Chronic Myelogenous Leukemia in chronic phase (CML-CP), previously treated with imatinib and have not achieved deep molecular response MedDRA version: 21.0 Level: LLT Classification code 10009012 Term: Chronic myelogenous leukemia System Organ Class: 100000004864
Conditions
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects eligible for inclusion in this study must meet all of the following criteria: 1. Signed informed consent must be obtained prior to participation in the study. 2. Male or female patients = 18 years of age with a confirmed diagnosis of CML-CP defined as: • 0.01% IS and = 1% IS at the time of randomization study entry as confirmed with a central assessment at screening; patients must not have achieved deep molecular response (MR4 IS) confirmed by 2 consecutive tests at any time during prior imatinib treatment. An isolated, single test result with BCR-ABL1 levels 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 creatinine clearance* within normal limits) - 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 creatinine clearance* within normal limits) - Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with creatinine clearance* within normal limits) *Creatinine clearance as calculated using Cockcroft-Gault formula Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 72 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 8
Exclusion criteria
Exclusion criteria: Subjects meeting any of the following criteria are not eligible for inclusion in this study. 1. Treatment failure according to European Leukemia Network criteria (Baccarani et al 2013) during imatinib treatment. • after 3 months of treatment no Complete Hematologic Response (CHR) and/or Ph+ > 95% • after 6 months of treatment BCR-ABL1 > 10% and/or Ph+ > 35% • after 12 months of treatment BCR-ABL1 > 1% and/or Ph+ > 0 • at any time loss of CHR, loss of CCyR, confirmed loss of MMR*, mutations, clonal chromosomal abnormalities in Ph+ cells (CCA/Ph+) *In 2 consecutive tests, of which one with a BCR-ABL level =1%. 2. Known second chronic phase of CML after previous progression to AP/BC. 3. Previous treatment with any TKIs other than imatinib. 4. History or current diagnosis of ECG abnormalities indicating significant risk or safety for subjects participating in the study such as: • History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to randomization • Concomitant clinically significant arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker • Resting QTcF = 450 msec (male) or = 460 msec (female) prior to randomization • 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 including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia • Concomitant medications with a "known" risk of Torsades de Pointes per crediblemeds.org that cannot be discontinued or replaced by safe alternative medication • inability to determine the QTcF interval 5. 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 clinically significant hyperlipidemia and high serum amylase). 6. History of acute pancreatitis within 1 year prior to randomization or past medical history of chronic pancreatitis. 7. History of chronic liver disease or ongoing acute liver disease. 8. History of other active malignancy within 3 years prior to randomization with the exception of basal cell skin cancer, indolent prostate cancer and carcinoma in situ treated curatively. 9. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (anti HBc) will be performed at study entry. If HBsAg or anti-HBc is positive, Hepatitis B surface antibody (anti-HBs) and/or HBVDNA measurement is recommended to confirm negative viral status. 10. 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). 11. Treatment with strong inducers or inhibitors of CYP3A that cannot be discontinued or switched to a different medication at least one week prior to the start of treatment and for the duration of the study: • Strong inducers or inhibitors of CYP3A • Substrates of CYP3A4/5 with narrow therapeutic index 12. Patients must avoid consumption of gr
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess whether asciminib 40 mg QD + imatinib or asciminib 60 mg QD + imatinib is more effective than continued imatinib;Secondary Objective: • - To estimate efficacy of switch to nilotinib - To estimate difference in efficacy between asciminib 60 mg + imatinib and switch to nilotinib - To estimate difference in efficacy between asciminib 40 mg + imatinib and switch to nilotinib • To assess additional parameters of the efficacy of - asciminib 60 mg added to imatinib vs continued imatinib or switch to nilotinib - asciminib 40 mg added to imatinib vs continued imatinib or switch to nilotinib • To characterize the safety and tolerability profile of asciminib 60 mg or 40 mg + imatinib vs continued imatinib or switch to nilotinib • To assess the pharmacokinetic profile of asciminib 60 mg or 40 mg and imatinib when administered in combination;Primary end point(s): • Molecular Response (MR)4.5 rate at 48 weeks;Timepoint(s) of evaluation of this end point: 48 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • - Molecular Response (MR)4.5 rate at 48 weeks - Difference in rate of MR4.5 at 48 weeks • - Rate of MR4.5 at 96 weeks - Rate of MR4.5 by 48 and 96 weeks - Sustained MR4.5 at 96 weeks - Time to MR4.5 • Incidence and severity of adverse events, changes in laboratory values, clinically notable ECG abnormalities and vital signs • Plasma concentrations of asciminib and imatinib when administered in combination. PK parameters include but are not limited to Cmax, Tmax, Cmin, AUClast and AUCtau;Timepoint(s) of evaluation of this end point: The assessments are done for each parameter according to visits indicated in the Visit Schedule. For more details please refer to Visit Evaluation Schedule table 8-1 and 8-2 of the protocol | — |
Countries
Australia, Austria, Canada, Chile, Czechia, Czech Republic, Denmark, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Poland, Portugal, Russian Federation, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactMedizinischer Infoservice (MCC)
Novartis Pharma GmbH
Outcome results
None listed