| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Myelogenous Leukemia in chronic phase (CML-CP) in newly diagnosed patients |
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| E.1.1.1 | Medical condition in easily understood language |
| CML is a bone marrow cancer caused by a gene mutation which causes over growth of white blood cells. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009012 |
| E.1.2 | Term | Chronic myelogenous leukemia |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To compare the efficacy of asciminib versus Investigator selected TKI, with respect to proportion of patients in Major Molecular Response (MMR) at Week 48.
2. To compare the efficacy of asciminib versus Investigator selected TKI, within the stratum of patients with imatinib as the pre-randomization selected TKI, with respect to proportion of patients in MMR at Week 48.
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| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of asciminib versus Investigator selected TKI, with respect to proportion of patients in MMR at Week 96.
2. To compare the efficacy of asciminib versus Investigator selected TKI, within the stratum of patients with imatinib as the pre-randomization selected TKI, with respect to proportion of patients in MMR at Week 96
3. To characterize the safety and tolerability profile of asciminib versus 2G TKIs: nilotinib, dasatinib or bosutinib
4. Other protocol-defined secondary objectives will apply; please see the protocol for a detailed list of all secondary objectives
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male or female patients ≥ 18 years of age.
2. Patients with CML-CP within 3 months of diagnosis.
3. Diagnosis of CML-CP with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations (presence of BCR-ABL1 in a review of a minimum 20 metaphases is required).
- Documented chronic phase CML will meet all the below criteria Hochhaus et al 2020:
•< 15% blasts in peripheral blood and bone marrow,
•< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
•< 20% basophils in the peripheral blood,
•Platelet count ≥ 100 x 109/L (≥ 100,000/mm3),
•No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1.
5. Adequate end organ function as defined by:
• Total bilirubin < 3 x ULN; patients with Gilbert’s syndrome may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
• Creatinine clearance (ClCr) ≥ 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
6. Patients must have the following laboratory values ≥ LLN 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 ClCr* ≥ 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 ClCr* ≥ 90 mL/min)
• Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with ClCr* ≥ 90 mL/min)
• For patients with mild to moderate renal impairment (ClCr* ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be ≥ LLN or corrected to within normal limits with supplements prior to randomization.
• *ClCr as calculated using Cockcroft-Gault formula
7. Ability to provide written informed consent prior to any study related screening procedures being performed.
8. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening which are amenable to standardized RQ-PCR quantification.
9. Other protocol-defined inclusion criteria may apply |
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| E.4 | Principal exclusion criteria |
1.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. Treatment with imatinib for ≤2 weeks is allowed, but no other treatment with tyrosine kinase inhibitors prior to study entry is permitted.
2.Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
3.Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one 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)
•QTc ≥ 450 msec (male patients), ≥460 msec (female patients) on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF ≥ 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
•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
4.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). Please refer to Section 6.3.1
5.History of significant congenital or acquired bleeding disorder unrelated to cancer.
6.Major surgery within 4 weeks prior to study entry or who have not recovered from prior surgery.
7.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
8.History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.
9.History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.
10. Other protocol-defined exclusion criteria may apply
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Major Molecular response (MMR) at Week 48 (Yes/No)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Major Molecular response (MMR) at Week 96 (Yes/No)
2. Time to discontinuation of study treatment due to Adverse Events (TTDAE)
3. Other protocol-defined secondary endpoints will apply; please see protocol for a detailed list of all secondary endpoints |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 96 weeks
2. 96 weeks after last patient first dose
3. Other protocol-defined timepoints of evaluation will apply; please see protocol for a full list of timepoints for all endpoints |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Singapore |
| Austria |
| Belgium |
| Bulgaria |
| Canada |
| China |
| Czechia |
| Denmark |
| Finland |
| Germany |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Netherlands |
| Norway |
| Portugal |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
| Vietnam |
| France |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study will occur 5 years from the date when the last patient enrolled into the study received the first dose of the randomized treatment. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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