Chronic Myelogenous Leukemia in chronic phase (CML-CP), previously treated with 2 or more tyrosine kinase inhibitors MedDRA version: 21.0 Level: LLT Classification code 10009012 Term: Chronic myelogenous leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Code: ABL001
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: asciminib
Current Sponsor code: ABL001
Other descriptive name: ABL001
Concentration unit: mg milligram(s)
Concentratio
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
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: - 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 (adapted from the 2013 ELN Guidelines Baccarani 2013)or intolerance to the most recent TKI therapy at the time of screening - 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-ABL1 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. 10. Patients must have the following e
Exclusion criteria
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 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 afte
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare the MMR rate at 24 weeks of asciminib versus bosutinib;Secondary Objective: To compare additional parameters of the efficacy of asciminib versus bosutinib;Primary end point(s): Major Molecular Response (MMR) rate at 24 weeks;Timepoint(s) of evaluation of this end point: 24 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): MMR rate at 96 weeks;Timepoint(s) of evaluation of this end point: 96 weeks | — |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Czechia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Japan, Jordan, Korea, Republic of, Lebanon, Mexico, Netherlands, Norway, Poland, Romania, Russian Federation, Saudi Arabia, Serbia, Spain, Switzerland, Turkey, United Kingdom, United States
Contacts
Public ContactMedical Dept - Desilsava Uzunova
Novartis Pharma Services
Outcome results
None listed