ENEST: Efficacy and Safety of Nilotinib (AMN107) Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00471328
• Collaborator: (none)
• Enrollment: 248
• Locations: 35
• Arms: 2
• Duration (Months): 51
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study evaluated the safety and efficacy of nilotinib versus current treatment in adults with gastrointestinal stromal tumors (GIST) who have either progressed or who were intolerant to the first and second line treatments.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Stromal Tumors	Drug: Nilotinib; Other: Best Supportive Care (BSC) +/- imatinib or sunitinib	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 248 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Multi-center Study to Evaluate the Efficacy of Nilotinib Versus Best Supportive Care With or Without a Tyrosine Kinase Inhibitor (Investigator's Choice) in Adult Patients With Gastrointestinal Stromal Tumors Resistant to Both Imatinib and Sunitinib
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nilotinib 400mg twice daily in core and extension phases of the study.	Drug: Nilotinib; Nilotinib 400 mg twice daily (bid); Other Names: AMN107, Tasigna®
Active Comparator: Control/cross-over to Nilotinib In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.	Drug: Nilotinib; Nilotinib 400 mg twice daily (bid); Other Names: AMN107, Tasigna® ; Other: Best Supportive Care (BSC) +/- imatinib or sunitinib; Can include pain medication, localized radiotherapy, nutritional support, and/or oxygen therapy and blood transfusions. Imatinib or sunitinib can be administered at the last tolerated dose and regimen or at the Investigator's choice.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) From Central Radiology Review Based on Primary Analysis (Data Cut-off: June, 2008) [Up to 16 months]

   Progression-free survival (PFS) is the time from date of randomization to the date of first documented progression or death due to any cause. If a participant has not had an event, progression-free survival is censored at the time of last adequate tumor assessment. Progression is defined according to Modified Response Evaluation Criteria in Solid Tumors (modified RECIST) criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.

2. Progression-free Survival (PFS) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set [Up to 34 months]

   PFS is defined as the time from the first date of cross-over to nilotinib therapy from the control arm to the date of the first observation of documented disease progression. Tumor assessment was based on the local investigator's measurement using Modified Response Evaluation Criteria in Solid Tumors (modified RECIST) criteria. Progression is defined according to modified RECIST criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.

Secondary Outcome Measures

1. Overall Survival Based on Primary Analysis (Data Cut-off:June, 2008) [Up to 16 months]

   Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, survival will be censored at the date of last contact.

2. Overall Survival During Core and Extension Phases of the Study [Up to 50 months (including core, extension and follow up period)]

   Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, survival will be censored at the date of last contact. This analysis included both Core and Extension data as well as survival follow up data.

3. Overall Survival for Treatment Crossover Analysis Set [Up to 34 months]

   For patients who crossed-over to nilotinib from the control arm, the overall survival was the time from the first dose date of nilotinib after switching from control arm to the date of death due to any cause. If death was not observed, the OS was censored at the latest date the patient was known to be alive.

4. Number of Responders With Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) From Central Radiology Review During Primary Analysis (Data Cut-off: June, 2008) [Up to 16 months]

   The best overall response is the best response recorded from randomization until disease progression. The CR/PR must be confirmed by at least two determinations at least 4 weeks apart before progression. Using modified RECIST criteria, a Complete Response is defined as disappearance of all lesions, and a Partial Response is defined as either 1) at least a 30% decrease in the sum of the longest diameter of target lesions and no new lesions or progression of non-target lesions or 2) disappearance of all target lesions but persistence of one or more non-target lesion(s).

5. Number of Responders With Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set [Up to 34 months]

   The best overall response (CR/PR) must be confirmed by at least two determinations at least 4 weeks apart before progression. Using modified RECIST criteria, a Complete Response is defined as disappearance of all lesions, and a Partial Response is defined as either 1) at least a 30% decrease in the sum of the longest diameter of target lesions and no new lesions or progression of non-target lesions or 2) disappearance of all target lesions but persistence of one or more non-target lesion(s).

