Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03578367

Collaborator

(none)

104

Enrollment

Locations

Arms

Anticipated Duration (Months)

2.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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)

Condition or Disease	Intervention/Treatment	Phase
CML Chronic Myelogenous Leukemia Leukemia, Myeloid Chronic Hematologic Diseases	Drug: Asciminib add-on Drug: Imatinib Drug: Nilotinib	Phase 2

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 subjects 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). The eligible subjects will be randomized 1:1:1:1 to receive asciminib 60 mg 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).

Subjects on the study will continue on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks after the last randomized subject received the first dose of treatment (the end of treatment (EOT) will be the same day for all the ongoing subjects). After the last dose received, every subject will be followed up for safety for 30 days.

An interim analysis will be performed when at least 40 (50%) patients have been randomized and have been followed for their 24 weeks visit assessment or have discontinued treatment. At the time of the interim analysis, if excessive toxicity without added benefit is observed in one of the investigational arms, discontinuation of that treatment arm will be considered. The decision to discontinue an investigational arm in the study will be taken based on the risk benefit balance of the two investigational arms, and in context of the other two treatment options available for the patients in the study, namely: continue on imatinib with no potential improvement of efficacy; or switch to nilotonib with a potential to improve efficacy however, with a relatively adverse safety profile as compared to imatinib. If a decision is taken to discontinue asciminib 60 mg + imatinib treatment arm at interim analysis, subjects ongoing on that treatment arm will be provided an opportunity to continue on the study at a lower dose (asciminib 40 mg + imatinib) if the investigator considers that is in the best interest of the patient.

Subjects on the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross-over (CO) to receive the add-on treatment within 4 weeks after week 48 visit. It is planned that these subjects cross-over to receive the asciminib 60 mg combination add-on treatment, as this dose provides higher exposure. Based on the results of the interim analysis or emerging data, cross-over may be changed to the asciminib 40 mg add-on treatment. The cross-over is at the discretion of the investigator and the patient. 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. Subjects on nilotinib are not allowed to cross- over to receive the add-on treatment.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

104 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 22, 2018

Actual Primary Completion Date :

Nov 8, 2021

Anticipated Study Completion Date :

Nov 21, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Asciminib 60mg QD + Imatinib 400mg QD Asciminib 60 mg taken once daily in combination with Imatinib 400 mg taken once daily	Drug: Asciminib add-on Asciminib 60 mg or 40 mg taken orally once daily in addition to Imatinib 400 mg taken orally once daily Other Names: ABL001 (asciminib), STI571 (imatinib)
Experimental: Asciminib 40mg QD + Imatinib 400mg QD Asciminib 40 mg taken once daily in combination with Imatinib 400 mg taken once daily	Drug: Asciminib add-on Asciminib 60 mg or 40 mg taken orally once daily in addition to Imatinib 400 mg taken orally once daily Other Names: ABL001 (asciminib), STI571 (imatinib)
Active Comparator: Imatinib 400mg QD Imatinib 400 mg taken once daily	Drug: Imatinib Imatinib 400 mg taken orally once daily Other Names: STI571, continuation treatment
Active Comparator: Nilotinib 300mg BID Nilotinib 300 mg taken twice daily	Drug: Nilotinib Nilotinib 300 mg taken orally twice daily (total daily dose of 600 mg) Other Names: AMN107, switch to nilotinib treatment

Outcome Measures

Primary Outcome Measures

Molecular Response (MR)^4.5 rate between asciminib+imatinib and imatinib alone [at 48 weeks]
Proportion of subjects still treated with the randomized treatment at 48 weeks and are in MR4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks (± assessment window), among all subjects randomized to the respective treatment arm.

