Nilotinib Versus Standard Imatinib (400/600 mg Every Day (QD)) Comparing the Kinetics of Complete Molecular Response for Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Pts With Evidence of Persistent Leukemia by Real-time Quantitative Polymerase Chain Reaction (RQ-PCR)

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Primary Purpose

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Nilotinib

Imatinib

About this trial

This is an interventional treatment trial for CHRONIC MYELOGENOUS LEUKEMIA focused on measuring MYELOGENOUS, LEUKEMIA, Chronic Phase, CML

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of chronic myeloid leukemia associated with BCR-ABL quantifiable by RQ-PCR Documented CCyR by bone marrow or BCR-ABL<1% IS in the past 12 months Persistent disease demonstrated by two PCR positive tests 3 months apart both during the past 6 months.

Treatment with imatinib for at least 2 years with 400 mg or 600 mg and a stable dose No other current or planned anti-leukemia therapies

Exclusion Criteria:

Patient has evidence of rising PCR (a confirmed >1 log increase in previous 6 months) Patient has received another investigational agent within last 6 months or tyrosine kinase inhibitors (TKIs) other than imatinib Prior allogeneic stem cell transplantation

Impaired cardiac function including any one of the following:

Inability to monitor the QT interval on electrocardiogram (ECG) Long QT syndrome or a known family history of long QT syndrome. Clinically significant resting brachycardia (<50 beats per minute) QTc > 450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc Myocardial infarction within 12 months prior to starting study Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension) History of or presence of clinically significant ventricular or atrial tachyarrhythmias Administration of cytokine therapy (e.g. G-CSF, GM-CSF or SCF) within 4 weeks prior to study entry

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Nilotinib

Imatinib

Arm Description

Participants received Nilotinib 400 mg orally twice daily (bid) for 48 months.

Participants received Imatinib 400 mg or 600 mg once daily (qd) (based on the participant's dose prior to randomization) for 48 months.

Outcomes

Primary Outcome Measures

Rate of Confirmed Best Cumulative Complete Molecular Response (CMR)

The rate of confirmed best cumulative CMR was defined as the number of participants who had confirmed CMR during the first 12 months of treatment after the randomization date. Participants who achieved confirmed best cumulative CMR during the first 12 months were considered responders. Participants who dropped out early or who did not provide sufficient data for any reason were considered to be non-responders. The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by real-time quantitative polymerase chain reaction (RQ-PCR) where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.

Secondary Outcome Measures

Rate of Confirmed Best Cumulative CMR

The rate of confirmed best cumulative CMR was defined as the number of participants who had confirmed CMR during the 24, 36 and 48 months post treatment after the randomization date. Participants who achieved confirmed best cumulative CMR during the first 12 months were considered responders. Participants who dropped out early or who did not provide sufficient data for any reason were considered to be non-responders. The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by RQ-PCR where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.

Number of Cross-over Participants With CMR

The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by RQ-PCR where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.

Progression Free Survival (PFS)

PFS was defined as the time from the date of randomization to the date of the earliest documented progression-defining event as follows: transformation to blast crisis or accelerated phase disease, or death from any cause.

Event-free Survival

Event-free survival was defined as the time from the date of randomization to the date of first occurrence of any of the following events on study treatment: loss of complete hematological response, confirmed loss of complete cytogenetic response (CCyR), confirmed loss of major molecular response (MMR), death from any cause during treatment, progression to the accelerated phase or blast crisis of chronic myelogenous leukemia (CML) per European Leukemia Network (ELN) criteria, whichever was earliest.

Overall Survival

Overall survival was defined as the time from the date of randomization to the date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment.

Full Information

NCT ID

NCT00760877

First Posted

September 25, 2008

Last Updated

October 4, 2016

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00760877

Brief Title

Nilotinib Versus Standard Imatinib (400/600 mg Every Day (QD)) Comparing the Kinetics of Complete Molecular Response for Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Pts With Evidence of Persistent Leukemia by Real-time Quantitative Polymerase Chain Reaction (RQ-PCR)

Official Title

An Open Label, Randomized Study of Nilotinib vs. Standard Imatinib (400/600 mg QD) Comparing the Kinetics of Complete Molecular Response for CML-CP Patients With Evidence of Persistent Leukemia by RQ-PCR.