6. Overall Clinical Benefit (Complete Response [CR]/Partial Response [PR] or Stable Disease [SD]) From Central Radiology Review Based on Primary Analysis (Data Cut-off: June, 2008) [Up to 16 months]

   The overall clinical benefit includes the best overall responses of CR, PR, or SD. The best overall responses of CR/PR must be confirmed by at least two determinations at least 4 weeks apart before progression. The best overall response of SD must have at least one SD (or better) at least 6 weeks (or 6 months or 12 months as applicable) after randomization but before progression.

7. Overall Clinical Benefit (Complete Response [CR]/Partial Response [PR] or Stable Disease [SD]) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set [Up to 34 months]

   The overall clinical benefit includes the best overall responses of CR, PR, or SD. The best overall responses of CR/PR must be confirmed by at least two determinations at least 4 weeks apart before progression. The best overall response of SD must have at least one SD (or better) at least 6 weeks (or 6 months or 12 months as applicable) after randomization but before progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria (Core Phase):

• Age ≥18 years

• Radiological confirmation of disease progression during imatinib and sunitinib therapy OR intolerance to imatinib and/or sunitinib

• At least one measurable site of disease on CT/MRI scan

• Physically fit even if not able to work

• Normal organ, electrolyte, and bone marrow function

Inclusion criteria (Extension Phase):

• Patients whose tumors had progressed on the control arm and had crossed over to the nilotinib arm.

• The study was stopped due to meeting the primary efficacy endpoint of PFS at the interim analysis.

• Patients who were still being treated at the close of the Core study on the control arm or nilotinib arm (whose tumors have not progressed at the time of the end of the Core study).

• Patients must have had documented, confirmed stable, partial or complete response as defined by the RECIST criteria at the time of entry into the Extension study with the exception of patients who had progressed on the control arm.

Exclusion criteria (Core Phase):

• Previous treatment with nilotinib or any other drug in this class or other targeted therapy

• Treatment with any cytotoxic and/or investigational cytotoxic drug ≤ 4 weeks prior to study entry

• Impaired cardiac function

• Use of coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon)

• Women who are pregnant or lactating

Exclusion criteria (Extension Phase):

• Use of other anticancer treatments or investigational drugs (with exception of the study drugs)

• Patients with a history of noncompliance with study drug treatment in the Core study protocol.

Other protocol-defined inclusion/exclusion criteria applied

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA's Jonsson Comprehensive Cancer Center	Los Angeles	California	United States	90095
2	Washington Hospital Center - Washington Cancer Institute	Washington	District of Columbia	United States	20010-2965
3	H. Lee Moffitt Cancer Center	Tampa	Florida	United States	33612
4	University of Chicago Hospital	Chicago	Illinois	United States	60637
5	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
6	Wayne State University/Wertz Clinical Cancer Center	Detroit	Michigan	United States	48201
7	Washington University School of Medicine - Siteman Cancer Center	St. Louis	Missouri	United States	63110
8	St. Vincent's Comprehensive Cancer Center	New York	New York	United States	10011
9	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157-1082
10	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111-2497
11	University of Texas/MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
12	Novartis Investigative Site	Auchenflower	Queensland	Australia	4066
13	Novartis Investigative Site	East Melbourne	Victoria	Australia	3002
14	Novartis Investigative Site	Vienna		Austria
15	Novartis Investigative Site	Toronto		Canada
16	Novartis Investigative Site	Praha 5		Czech Republic
17	Novartis Investigative Site	Bordeaux		France
18	Novartis Investigative Site	Lyon		France
19	Novartis Investigative Site	Marseille		France
20	Novartis Investigative Site	Berlin		Germany
21	Novartis Investigative Site	Duesseldorf		Germany
22	Novartis Investigative Site	Essen		Germany
23	Novartis Investigative Site	Frankfurt		Germany
24	Novartis Investigative Site	Hannover		Germany
25	Novartis Investigative Site	Koln		Germany
26	Novartis Investigative Site	Mannheim		Germany
27	Novartis Investigative Site	Muenchen		Germany
28	Novartis Investigative Site	Tubingen		Germany
29	Novrtis Investigative Site	Bologna		Italy
30	Novartis Investigative Site	Milan		Italy
31	Novartis Investigative Site	Seoul		Korea, Republic of
32	Novartis Investigative Site	Leiden		Netherlands
33	Novartis Investigative Site	Warszawa		Poland
34	Novartis Investigative Site	Madrid		Spain
35	Novartis Investigative Site	Chur		Switzerland

