| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Philadelphia Chromosome-Positive 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 |
The primary objective of the study is to assess the tolerability of asciminib versus nilotinib, in participants with newly diagnosed CML-CP, with respect to the time to discontinuation of study treatment due to adverse event (TTDAE).
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| E.2.2 | Secondary objectives of the trial |
- To compare the efficacy of asciminib versus nilotinib at and by all scheduled data collection time points
-Time to Treatment Discontinuation (TTD) forselected reasons of discontinuation
-To assess the effect of asciminib versus nilotinib on patient-reported disease-related symptoms, functioning, and health-related quality of life (HRQoL).
-To characterize the safety and tolerability profile of asciminib versus nilotinib during the course of study.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients ≥ 18 years of age.
3. Patients with CML-CP within 3 months of diagnosis.
4. Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of the Philadelphia (Ph) chromosome. A cryptic Ph chromosome should be confirmed by metaphase Fluorescence In Situ Hybridization (FISH).
• 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 109/L (≥ 100,000/mm3),
• No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.
5. Evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2] which is amenable to standardized RQ-PCR quantification by the central laboratory assessment. However, if a local qualitative assay, validated according to local regulation, from an accredited local laboratory has confirmed evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2], these results can be used for eligibility if the central RQ-PCR are not available at the time of randomization.
6. ECOG performance status of 0 or 1.
7. 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.
8. 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.
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| E.4 | Principal exclusion criteria |
Participants meeting any of the following criteria are not eligible for inclusion in this study.
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.
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 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 crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study treatment 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).
5. History of significant congenital or acquired bleeding disorder unrelated to cancer.
6. Major surgery within 4 weeks prior to study entry or patients 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. 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.
11. History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening.
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatment (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
13. Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
14. Pregnant or nursing (lactating) women
15. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for a period of time after stopping study medication. For asciminib, this period of time is 3 days after last dose; if local regulations or locally approved prescribing information differ from the protocol required duration of contraception, the longer duration must be followed and the same requirements will be described in the ICF. Participants taking nilotinib should be willing to follow contraception requirements in the locally-applicable prescribing information for nilotinib.
16. Known hypersensitivity to the study treatment.
Note: The Investigator has the discretion to include/exclude a patient in the study, who will be found to have symptoms representative of COVID-19 or tested positive for COVID-19 during the screening phase. Such patients should be managed as per the country specific guidelines related to COVID-19. For patients who test positive for COVID-19, re-testing is recommended before initiating study treatment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
-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)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From date of first dose to date of treatment discontinuation due to AE, assessed up to 4.5 years |
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| E.5.2 | Secondary end point(s) |
• MMR at all scheduled data collection time points.
• MMR by all scheduled data collection time points.
• MR4.0 and MR4.5 at and by all scheduled data collection time points.
• Complete Hematological Response (CHR) at and by all scheduled data collection time points.
• BCR::ABL1 ≤1% at and by all data collection time points.
• Duration of MMR, MR4.0, MR4.5.
• Time to first* MMR, first MR4.0, first MR4.5.
• Time to treatment failure.
• Event Free Survival.
• Progression free survival.
• Overall survival.
• TTD due to selected reasons (i.e. Discontinuation due to lack of efficacy/treatment failure/disease progression/ suboptimal response/death)
• Change from baseline in overall scores and individual scales of the EORTC QLQ-C30, EORTC QLQ-CML24.
• Type, frequency and severity of adverse events, dose modification due to adverse event, changes in laboratory values that fall outside the pre-determined ranges and clinically notable ECG changes, and other safety data (vital signs, physical examination).
*by competing risk analysis |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | 94 |
| 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 |
| Argentina |
| Malaysia |
| Oman |
| Singapore |
| United Arab Emirates |
| Switzerland |
| Canada |
| India |
| Jordan |
| Korea, Republic of |
| Lebanon |
| South Africa |
| Turkey |
| United Kingdom |
| Bulgaria |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Romania |
| Slovakia |
| Sweden |
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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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| End of study is defined as when the necessary number of events for primary analysis have been reached and when end of treatment and the last PRO assessments have been completed. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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