Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Been Previously Treated With Imatinib and Have Not Achieved Deep Molecular Response.

Novartis Pharmaceuticals104 enrolled

Overview

To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib in pre-treated patients with Chronic Myeloid Leukemia in chronic phase (CML-CP). An asciminib single agent arm (80 mg daily) was added after the primary analysis to evaluate if asciminib alone could lead to MR4.5 patients in Imatinib for at least one year who have never achieved deep molecular response (DMR).

The study was a Phase 2, multi-center, open-label, randomized study of asciminib in two different doses (40 mg or 60 mg) in combination with imatinib 400 mg versus continued imatinib versus switch to nilotinib in participants with chronic myeloid leukemia in chronic phase (CML-CP) who had been previously treated with imatinib first line therapy for at least one year and had not achieved deep molecular response (DMR). Eligible participants were randomized 1:1:1:1 to receive asciminib 60 mg once daily (QD) as add-on therapy to imatinib 400 mg QD, or 40 mg QD as add-on therapy to imatinib 400 mg QD, or to continue imatinib 400 mg QD, or to switch to nilotinib 300 mg twice a day (BID). During the trial, there was no switch allowed. It was just at the moment of the randomization that the participants were selected to asciminib add-on arms or nilotinib. Participants on the imatinib continuation arm who had not achieved MR4.5 at 48 weeks were allowed to cross-over ((CO) to receive the add-on treatment within 4 weeks after week 48 visit to receive the asciminib 60 mg combination add-on treatment, as this dose provided higher exposure. The cross-over was at the discretion of the investigator and the participant. Apart from a polymerase chain reaction (PCR) result of below MR4.5 at Week 48 visit, there were no other entry criteria for the cross-over part. Participants on nilotinib were not allowed to cross-over to receive the add-on treatment. Participants on the study continued on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks (in arms 1 to 4) after the last participant had received the first dose of treatment. After the last dose was received, every participant was followed up for safety for 30 days.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

Interventions

Asciminib add-onDRUG

Asciminib was supplied as 40 mg and 20 mg tablets and taken orally once daily.

ImatinibDRUG

Imatinib was supplied as 400 mg and 100 mg tablets and taken orally once daily.

NilotinibDRUG

Nilotinib was supplied as 150 mg and 200 mg hard gelatin capsules and taken orally twice daily.

Asciminib 80mg QD (asciminib single agent (ASAC))DRUG

Asciminib was supplied as 40 mg and 20 mg tablets and taken orally once daily (in the fasted state) on a continuous schedule (QD).

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male or female patients ≥ 18 years of age with a confirmed diagnosis of CML-CP. * Minimum of one year (12 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 400 mg QD at randomization and had no dose change in the past three months). For Korea only: (i) a minimum of one year (12 calendar months) of prior treatment with imatinib for patients with BCR::ABL1 levels \> 0.1%, ≤ 1% IS at the time of randomization. (ii) a minimum of two years (24 calendar months) of prior treatment with imatinib for patients with BCR::ABL 1 levels \> 0.01%, ≤ 0.1% IS at the time of randomization. * BCR::ABL1 levels \> 0.01% IS (International Scale) and ≤ 1% IS at the time of randomization 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 \< 0.01 % (MR4 IS) is allowed, however, it should not have been observed within the 9 months prior to randomization * Patient must meet the following laboratory values before randomization: * Absolute Neutrophil Count ≥ 1.5 x 10E9/L * Platelets ≥ 75 x 10E9/L * Hemoglobin ≥ 9 g/dL * Serum creatinine \< 1.5 mg/dL * Total bilirubin ≤ 1.5 x ULN (Upper Limit of Normal) except for patients with Gilbert's syndrome who may only be included with total bilirubin ≤ 3.0 x ULN * Aspartate transaminase (AST) ≤ 3.0 x ULN * Alanine transaminase (ALT) ≤ 3.0 x ULN * Alkaline phosphatase ≤ 2.5 x ULN * Serum lipase ≤ 1.5 x ULN * Participants must have the following laboratory values ≥ Lower Limit of Normal or corrected to within normal limits with supplements prior to randomization: potassium increase of up to 6.0 mmol/L is acceptable if associated with creatinine clearance within normal limits ; 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 increase up to 3.0 mg/dL or 1.23 mmol/L if associated with creatinine clearance within normal limits. Key Exclusion Criteria: * Treatment failure according to European Leukemia Network (ELN) criteria 2013 during imatinib treatment. * Known second chronic phase of CML after previous progression to Accelerated Phase (AP)/Blast Crisis (BC). * Previous treatment with any tyrosine kinase inhibitors (TKIs) other than imatinib. * History or current diagnosis of ECG abnormalities indicating significant risk or safety for participants participating in the study such as: * History of myocardial infarction, angina pectoris, coronary artery bypass graft within 6 months prior to randomization * Concomitant clinically significant arrhythmias * 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 * Concomitant medications with a "known" risk of Torsades de Pointes * 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 medical history of chronic pancreatitis; on-going acute liver disease or history of chronic liver disease 7. 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.

Locations (30)

Georgia Regents University

Augusta, Georgia, United States

Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States

Novartis Investigative Site

Vienna, Austria

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Brno, Czechia

Novartis Investigative Site

Copenhagen, Denmark

Novartis Investigative Site

Bordeaux, France

Novartis Investigative Site

Dresden, Germany

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Roma, RM, Italy

...and 20 more locations

Outcomes

Primary Outcomes

Molecular Response (MR)^4.5 Rate at 48 Weeks and Difference in Rate Between Asciminib + Imatinib and Imatinib Alone

Percentage of participants still treated with the randomized treatment at 48 weeks and are in MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) at 48 weeks (± assessment window), among all participants in the asciminib add-on arms vs imatinib arm.