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00471328
• Other Study ID Numbers: CAMN107A2201; 2006-002267-11; NCT00488150
• First Posted: May 9, 2007
• Last Update Posted: Jun 12, 2012
• Last Verified: Jun 1, 2012

• Keywords provided by Novartis Pharmaceuticals: GIST; adults; imatinib resistant; sunitinib resistant; AMN107; nilotinib; treatment; Gastrointestinal stromal tumor (GIST)
• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors; Sunitinib; Imatinib Mesylate

Study Results

Participant Flow

Recruitment Details	Patients ongoing on treatment at primary analysis had option to enter extension. Patients in control arm were allowed cross over to Nilotinib arm at disease progression and considered as part of extension. Patients entering the extension part on control arm were permitted to cross over to the nilotinib only upon documented disease progression.

Arm/Group Title	Nilotinib	Control/Cross Over to Nilotinib
Arm/Group Description	400 mg was taken orally twice daily in core and extension phase of the study	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Period Title: Core Phase
STARTED	165	83
Crossover to Nilotinib:Started Extension	0	53
COMPLETED	58	16
NOT COMPLETED	107	67
Period Title: Core Phase
STARTED	41	67
Started:CrossOver Before PrimaryAnalysis	0	53
Started:CrossOver After PrimaryAnalysis	0	4
Started:CrossOver During Extension	0	10
COMPLETED	0	0
NOT COMPLETED	41	67

Baseline Characteristics

Arm/Group Title	Nilotinib	Control/Cross Over to Nilotinib	Total
Arm/Group Description	400 mg was taken orally twice daily in core and extension phase of the study	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.	Total of all reporting groups
Overall Participants	165	83	248
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	118 71.5%	57 68.7%	175 70.6%
>=65 years	47 28.5%	26 31.3%	73 29.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.4 (12.69)	58.6 (10.57)	57.8 (12.01)
Sex: Female, Male (Count of Participants)
Female	64 38.8%	36 43.4%	100 40.3%
Male	101 61.2%	47 56.6%	148 59.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	21 12.7%	11 13.3%	32 12.9%
Native Hawaiian or Other Pacific Islander	2 1.2%	0 0%	2 0.8%
Black or African American	2 1.2%	4 4.8%	6 2.4%
White	134 81.2%	67 80.7%	201 81%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	6 3.6%	1 1.2%	7 2.8%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) From Central Radiology Review Based on Primary Analysis (Data Cut-off: June, 2008)
Description	Progression-free survival (PFS) is the time from date of randomization to the date of first documented progression or death due to any cause. If a participant has not had an event, progression-free survival is censored at the time of last adequate tumor assessment. Progression is defined according to Modified Response Evaluation Criteria in Solid Tumors (modified RECIST) criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.
Time Frame	Up to 16 months

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population was defined as all randomized patients and was used as the primary efficacy population.

Arm/Group Title	Nilotinib	Control/Cross Over to Nilotinib
Arm/Group Description	400 mg was taken orally twice daily in core and extension phase of the study	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	165	83
Median (95% Confidence Interval) [days]	109.0	111.0

2. Secondary Outcome

Title	Overall Survival Based on Primary Analysis (Data Cut-off:June, 2008)
Description	Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, survival will be censored at the date of last contact.
Time Frame	Up to 16 months

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population was defined as all randomized participants and was used as the primary efficacy population.

