A Study to Investigate Tolerability and Efficacy of Asciminib (Oral) Versus Nilotinib (Oral) in Adult Participants (≥18 Years of Age) With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP)

Study Overview
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Brief Summary
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The study is designed to compare the tolerability of asciminib versus nilotinib for the treatment of newly diagnosed, previously untreated patients with Positive Chronic Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP).

Detailed Description
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This study is a phase IIIb, multi-center, open-label, randomized study of oral asciminib 80 mg once daily (QD) versus nilotinib 300 mg twice daily (BID) in adult patients with newly diagnosed Ph+ CML-CP. Participants will be randomized in the study in a 1:1 ratio to asciminib or nilotinib. No crossover of study treatment across arms will be allowed. Participants will be treated until unacceptable toxicity, disease progression and/or at the discretion of the investigator or the participants. A safety follow up visit/call will be performed approximately 30 days after end of treatment visit. Participants who discontinue study treatment prematurely due to any reason, will be followed up for survival and progression (to Accelerated Phase (AP)/Blast Crisis (BC)) up until end of study.

Official Title
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A Phase IIIb, Multi-center, Open-label, Randomized Study of Tolerability and Efficacy of Oral Asciminib Versus Nilotinib in Patients With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase.

Conditions
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Philadelphia Chromosome-Positive Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Asciminib
* Drug: Nilotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with CML-CP within 3 months of diagnosis. Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of the Philadelphia chromosome Documented chronic phase CML will meet all the below criteria Baccarani et al 2013: < 15% blasts in peripheral blood and bone marrow, < 30% blasts plus promyelocytes in peripheral blood and bone marrow, < 20% basophils in the peripheral blood, PLT count ≥ 100 x 10^9/L (≥ 100,000/mm3), except treatment induced thrombocytopenia No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly. Evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2] which is amenable to standardized RQ-PCR quantification by the central laboratory assessment. ECOG performance status of 0 or 1. Adequate end organ function as defined by: Total bilirubin (TBL) < 3 x ULN; patients with Gilbert's syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN, CrCl ≥ 30 mL/min as calculated using Cockcroft-Gault formula, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis. Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization: Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min)**, Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min), Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl* ≥ 90 mL/min), For patients with mild to moderate renal impairment (CrCl* ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be within normal limits or corrected to within normal limits with supplements prior to randomization. CrCl as calculated using Cockcroft-Gault formula. **Pseudohyperkaliemia in case of thrombocytosis is not an exclusion criterion. Exclusion Criteria: Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea and/or anagrelide. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required). Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following: History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment. 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 ≥ 450 ms on the average of three serial baseline ECG (using the QTcF formula). If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia. Concomitant medication(s) with a Known risk of Torsades de Pointes per www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication. Inability to determine the QTcF interval. Severe and/or uncontrolled concurrent medical disease that in the opinion of the Investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection; uncontrolled arterial or pulmonary hypertension, uncontrolled clinically significant hyperlipidemia). History of significant congenital or acquired bleeding disorder unrelated to cancer. Major surgery within 4 weeks prior to study entry or patients who have not recovered from prior surgery. History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively. History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis. History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease. Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is positive, HBV-DNA evaluation will be carried out at screening. A patient having positive HBV-DNA will not be enrolled in the study. Also, a patient with positive HBsAg will not be enrolled in the study. HCV Ab testing will also be performed at screening. For details on the criteria see Appendix 4. History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening. Other protocol-defined Inclusion/exclusion criteria will apply.