Study Type

Interventional

2. Study Status

Record Verification Date

October 2016

Overall Recruitment Status

Completed

Study Start Date

June 2009 (undefined)

Primary Completion Date

July 2015 (Actual)

Study Completion Date

July 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee

No

5. Study Description

Brief Summary

The primary goal of this study was to determine the rate of confirmed best cumulative complete molecular response (CMR) within the first year of study therapy with imatinib or nilotinib. The study also explored the impact and significance of the achieved CMR on patient outcomes (progression free survival (PFS), event free survival (EFS) and overall survival (OS), characterized the kinetics of CMR achieved in both treatment arms and after the cross-over.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

CHRONIC MYELOGENOUS LEUKEMIA

Keywords

MYELOGENOUS, LEUKEMIA, Chronic Phase, CML

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

207 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Nilotinib

Arm Type

Experimental

Arm Description

Participants received Nilotinib 400 mg orally twice daily (bid) for 48 months.

Arm Title

Imatinib

Arm Type

Active Comparator

Arm Description

Participants received Imatinib 400 mg or 600 mg once daily (qd) (based on the participant's dose prior to randomization) for 48 months.

Intervention Type

Drug

Intervention Name(s)

Nilotinib

Intervention Description

Supplied in 200 mg capsules

Intervention Type

Drug

Intervention Name(s)

Imatinib

Other Intervention Name(s)

Glivec/Gleevec

Intervention Description

Supplied in 100 mg and 400 mg capsules

Primary Outcome Measure Information:

Title

Rate of Confirmed Best Cumulative Complete Molecular Response (CMR)

Description

The rate of confirmed best cumulative CMR was defined as the number of participants who had confirmed CMR during the first 12 months of treatment after the randomization date. Participants who achieved confirmed best cumulative CMR during the first 12 months were considered responders. Participants who dropped out early or who did not provide sufficient data for any reason were considered to be non-responders. The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by real-time quantitative polymerase chain reaction (RQ-PCR) where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Rate of Confirmed Best Cumulative CMR

Description

The rate of confirmed best cumulative CMR was defined as the number of participants who had confirmed CMR during the 24, 36 and 48 months post treatment after the randomization date. Participants who achieved confirmed best cumulative CMR during the first 12 months were considered responders. Participants who dropped out early or who did not provide sufficient data for any reason were considered to be non-responders. The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by RQ-PCR where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.

Time Frame

24 months, 36 month, 48 months

Title

Number of Cross-over Participants With CMR

Description

The definition of CMR is undetectable BCR-ABL (fusion gene formed between bcr gene from chromosome 22 and abl gene from chromosome 9) where BCR-ABL ratio in % international scale (IS) ≤ 0.00001 by RQ-PCR where there was no detectable BCR-ABL and 1) the test had a sensitivity of at least 4.5 logs below the standardized baseline; 2) RQ-PCR negativity was confirmed on the next RQ-PCR sample (usually 3 months later); and 3) the date of confirmed CMR was the date of the first of two negative results with sensitivity >4.5 logs.

Time Frame

24 months, 36 months, 48 months

Title

Progression Free Survival (PFS)

Description

PFS was defined as the time from the date of randomization to the date of the earliest documented progression-defining event as follows: transformation to blast crisis or accelerated phase disease, or death from any cause.

Time Frame

48 months

Title

Event-free Survival

Description

Event-free survival was defined as the time from the date of randomization to the date of first occurrence of any of the following events on study treatment: loss of complete hematological response, confirmed loss of complete cytogenetic response (CCyR), confirmed loss of major molecular response (MMR), death from any cause during treatment, progression to the accelerated phase or blast crisis of chronic myelogenous leukemia (CML) per European Leukemia Network (ELN) criteria, whichever was earliest.

Time Frame

48 months

Title

Overall Survival

Description

Overall survival was defined as the time from the date of randomization to the date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment.

Time Frame

48 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

Inclusion Criteria: Diagnosis of chronic myeloid leukemia associated with BCR-ABL quantifiable by RQ-PCR Documented CCyR by bone marrow or BCR-ABL<1% IS in the past 12 months Persistent disease demonstrated by two PCR positive tests 3 months apart both during the past 6 months. Treatment with imatinib for at least 2 years with 400 mg or 600 mg and a stable dose No other current or planned anti-leukemia therapies Exclusion Criteria: Patient has evidence of rising PCR (a confirmed >1 log increase in previous 6 months) Patient has received another investigational agent within last 6 months or tyrosine kinase inhibitors (TKIs) other than imatinib Prior allogeneic stem cell transplantation Impaired cardiac function including any one of the following: Inability to monitor the QT interval on electrocardiogram (ECG) Long QT syndrome or a known family history of long QT syndrome. Clinically significant resting brachycardia (<50 beats per minute) QTc > 450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc Myocardial infarction within 12 months prior to starting study Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension) History of or presence of clinically significant ventricular or atrial tachyarrhythmias Administration of cytokine therapy (e.g. G-CSF, GM-CSF or SCF) within 4 weeks prior to study entry