Arm/Group Title	Nilotinib	Control/Cross Over to Nilotinib
Arm/Group Description	400 mg was taken orally twice daily in core and extension phase of the study	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	165	83
Median (95% Confidence Interval) [days]	332.0	280.0

3. Secondary Outcome

Title	Overall Survival During Core and Extension Phases of the Study
Description	Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, survival will be censored at the date of last contact. This analysis included both Core and Extension data as well as survival follow up data.
Time Frame	Up to 50 months (including core, extension and follow up period)

Outcome Measure Data

Analysis Population Description

Core Full Analysis Set (Core FAS): included all randomized patients included in the Core study. Analyses based on Core FAS does not account for treatment crossover i.e.pooling all data both before and after crossover. This analysis set was used to conduct an overall survival analysis.

Arm/Group Title	Nilotinib	Control/Cross Over to Nilotinib
Arm/Group Description	400 mg was taken orally twice daily in core and extension phase of the study	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	165	83
Median (95% Confidence Interval) [days]	361	300

4. Secondary Outcome

Title	Overall Survival for Treatment Crossover Analysis Set
Description	For patients who crossed-over to nilotinib from the control arm, the overall survival was the time from the first dose date of nilotinib after switching from control arm to the date of death due to any cause. If death was not observed, the OS was censored at the latest date the patient was known to be alive.
Time Frame	Up to 34 months

Outcome Measure Data

Analysis Population Description

Treatment Crossover Analysis Set: All patients who crossed over from control arm to nilotinib after completing the Core study or during the Extension study after disease progression.

Arm/Group Title	Control/Cross Over to Nilotinib
Arm/Group Description	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression and cross-overed to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	67
Median (95% Confidence Interval) [days]	231

5. Primary Outcome

Title	Progression-free Survival (PFS) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set
Description	PFS is defined as the time from the first date of cross-over to nilotinib therapy from the control arm to the date of the first observation of documented disease progression. Tumor assessment was based on the local investigator's measurement using Modified Response Evaluation Criteria in Solid Tumors (modified RECIST) criteria. Progression is defined according to modified RECIST criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.
Time Frame	Up to 34 months

Outcome Measure Data

Analysis Population Description

Treatment Crossover Analysis Set: All patients who crossed over from control arm to nilotinib after completing the Core study or during the Extension study after disease progression.

Arm/Group Title	Control/Cross Over to Nilotinib
Arm/Group Description	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression and cross-overed to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	67
Median (95% Confidence Interval) [days]	84

6. Secondary Outcome

Title	Number of Responders With Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) From Central Radiology Review During Primary Analysis (Data Cut-off: June, 2008)
Description	The best overall response is the best response recorded from randomization until disease progression. The CR/PR must be confirmed by at least two determinations at least 4 weeks apart before progression. Using modified RECIST criteria, a Complete Response is defined as disappearance of all lesions, and a Partial Response is defined as either 1) at least a 30% decrease in the sum of the longest diameter of target lesions and no new lesions or progression of non-target lesions or 2) disappearance of all target lesions but persistence of one or more non-target lesion(s).
Time Frame	Up to 16 months

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population was defined as all randomized patients and was used as the primary efficacy population.

Arm/Group Title	Nilotinib	Control/Cross Over to Nilotinib
Arm/Group Description	400 mg was taken orally twice daily in core and extension phase of the study	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	165	83
Number [Participants]	1 0.6%	0 0%

7. Secondary Outcome

Title	Number of Responders With Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set
Description	The best overall response (CR/PR) must be confirmed by at least two determinations at least 4 weeks apart before progression. Using modified RECIST criteria, a Complete Response is defined as disappearance of all lesions, and a Partial Response is defined as either 1) at least a 30% decrease in the sum of the longest diameter of target lesions and no new lesions or progression of non-target lesions or 2) disappearance of all target lesions but persistence of one or more non-target lesion(s).
Time Frame	Up to 34 months

Outcome Measure Data

Analysis Population Description

Treatment Crossover Analysis Set: All patients who crossed over from control arm to nilotinib after completing the Core study or during the Extension study after disease progression.