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
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Asciminib<br>Participants will receive asciminib 80 mg QD | Drug: Asciminib<br>* Asciminib 80 mg QD administered under fasting conditions.<br>* Other names: ABL001;|
| Active Comparator: Nilotinib<br>Participants will receive nilotinib 300 mg BID | Drug: Nilotinib<br>* Nilotinib 300 mg BID administered under fasting conditions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to discontinuation of study treatment due to adverse event (TTDAE). | TTDAE is defined as the time from the date of first dose of study treatment to the date of discontinuation of study treatment due to adverse event (AE). | From date of first dose to date of treatment discontinuation due to AE, assessed up to 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with Major Molecular response (MMR) at scheduled data collection time points | MMR will be assessed using fusion gene of the BCR and ABL genes (BCR-ABL) transcript levels measured by realtime quantitative polymerase chain reaction. The percentage of participants with MMR at each time point will be assessed. | Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. | 
| Percentage of participants with Major Molecular response (MMR) by scheduled data collection time points | MMR will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. The percentage of participants who meet the criteria for having achieved the endpoint (MMR) at or before the specified visit will be calculated. | Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. | 
| Percentage of participants with MR4.0 at scheduled data collection time points | MR4.0 will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. The percentage of participants with MR4.0 at each time point will be assessed. | Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. | 
| Percentage of participants with MR4.0 by scheduled data collection time points | MR4.0 will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. The percentage of participants who meet the criteria for having achieved the endpoint (MR4.0) at or before the specified visit will be calculated | Screening, week 4, week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years | 
| Percentage of participants with MR4.5 at scheduled data collection time points | MR4.5 will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. The percentage of participants with MR4.5 at each time point will be assessed. | Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. | 
| Percentage of participants with MR4.5 by scheduled data collection time points | MR4.5 will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. The percentage of participants who meet the criteria for having achieved the endpoint (MR4.5) at or before the specified visit will be calculated | Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. | 
| Percentage of participants with Complete Hematological response (CHR) at scheduled data collection time points | Hematologic response will be assessed by complete blood count and physical examination at each visit. The percentage of participants with CHR at each time point will be assessed. | Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. | 
| Percentage of participants with Complete Hematological response (CHR) by scheduled data collection time points | Hematologic response will be assessed by complete blood count and physical examination at each visit. The percentage of participants who meet the criteria for having achieved the endpoint (CHR) at or before the specified visit will be calculated | Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. | 
| Percentage of participants with BCR::ABL1 ratio ≤1% by Week 48 and Week 96. | The percentage of participants who meet the criteria for having achieved BCR::ABL1 ratio ≤1% at or before the specified visit will be calculated | Week 48 and Week 96 | 
| Duration of MMR | Duration of MMR is defined as the time between the date of the first documented achievement MMR and the earliest date of loss of MMR, treatment failure, progression to AP/BC, or CML-related death. | From the date of the first documented molecular response at MMR level to the date of first documented loss of MMR or death due to any cause, whichever occurs first, assessed up to approximately 4.5 years. | 
| Duration of MR4.0 | Duration of MR4.0 is defined as the time between the date of the first documented achievement MR4 and the earliest date of loss of MR4, treatment failure, progression to AP/BC, or CML-related death | From the date of the first documented molecular response at MR4 level to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to approximately 4.5 years. | 
| Duration of MR4.5 | Duration of MR4.5 is defined as the time between the date of the first documented achievement MR4.5 and the earliest date of loss of MR4.5, treatment failure, progression to AP/BC, or CML-related death. | From the date of the first documented molecular response at MR4.5 level to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to approximately 4.5 years. | 
| Time to first MMR | Time to first MMR is defined as the time from the date of randomization to the date of the first documented occurrence of MMR. | From the date of randomization to the date of the first MMR, assessed up to approximately 4.5 years. | 
| Time to first MR4.0 | Time to first MR4.0 is defined as the time from the date of randomization to the date of the first documented occurrence of MR4. | From the date of randomization to the date of the first MR4, assessed up to approximately 4.5 years. | 
| Time to first MR4.5 | Time to first MR4.5 is defined as the time from the date of randomization to the date of the first documented occurrence of MR4.5. | From the date of randomization to the date of the first MR4.5, assessed up to approximately 4.5 years. | 
| Time to treatment failure (TTF). | TTF is defined as the time from date of randomization to the first/earliest documented date of any of the following events: Treatment failure per European leukemia network (ELN) criteria, Confirmed loss of MMR (in 2 consecutive tests) at any time while on study treatment, Discontinuation from study treatment due to any reason | Up to approximately 4.5 years. | 
| Event free survival (EFS) | EFS is defined as the time from the date of the first dose of study treatment to the earliest occurrence of treatment failure, confirmed lost of MMR, discontinuation due to AE, progression to AP/BC, and death from any cause. | Up to approximately 4.5 years. | 
| Progression free survival (PFS). | PFS is defined as the time from the date of randomization to the earliest occurrence of progression to AP/BC or death from any cause. | Up to approximately 4.5 years. | 
| Overall survival (OS). | OS is defined as the time from the date of randomization to the date of death from any cause. | Up to approximately 4.5 years. | 
| Time to treatment discontinuation (TTD) due to selected reasons | TTD is the time from the date of first dose of study treatment to the date of discontinuation of study treatment due to lack of efficacy, treatment failure, disease progression, suboptimal response or death | Up to approximately 4.5 years | 
| Change from baseline in overall scores and individual scales of the European organization for research and treatment of cancer - quality of life questionnaire (EORTC QLQ-C30) | Change from baseline in Overall Scores and individual domains of the EORTC QLQ-C30. The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures based on the participant's experience over the past week. These include five functional scales (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. | Baseline, every 4 weeks from Week 4 to Week 12, after Week 24, Week 48, Week 96, EOT and every 4 weeks until 12 weeks after EOT, assessed up to approximately 4.5 years. | 
| Change from baseline in overall scores and individual scales of the European organization for research and treatment of cancer CML module (EORTC QLQ-CML24) | Change from baseline in Overall Scores and individual domains of the EORTC QLQ-CML24. The EORTC QLQ-CML24 assesses specific concepts relevant to the experience of patients with CML. The QLQ-CML24 has 24 items which assess symptom burden, impact on daily life and on worry/mood, body image problems, and satisfaction with care and with social life based on the participant's experience over the past week. | Baseline, every 4 weeks from Week 4 to Week 12, after Week 24, Week 48, Week 96, EOT and every 4 weeks until 12 weeks after EOT, assessed up to approximately 4,5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloid Leukemia, ABL001, Phase 3, tyrosine kinase inhibitor, Chronic myelogenous leukemia (CML), chronic myeloid leukemia (CML), chronic myelocytic leukemia (CML), chronic granulocytic leukemia (CGL), cancer of the white blood cells, clonal bone marrow stem cell disorder proliferation of mature granulocytes, Chronic Myeloproliferative Disorders