Imatinib
* Drug: Asciminib + Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old Willing and able to give informed consent Newly diagnosed with CML in chronic phase within 6 months from confirmed diagnosis 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) 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. 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.) Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single group frontline asciminib
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Asciminib<br>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. | Drug: Asciminib<br>* Potent tyrosine kinase inhibitor that displays anti-tumor activity by specifically targeting the ABL myristate-binding pocket (STAMP).<br>* Other names: ABL001;Drug: Ascimininb + Nilotinib<br>* For subjects that do not achieve MR4.5 (molecular response) after 24 months of single-agent asciminib will be offered the addition of nilotinib 300mg, once daily, with the goal of attaining MR4.5.<br>* Other names: ABL001 + TASIGNA;Drug: Asciminib + Imatinib<br>* For subjects that do not achieve MR4.5 (molecular response) after 24 months of single-agent asciminib will be offered the addition of imatinib 300mg, once daily, with the goal of attaining MR4.5.<br>* Other names: ABL001 + Gleevec;Drug: Asciminib + Dasatinib<br>* For subjects that do not achieve MR4.5 (molecular response) after 24 months of single-agent asciminib will be offered the addition of dasatinib 50mg, once daily, with the goal of attaining MR4.5.<br>* Other names: ABL001 + Sprycel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Outcome Measure 1: Deep Molecular Response | This measure is the number of subjects in deep molecular response (DMR) defined as breakpoint cluster region ABL proto-oncogene 1 (BCR-ABL1) <0.0032% International Standard (IS) by real-time quantitative polymerase chain reaction (RT-PCR). | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Myeloid Leukemia, Adult CML, tyrosine kinase inhibitors, H. Jean Khoury Cure CML Consortium, HJKC3-0004