Arm/Group Title	Control/Cross Over to Nilotinib
Arm/Group Description	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression and cross-overed to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	67
Number [Participants]	1 0.6%

8. Secondary Outcome

Title	Overall Clinical Benefit (Complete Response [CR]/Partial Response [PR] or Stable Disease [SD]) From Central Radiology Review Based on Primary Analysis (Data Cut-off: June, 2008)
Description	The overall clinical benefit includes the best overall responses of CR, PR, or SD. The best overall responses of CR/PR must be confirmed by at least two determinations at least 4 weeks apart before progression. The best overall response of SD must have at least one SD (or better) at least 6 weeks (or 6 months or 12 months as applicable) after randomization but before progression.
Time Frame	Up to 16 months

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population was defined as all randomized patients and was used as the primary efficacy population.

Arm/Group Title	Nilotinib	Control/Cross Over to Nilotinib
Arm/Group Description	400 mg was taken orally twice daily in core and extension phase of the study	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression followed by cross-over to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	165	83
CR/PR/SD	52.7 31.9%	44.6 53.7%
CR/PR/SD lasting > 6 months	7.3 4.4%	1.2 1.4%
CR/PR/SD lasting > 12 months	0.6 0.4%	0 0%

9. Secondary Outcome

Title	Overall Clinical Benefit (Complete Response [CR]/Partial Response [PR] or Stable Disease [SD]) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set
Description	The overall clinical benefit includes the best overall responses of CR, PR, or SD. The best overall responses of CR/PR must be confirmed by at least two determinations at least 4 weeks apart before progression. The best overall response of SD must have at least one SD (or better) at least 6 weeks (or 6 months or 12 months as applicable) after randomization but before progression.
Time Frame	Up to 34 months

Outcome Measure Data

Analysis Population Description

Treatment Crossover Analysis Set: All patients who crossed over from control arm to nilotinib after completing the Core study or during the Extension study after disease progression.

Arm/Group Title	Control/Cross Over to Nilotinib
Arm/Group Description	In core study phase, patients in this arm received Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose or at the investigator's choice until documented disease progression and cross-overed to nilotinib arm. Patients entering the extension study on this control arm were permitted to cross over to nilotinib arm only upon documented disease progression.
Measure Participants	67
CR/PR/SD	37.3 22.6%
CR/PR/SD lasting > 6 months	7.5 4.5%
CR/PR/SD lasting > 12 months	6.0 3.6%