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Caba

State/Province

Buenos Aires

ZIP/Postal Code

C1221ADH

Country

Argentina

Facility Name

Novartis Investigative Site

City

St. Leonards

State/Province

New South Wales

ZIP/Postal Code

2065

Country

Australia

Facility Name

Novartis Investigative Site

City

Westmead

State/Province

New South Wales

ZIP/Postal Code

2145

Country

Australia

Facility Name

Novartis Investigative Site

City

Herston

State/Province

Queensland

ZIP/Postal Code

4029

Country

Australia

Facility Name

Novartis Investigative Site

City

South Brisbane

State/Province

Queensland

ZIP/Postal Code

4101

Country

Australia

Facility Name

Novartis Investigative Site

City

Woolloongabba

State/Province

Queensland

ZIP/Postal Code

4102

Country

Australia

Facility Name

Novartis Investigative Site

City

Adelaide

State/Province

South Australia

ZIP/Postal Code

5000

Country

Australia

Facility Name

Novartis Investigative Site

City

Parkville

State/Province

Victoria

ZIP/Postal Code

3050

Country

Australia

Facility Name

Novartis Investigative Site

City

Prahran

State/Province

Victoria

ZIP/Postal Code

3181

Country

Australia

Facility Name

Novartis Investigative Site

City

Nedlands

State/Province

Western Australia

ZIP/Postal Code

6009

Country

Australia

Facility Name

Novartis Investigative Site

City

Belo Horizonte

State/Province

MG

ZIP/Postal Code

30130-100

Country

Brazil

Facility Name

Novartis Investigative Site

City

Curitiba

State/Province

PR

ZIP/Postal Code

80060-900

Country

Brazil

Facility Name

Novartis Investigative Site

City

Rio de Janeiro

State/Province

RJ

ZIP/Postal Code

21941-913

Country

Brazil

Facility Name

Novartis Investigative Site

City

Campinas

State/Province

SP

ZIP/Postal Code

13083-970

Country

Brazil

Facility Name

Novartis Investigative Site

City

Sao Paulo

State/Province

SP

ZIP/Postal Code

05403-000

Country

Brazil

Facility Name

Novartis Investigative Site

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V5Z 1M9

Country

Canada

Facility Name

Novartis Investigative Site

City

Hamilton

State/Province

Ontario

ZIP/Postal Code

L8H 4J9

Country

Canada

Facility Name

Novartis Investigative Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2M9

Country

Canada

Facility Name

Novartis Investigative Site

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H1T 2M4

Country

Canada

Facility Name

Novartis Investigative Site

City

Québec

State/Province

Quebec

ZIP/Postal Code

G1J 1Z4

Country

Canada

Facility Name

Novartis Investigative Site

City

Bordeaux

ZIP/Postal Code

33076

Country

France

Facility Name

Novartis Investigative Site

City

Creteil

ZIP/Postal Code

94010

Country

France

Facility Name

Novartis Investigative Site

City

Lyon cedex 04

ZIP/Postal Code

69317

Country

France

Facility Name

Novartis Investigative Site

City

Paris

ZIP/Postal Code

75010

Country

France

Facility Name

Novartis Investigative Site

City

Vandoeuvre les Nancy

ZIP/Postal Code

54511

Country

France

Facility Name

Novartis Investigative Site

City

Malaga

State/Province

Andalucia

ZIP/Postal Code

29010

Country

Spain

Facility Name

Novartis Investigative Site

City

Barcelona

State/Province

Cataluña

ZIP/Postal Code

08036

Country

Spain

Facility Name

Novartis Investigative Site

City

Pamplona

State/Province

Navarra

ZIP/Postal Code

31008

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28006

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28007

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

24948656

Citation

Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014 Jul 31;124(5):729-36. doi: 10.1182/blood-2013-12-544015. Epub 2014 Jun 19.

Results Reference

derived

CHRONIC MYELOGENOUS LEUKEMIA

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial