Clinical trial NCT03578367: Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
Official title: A Phase 2, Multi-center, Open-label, Randomized Study of Oral Asciminib Added to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients With CML-CP Who Have Been Previously Treated With Imatinib and Have Not Achieved Deep Molecular Response
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: CML
Chronic Myelogenous Leukemia
Leukemia, Myeloid Chronic
Hematologic Diseases
Keywords: CML
Chronic Myelogenous Leukemia
leukemia, myeloid chronic
Hematologic Diseases
Asciminib
ABL001
Imatinib
Nilotinib
deep molecular response
DMR
Ph+ CML
chronic phase
cancer of the white blood cells
tyrosine kinase inhibitor
leukemia, myeloid
leukemia
CML with Ph+
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-07-06
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Treatment arms 1 - 4 randomized
Primary purpose: TREATMENT

Brief summary: To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib versus asciminib 80mg in pre-treated patients with Chronic Myeloid Leukemia in chronic phase (CML-CP)

Detailed description: The study is 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 have been previously treated with imatinib first line therapy for at least one year and have 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).

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 is 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 are no other entry criteria for the cross-over part. Participants on nilotinib are not allowed to cross- over to receive the add-on treatment.

Participants on the study will continue on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks (in arms 1 to 4) after the last participant received the first dose of treatment. After the last dose received, every participant will be followed up for safety for 30 days.

Eligibility criteria: Inclusion Criteria:

* Male or female patients ≥ 18 years of age with a confirmed diagnosis of Chronic Myeloid Leukemia in chronic phase (CML-CP).
* Minimum of one year (12 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 300mg or 400 mg QD at randomization

For Korea only:

(i)a minimum of one year (12 calendar months) of prior treatment with imatinib for patients with BCR-ABL 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 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
* Participantss 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 kinese 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.

Other protocol defined inclusion/exclusion may apply.

Primary outcomes:
measure: Molecular Response (MR)^4.5 Rate at 48 Weeks
timeFrame: at Week 48
Secondary outcomes:
measure: Rate of MR^4.5 at 48 Weeks
timeFrame: at Week 48
measure: Rate of MR^4.5 by 48 Weeks
timeFrame: by 48 weeks
measure: Rate of MR^4.5 at 96 Weeks
timeFrame: at 96 weeks
measure: Rate of MR^4.5 by 96 Weeks
timeFrame: by 96 weeks
measure: Sustained MR^4.5 From 48 Weeks Until 96 Weeks
timeFrame: at 96 weeks
measure: Time to MR^4.5
timeFrame: 96/48 weeks after the last rand./enrolled (asciminib 80mg cohort) participant received the first study dose
measure: Duration of MR^4.5
timeFrame: 96/48 weeks after the last rand./enrolled (asciminib 80mg cohort) participant received the first study dose
measure: Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - Cmax
timeFrame: up to 96 weeks
measure: Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - Tmax
timeFrame: up to 96 weeks
measure: Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - Cmin
timeFrame: up to 96 weeks
measure: Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - AUClast
timeFrame: up to 96 weeks
measure: Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - AUCtau
timeFrame: up to 96 weeks
measure: MR^4.5 Rate at 48 Weeks
timeFrame: at 48 weeks
measure: Pharmacokinetic Profile of Asciminib 80mg QD - Cmax
timeFrame: up to 48 weeks
measure: Pharmacokinetic Profile of Asciminib 80mg QD - Tmax
timeFrame: up to 48 weeks
measure: Pharmacokinetic Profile of Asciminib 80mg QD - Cmin
timeFrame: up to 48 weeks
measure: Pharmacokinetic Profile of Asciminib 80mg QD - AUClast
timeFrame: up to 48 weeks
measure: Pharmacokinetic Profile of Asciminib 80mg QD - AUCtau
timeFrame: up to 48 weeks
Other outcomes:
Locations:
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Brno Bohunice
country: Czechia
facility: Novartis Investigative Site
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Uijeongbu si
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Krakow
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Changhua
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: