| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Myelogenous Leukemia in chronic phase (CML-CP), previously treated with 2 or more tyrosine kinase inhibitors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Myelogenous Leukemia is a cancer of the blood characterized by a gene mutation (Philadelphia chromosome) which causes proliferation of white blood cells in the bone marrow. |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To compare the MMR rate at 24 weeks of asciminib versus bosutinib |
|
| E.2.2 | Secondary objectives of the trial |
| To compare additional parameters of the efficacy of asciminib versus bosutinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
2. Patients must meet all of the following laboratory values at the screening visit:
- < 15% blasts in peripheral blood and bone marrow
- < 30% blasts plus promyelocytes in peripheral blood and bone marrow
- < 20% basophils in the peripheral blood
- ≥ 50 x 109/L (≥ 50,000/mm3) platelets
- Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior to screening) is acceptable
- No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
3.a BCR-ABL1 ratio >0.1% IS according to central laboratory at the screening examination, for patients intolerant to the most recent TKI
therapy
4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib, dasatinib, radotinib or ponatinib)
5. Failure or intolerance to the most recent TKI therapy at the time of screening (adapted from the 2013 ELN Guidelines Bacarrani 2013)
- Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as follows. Patients must meet at least 1 of the following criteria.
Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases
Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases
Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases
At any time after the initiation of therapy, loss of CHR, CCyR or PCyR
At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to study treatment
At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL ratio ≥ 1% IS
At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+
- Intolerance is defined as:
Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal)
Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
7. Adequate end organ function as defined by (as per central laboratory tests):
- Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
- Aspartate transaminase (AST) ≤ 3.0 x ULN
- Alanine transaminase (ALT) ≤ 3.0 x ULN
- 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
- Alkaline phosphatase ≤ 2.5 x ULN
- Creatinine clearance ≥ 50 mL/min as calculated using Cockcroft-Gault formula
8. Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study medications. Orange
juice is allowed.
9. Written informed consent obtained prior to any screening procedures.
10a. Patients must have the following electrolyte values within normal limits (as per central laboratory tests) or corrected to be within normal limits with supplements prior to first dose of study medication:
- Potassium (potassium increase of up to 6.0 mmol/L is acceptable at
study entry if associated with creatinine clearance within normal limits)
- Magnesium
- Total calcium (corrected for serum albumin) (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable at study entry if associated
with creatinine clearance within normal limits)
• Magnesium, with the exception of magnesium
- Magnesium, with the exception of magnesium increase > ULN – 3.0 mg/dL; > ULN - 1.23 mmol/L associated with creatinine clearance (calculated using Cockcroft-Gault formula) Glomerular Filration Rate (GFR) within normal limits.
11. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening which are amenable to standardized RQ-PCR quantification. |
|
| E.4 | Principal exclusion criteria |
1. Known presence of the T315I or V299L mutation at any time prior to study entry
2. Known second chronic phase of CML after previous progression to AP/BC
3. Previous treatment with a hematopoietic stem-cell transplantation
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
5. 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 ≥450 msec (male patients), ≥460 msec (female patients)
- 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 https://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
6. 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, pulmonary
hypertension)
7. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
8. History of acute or chronic liver disease
9. Known presence of significant congenital or acquired bleeding disorder unrelated to cancer
10. 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
11. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)
13. Treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with study treatment
- Moderate or strong inducers of CYP3A
- Moderate or strong inhibitors of CYP3A / P-gp
14. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of its excipients
15. Previous treatment with or known/ suspected hypersensitivity to bosutinib or any of its excipients
16. Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer
17. Pregnant or nursing (lactating) women
18. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 days after last dose of asciminib and one month after last dose of bosutinib.. Highly effective contraception
methods include - see details in protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Major Molecular Response (MMR) rate at 24 weeks |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| 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 |
| Chile |
| Colombia |
| Switzerland |
| Hong Kong |
| Australia |
| Brazil |
| Canada |
| Israel |
| Japan |
| Jordan |
| Korea, Republic of |
| Lebanon |
| Mexico |
| Russian Federation |
| Saudi Arabia |
| Serbia |
| United Kingdom |
| United States |
| Belgium |
| Bulgaria |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Romania |
| Spain |
| Türkiye |
|
| 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
|
The patients are treated in the study up to end of study treatment period defined as up to 96 weeks after the last patient receives the first dose or up to 48 weeks after the last patient has switched to asciminib treatment whichever is longer unless patients have discontinued treatment earlier. The end of the study, concluding the survival followup, will occur 5 years from the date when the last patient enrolled into
the study receives the first dose of the randomized treatment. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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