Time frame: at Week 48

Secondary Outcomes

Rate of MR^4.5 at 48 Weeks (Asciminib add-on Arms vs Nilotinib)

Percentage of participants in MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) at 48 weeks in asciminib add-on arms vs nilotinib arm.

Time frame: at Week 48

Rate of MR^4.5 by 48 Weeks (Randomized Arms)

Best observed MR\^4.5 rate (BCR::ABL1 ratio of ≤ 0.0032%) up to 48 weeks, i.e. the percentage of participants who achieved MR 4.5 anytime up to 48 weeks.

Time frame: by 48 weeks

Rate of MR^4.5 at 96 Weeks (Randomized Arms) and Difference in Rate Between Asciminib + Imatinib and Nilotinib Alone

Percentage of participants in MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) at 96 weeks in asciminib add-on arms vs nilotinib arm.

Time frame: at Week 96

Rate of MR^4.5 by 96 Weeks (Randomized Arms)

Best observed MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) rate up to 96 weeks, i.e. the percentage of participants who achieved MR\^4.5 anytime up to 96 weeks.

Time frame: by 96 weeks

Sustained MR^4.5 From at 96 Weeks (Randomized Arms)

Sustained MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) rate was defined as the percentage of participants who were in MR4.5 at 48 weeks and 96 weeks and who had no loss of MR4.5 in between those 2 time points.

Time frame: at 96 weeks

Time to MR^4.5 (Randomized Arms)

Time to MR\^4.5 is the time from first dose to first MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) computed only for participants who achieved MR\^4.5 at least once before the cut-off date.

Time frame: 96 weeks after the last participant received the first study dose

Duration of MR^4.5 (Randomized Arms)

Duration of MR\^4.5 was defined as the time from the first documented MR\^4.5 and the end date of MR\^4.5, i.e., the earliest date of loss of MR\^4.5 or CML-related death. Confirmed loss of MR\^4.5 is defined as an increase of the BCR::ABL1 ratio to \>0.0032% in two consecutive blood samples, by International Scale.

Time frame: 96 weeks after the last participant received the first study dose

Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - Cmax (Randomized Arms)

The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1).

Time frame: Week 2 Day 14: pre-dose (0h), 1h, 2h, 3hr 4h and 8h post-dose; Week 4 Day 28: pre-dose (0h) 2h, 3h, 4h post-dose

Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - Tmax (Randomized Arms)

The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time).

Time frame: Week 2 Day 14: pre-dose (0h), 1h, 2h, 3hr 4h and 8h post-dose; Week 4 Day 28: pre-dose (0h) 2h, 3h, 4h post-dose

Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - Cmin (Randomized Arms)

Minimum drug plasma(serum/blood) concentration

Time frame: Week 2 Day 14: pre-dose (0h), Week 4 Day 28: pre-dose (0h)

Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - AUClast (Randomized Arms)

The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x time x volume-1).

Time frame: Week 2 Day 14: pre-dose (0h), 1h, 2h, 3hr 4h and 8h post-dose

Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - AUCtau (Randomized Arms)

The AUC calculated to the end of a dosing interval (tau) at steady-state

Time frame: Week 2 Day 14: pre-dose (0h), 1h, 2h, 3hr 4h and 8h post-dose

Molecular Response (MR) 4.5 Rate at 48 Weeks (Asciminib Single Agent Cohort (ASAC))

Percentage of participants on asciminib 80 mg QD with MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) at 48 weeks.

Time frame: at Week 48

Time to MR^4.5 (ASAC)

Time from first dose of asciminib 80 mg QD to first MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) computed only for participants who achieved MR\^4.5.

Time frame: 48 weeks after the last enrolled participant (asciminib 80 mg cohort) received the first study dose

Duration of MR^4.5 (ASAC)

Time from first MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) until confirmed loss of MR\^4.5 or CML-related death.

Time frame: 48 weeks after the last enrolled participant (asciminib 80 mg cohort) received the first study dose

Pharmacokinetic Profile of Asciminib 80mg QD - Cmax (ASAC)

The maximum (peak) observed plasma drug concentration after oral dose administration (mass x volume-1).

Time frame: Week 2 Day 14: 0h (pre-dose), 1h, 2h, 3h, 4h, 8h post-dose; Week 4 Day 28: 0h (pre-dose), 2h, 3h, 4h post-dose

Pharmacokinetic Profile of Asciminib 80mg QD - Tmax (ASAC)

The time to reach maximum (Cmax) plasma drug concentration after oral dose administration (time).

Time frame: Week 2 Day 14: 0h (pre-dose), 1h, 2h, 3h, 4h, 8h post-dose; Week 4 Day 28: 0h (pre-dose), 2h, 3h, 4h post-dose

Pharmacokinetic Profile of Asciminib 80mg QD - Cmin (ASAC)

Minimum drug plasma (serum/blood) concentration

Time frame: Week 2 Day 14: 0h (pre-dose), Week 4 Day 28: 0h (pre-dose)

Pharmacokinetic Profile of Asciminib 80mg QD - AUClast (ASAC)

The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x time x volume-1).

Time frame: Week 2 Day 14: 0h (pre-dose), 1h, 2h, 3h, 4h, 8h post-dose

Pharmacokinetic Profile of Asciminib 80mg QD - AUCtau (ASAC)

The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)

Time frame: Week 2 Day 14: 0h (pre-dose), 1h, 2h, 3h, 4h, 8h post-dose

Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Been Previously Treated With Imatinib and Have Not Achieved Deep Molecular Response.

Overview

Conditions

Interventions

Eligibility

Locations (30)

Outcomes

Primary Outcomes

Secondary Outcomes