Protocol Number: HJKC3-0003. Treatment Free Remission After Combination Therapy With Asciminib (ABL001) Plus Imatinib in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed After a Prior Attempt at TKI Discontinuation

Study Overview
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Brief Summary
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This is a single-arm phase II study that will enroll a minimum of 41 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 imatinib. All patients must be restarted on imatinib at the time of relapse in order to be eligible for this trial.

Detailed Description
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This trial will use a combination of asciminib 40 mg by mouth (PO) twice daily (BID) plus imatinib (maximum dose of 400 mg PO once daily) in the combination treatment phase. The BCR-ABL tyrosine kinase inhibitor (TKI) that will be used for this trial is imatinib. All eligible patients will begin asciminib in combination with imatinib on cycle 1 day 1 of the combination phase. They will continue combination therapy for a total of 12 cycles (minimum of 12 months). Each cycle will be  28 days. 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 imatinib and be monitored off treatment. The primary endpoint of this study is the 12-month second TFR rate after completion of 12 cycles of combination therapy. Patients will remain in the TFR phase of the study for up to three years and will have central polymerase chain reaction (PCR) testing during the first two years. Therefore, the total duration of the subject participation trial will be approximately five years (one year on combination treatment phase plus three years in the TFR phase plus one year of long-term follow-up post TFR or early discontinuation.

Official Title
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Protocol Number: HJKC3-0003. Treatment Free Remission After Combination Therapy With Asciminib (ABL001) Plus Imatinib in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed After a Prior Attempt at TKI Discontinuation

Conditions
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Chronic Phase Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: Asciminib
* Drug: Imatinib


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. Diagnosed with CML in chronic phase and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR-ABL protein. Subtype classification whether b3a2 (e14a2) or b2a2 (e13a2) is not required for study eligibility. Must have a documented history of attempting only one prior imatinib discontinuation under the guidance of a treating physician. Must have met all the following criteria prior to first attempt to discontinue their imatinib: Stable molecular response (MR4; < 0.01% IS) for > 2 years, as documented on at least four tests, performed at least three months apart (e.g. If a patient has had >4 PCR tests performed during the two years leading up to their initial TKI discontinuation, any value between 0.01 and 0.05% IS is considered a stable result, however, at least four tests must be < 0.01% IS). Treatment with imatinib for a minimum of three years prior to discontinuing imatinib. Must have relapsed (defined as loss of major molecular response (MMR), real-time quantitative polymerase chain reaction (RQ-PCR) for BCR-ABL >0.1% IS after first attempted imatinib discontinuation. After first failed TFR attempt, must have a minimum duration of one year of retreatment with imatinib (up to 400mg PO QD), and must plan to remain on imatinib for a minimum of 12 months during the combination treatment phase. Eastern Cooperative Oncology Group (ECOG) performance status 0-3. Must have a RQ-PCR for BCR-ABL < 0.0032% IS (MR4.5) reported by the trial designated central lab at the time of study enrollment. 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: A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study. History of accelerated or blast phase CML. A 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 platelet (PLT) count < 100 × 109/L or an absolute neutrophil count (ANC) of < 1 × 109/L or hemoglobin < 8 g/dL. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≥3 times the institutional upper limit of normal. Creatinine ≥ 2 times the institutional upper limit of normal. Total bilirubin ≥ 1.5 times the institutional upper limit of normal (unless direct bilirubin is within normal limits). Lipase > institutional upper limit of normal. Pregnant or lactating. Unable to comply with lab appointment schedule and patient-reported outcome (PRO) assessments. Another investigational drug within four 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. Screening 12-lead ECG showing a baseline corrected QT interval >480msec (patients with a pacemaker will still be eligible with QTc>500msec). Eligibility for the TFR Phase: Stable molecular response (MR4.5; < 0.0032% IS) documented on at least three tests (may include TFR phase screening PCR) by the trial designated lab, performed approximately three months apart while on combination phase TFR phase screening PCR RQ-PCR for BCR-ABL < 0.0032% IS (MR4.5) by the trial designated lab ECOG 0-3 Completion of 12 cycles on the combination therapy phase

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination Therapy and Remission Phase<br>All eligible patients will begin a combination of asciminib plus imatinib 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 imatinib and be monitored off treatment. | Drug: Asciminib<br>* 40 mg by mouth (PO) twice a day (BID).<br>* Other names: ABL001;Drug: Imatinib<br>* 400 mg by mouth (PO) once daily<br>* Other names: Glivec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year second treatment-free remission. | This will be measured by the number of subjects who achieve one-year treatment-free remission after 12 months of combination therapy with imatinib plus asciminib. These subjects have previously failed a first treatment free remission attempt. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic myelogenous leukemia, treatment-free remission, tyrosine kinase inhibitors, H. Jean Khoury Cure CML Consortium