Adverse Events

Arm/Group Title	Nilotinib(Core +Extension)		Control(Core + Extension)		Crossover Nilotinib Therapy
Arm/Group Description	Patients randomized to 400 mg Nilotinib which was taken orally twice daily. The safety is assessed using these patient's data from both core and extension phase of the study.		Patients randomized to control arm, Best Supportive Care (BSC) with or without imatinib or sunitinib at the last tolerated dose before the study or at the dose of the investigator's choice. The safety is assessed using these patient's data from both core and extension phase of the study.		All patients who crossed over from control arm to nilotinib after completing the Core study or during the Extension study after disease progression were included in safety assessment.
All Cause Mortality
	Nilotinib(Core +Extension)		Control(Core + Extension)		Crossover Nilotinib Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Nilotinib(Core +Extension)		Control(Core + Extension)		Crossover Nilotinib Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	81/165 (49.1%)		27/83 (32.5%)		32/67 (47.8%)
Blood and lymphatic system disorders
Anaemia	6/165 (3.6%)		7/83 (8.4%)		5/67 (7.5%)
Febrile neutropenia	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Lymphadenopathy	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Cardiac disorders
Angina pectoris	2/165 (1.2%)		0/83 (0%)		0/67 (0%)
Cardiac arrest	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Cyanosis	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Myocardial infarction	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Sinus bradycardia	2/165 (1.2%)		0/83 (0%)		0/67 (0%)
Congenital, familial and genetic disorders
Spinocerebellar ataxia	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Endocrine disorders
Hypothyroidism	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Abdominal distension	1/165 (0.6%)		0/83 (0%)		1/67 (1.5%)
Abdominal pain	21/165 (12.7%)		5/83 (6%)		3/67 (4.5%)
Abdominal pain lower	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Abdominal pain upper	2/165 (1.2%)		0/83 (0%)		0/67 (0%)
Ascites	2/165 (1.2%)		2/83 (2.4%)		0/67 (0%)
Constipation	1/165 (0.6%)		0/83 (0%)		2/67 (3%)
Diarrhoea	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Duodenal ulcer	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Enteritis	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Gastrointestinal haemorrhage	3/165 (1.8%)		2/83 (2.4%)		2/67 (3%)
Gastrointestinal motility disorder	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Haematemesis	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Haematochezia	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Ileus	2/165 (1.2%)		0/83 (0%)		1/67 (1.5%)
Intestinal obstruction	3/165 (1.8%)		2/83 (2.4%)		1/67 (1.5%)
Lower gastrointestinal haemorrhage	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Mechanical ileus	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Melaena	2/165 (1.2%)		0/83 (0%)		0/67 (0%)
Nausea	3/165 (1.8%)		0/83 (0%)		0/67 (0%)
Obstruction gastric	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Oesophageal ulcer	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Rectal haemorrhage	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Small intestinal obstruction	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Subileus	3/165 (1.8%)		1/83 (1.2%)		0/67 (0%)
Upper gastrointestinal haemorrhage	0/165 (0%)		0/83 (0%)		2/67 (3%)
Vomiting	9/165 (5.5%)		1/83 (1.2%)		1/67 (1.5%)
General disorders
Asthenia	0/165 (0%)		1/83 (1.2%)		1/67 (1.5%)
Chest pain	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Fatigue	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
General physical health deterioration	16/165 (9.7%)		3/83 (3.6%)		10/67 (14.9%)
Generalised oedema	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Hyperpyrexia	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Multi-organ failure	0/165 (0%)		1/83 (1.2%)		1/67 (1.5%)
Oedema peripheral	0/165 (0%)		0/83 (0%)		3/67 (4.5%)
Pain	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Performance status decreased	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Pyrexia	5/165 (3%)		2/83 (2.4%)		1/67 (1.5%)
Hepatobiliary disorders
Cholestasis	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Hepatic failure	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Hepatomegaly	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Hepatorenal failure	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Hyperbilirubinaemia	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Portal vein thrombosis	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Infections and infestations
Abdominal infection	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Alpha haemolytic streptococcal infection	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Bacteraemia	1/165 (0.6%)		1/83 (1.2%)		0/67 (0%)
Bacterial sepsis	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Empyema	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Escherichia infection	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Fungaemia	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Klebsiella sepsis	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Perihepatic abscess	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Pneumonia	2/165 (1.2%)		1/83 (1.2%)		2/67 (3%)