Secondary Outcome Measures

MR^4.5 rate at 48 weeks [at 48 weeks]
Difference in the proportion of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib
Rate of MR^4.5 at 96 weeks [at 96 weeks]
Proportion of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 96 weeks
Rate of MR^4.5 by 48 and 96 weeks [by 48 weeks and 96 weeks]
Best observed rate of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) under randomized treatment up to the specific time point
Sustained MR^4.5 from 48 weeks until 96 weeks [from 48 weeks until 96 weeks]
Percentage of participants who are in MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at both 48 and 96 weeks and who have no loss of MR^4.5 in between those two time points. This endpoint will be analyzed at 96 weeks.
Time to MR^4.5 [up to 96 weeks]
Time to MR^4.5 is the time from randomization to first MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) computed only for subjects who achieved MR^4.5
Difference in rate of MR^4.5 at 48 weeks [at 48 weeks]
Difference in the proportion of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib
Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmax [up to Week 4 Day 28]
The maximum (peak) observed drug concentration after dose administration
Pharmacokinetic profile of asciminib and imatinib when administered in combination - Tmax [up to Week 4 Day 28]
The time to reach maximum (peak) drug concentration after dose administration
Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmin [up to 96 weeks]
Minimum drug concentration
Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUClast [up to Week 4 Day 28]
The AUC from time zero to the last measurable concentration sampling time (Tlast)
Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUCtau [up to Week 4 Day 28]
The AUC calculated to the end of a dosing interval (tau) at steady-state

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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-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

Patients 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 subjects 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

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)
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
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Georgia Regents University	Augusta	Georgia	United States	30912
2	University of Chicago	Chicago	Illinois	United States	60637
3	Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21205
4	Saint Agnes Healthcare Cancer Institute	Baltimore	Maryland	United States	21229
5	SUNY Stony Brook Medical Oncology Hematology/Oncology	Stony Brook	New York	United States	11794-8174
6	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
7	Novartis Investigative Site	Darlinghurst	New South Wales	Australia	2010
8	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
9	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
10	Novartis Investigative Site	Graz		Austria	8036
11	Novartis Investigative Site	Wien		Austria	1140
12	Novartis Investigative Site	Montreal	Quebec	Canada	H1T 2M4
13	Novartis Investigative Site	Temuco	Araucania	Chile	4800827
14	Novartis Investigative Site	Vina del Mar	Valparaiso	Chile	2540364
15	Novartis Investigative Site	Brno - Bohunice		Czechia	639 01
16	Novartis Investigative Site	Copenhagen		Denmark	DK-2100
17	Novartis Investigative Site	Bordeaux		France	33076
18	Novartis Investigative Site	Mannheim	Baden-Wuerttemberg	Germany	68305
19	Novartis Investigative Site	Berlin		Germany	13353
20	Novartis Investigative Site	Dresden		Germany	01307
21	Novartis Investigative Site	Hong Kong		Hong Kong
22	Novartis Investigative Site	Bologna	BO	Italy	40138
23	Novartis Investigative Site	Milano	MI	Italy	20162
24	Novartis Investigative Site	Roma	RM	Italy	00161
25	Novartis Investigative Site	Shinagawa ku	Tokyo	Japan	141 8625
26	Novartis Investigative Site	Uijeongbu si	Gyeonggi Do	Korea, Republic of	11759
27	Novartis Investigative Site	Seoul	Seocho Gu	Korea, Republic of	06591
28	Novartis Investigative Site	Seoul		Korea, Republic of	03080
29	Novartis Investigative Site	Krakow		Poland	31 531
30	Novartis Investigative Site	Warszawa		Poland	02 776
31	Novartis Investigative Site	Wroclaw		Poland	50 367
32	Novartis Investigative Site	Lisboa		Portugal	1099 023
33	Novartis Investigative Site	Porto		Portugal	4200-072
34	Novartis Investigative Site	Moscow		Russian Federation	125167
35	Novartis Investigative Site	Moscow		Russian Federation	125284
36	Novartis Investigative Site	Saint Petersburg		Russian Federation	191024
37	Novartis Investigative Site	Saint Petersburg		Russian Federation	197341
38	Novartis Investigative Site	Sevilla	Andalucia	Spain	41009
39	Novartis Investigative Site	Las Palmas de Gran Canaria		Spain	35010
40	Novartis Investigative Site	Madrid		Spain	28034
41	Novartis Investigative Site	Valencia		Spain	46026
42	Novartis Investigative Site	Changhua		Taiwan	50006
43	Novartis Investigative Site	Taipei		Taiwan	10002
44	Novartis Investigative Site	Taoyuan		Taiwan	33305
45	Novartis Investigative Site	Wirral	Merseyside	United Kingdom	CH63 4JY
46	Novartis Investigative Site	London		United Kingdom	W12 0HS
47	Novartis Investigative Site	Oxford		United Kingdom	OX3 7LJ