Pneumonia haemophilus	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Pyelonephritis acute	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Sepsis	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Septic shock	1/165 (0.6%)		1/83 (1.2%)		0/67 (0%)
Staphylococcal infection	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Urinary tract infection	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Injury, poisoning and procedural complications
Overdose	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Investigations
Blood creatinine increased	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Haemoglobin decreased	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Weight decreased	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/165 (1.2%)		0/83 (0%)		0/67 (0%)
Dehydration	2/165 (1.2%)		1/83 (1.2%)		1/67 (1.5%)
Hypercalcaemia	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Hyperglycaemia	1/165 (0.6%)		0/83 (0%)		1/67 (1.5%)
Hyperuricaemia	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Hypoglycaemia	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Hypokalaemia	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Hypovolaemia	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Malnutrition	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/165 (1.8%)		1/83 (1.2%)		1/67 (1.5%)
Bone pain	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Infected neoplasm	2/165 (1.2%)		0/83 (0%)		0/67 (0%)
Metastases to liver	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Neoplasm malignant	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Neoplasm progression	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Rectal cancer	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Tumour compression	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Tumour haemorrhage	1/165 (0.6%)		0/83 (0%)		1/67 (1.5%)
Tumour pain	1/165 (0.6%)		1/83 (1.2%)		0/67 (0%)
Nervous system disorders
Cerebrovascular accident	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Coma	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Convulsion	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Depressed level of consciousness	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Headache	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Hepatic encephalopathy	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Ischaemic stroke	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Metabolic encephalopathy	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Nystagmus	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Renal and urinary disorders
Haematuria	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Hydronephrosis	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Renal failure acute	2/165 (1.2%)		0/83 (0%)		2/67 (3%)
Urinary retention	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Reproductive system and breast disorders
Pelvic pain	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/165 (2.4%)		1/83 (1.2%)		4/67 (6%)
Dyspnoea exertional	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Lung disorder	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Pleural effusion	1/165 (0.6%)		2/83 (2.4%)		1/67 (1.5%)
Pulmonary embolism	3/165 (1.8%)		2/83 (2.4%)		2/67 (3%)
Pulmonary oedema	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Vascular disorders
Deep vein thrombosis	0/165 (0%)		1/83 (1.2%)		0/67 (0%)
Hypotension	2/165 (1.2%)		0/83 (0%)		0/67 (0%)
Inferior vena caval occlusion	0/165 (0%)		0/83 (0%)		1/67 (1.5%)
Intra-abdominal haemorrhage	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Venous thrombosis limb	1/165 (0.6%)		0/83 (0%)		0/67 (0%)
Other (Not Including Serious) Adverse Events
	Nilotinib(Core +Extension)		Control(Core + Extension)		Crossover Nilotinib Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	159/165 (96.4%)		73/83 (88%)		58/67 (86.6%)
Blood and lymphatic system disorders
Anaemia	39/165 (23.6%)		17/83 (20.5%)		12/67 (17.9%)
Neutropenia	1/165 (0.6%)		7/83 (8.4%)		0/67 (0%)
Eye disorders
Eyelid oedema	3/165 (1.8%)		7/83 (8.4%)		0/67 (0%)
Gastrointestinal disorders
Abdominal distension	17/165 (10.3%)		6/83 (7.2%)		5/67 (7.5%)
Abdominal pain	61/165 (37%)		19/83 (22.9%)		13/67 (19.4%)
Abdominal pain lower	3/165 (1.8%)		3/83 (3.6%)		4/67 (6%)
Abdominal pain upper	21/165 (12.7%)		6/83 (7.2%)		8/67 (11.9%)
Ascites	3/165 (1.8%)		5/83 (6%)		3/67 (4.5%)
Constipation	41/165 (24.8%)		9/83 (10.8%)		10/67 (14.9%)
Diarrhoea	28/165 (17%)		20/83 (24.1%)		5/67 (7.5%)
Dyspepsia	13/165 (7.9%)		6/83 (7.2%)		1/67 (1.5%)
Nausea	51/165 (30.9%)		33/83 (39.8%)		13/67 (19.4%)
Stomatitis	13/165 (7.9%)		4/83 (4.8%)		1/67 (1.5%)
Vomiting	33/165 (20%)		25/83 (30.1%)		14/67 (20.9%)
General disorders
Asthenia	46/165 (27.9%)		6/83 (7.2%)		9/67 (13.4%)
Fatigue	46/165 (27.9%)		15/83 (18.1%)		12/67 (17.9%)
Oedema peripheral	30/165 (18.2%)		26/83 (31.3%)		13/67 (19.4%)
Pyrexia	31/165 (18.8%)		7/83 (8.4%)		8/67 (11.9%)
Hepatobiliary disorders
Hyperbilirubinaemia	14/165 (8.5%)		1/83 (1.2%)		4/67 (6%)
Investigations
Alanine aminotransferase increased	14/165 (8.5%)		1/83 (1.2%)		0/67 (0%)
Aspartate aminotransferase increased	12/165 (7.3%)		6/83 (7.2%)		0/67 (0%)
Blood alkaline phosphatase increased	15/165 (9.1%)		4/83 (4.8%)		1/67 (1.5%)
Lipase increased	11/165 (6.7%)		0/83 (0%)		1/67 (1.5%)
Weight decreased	34/165 (20.6%)		7/83 (8.4%)		20/67 (29.9%)
Metabolism and nutrition disorders
Decreased appetite	47/165 (28.5%)		18/83 (21.7%)		16/67 (23.9%)
Hyperglycaemia	10/165 (6.1%)		2/83 (2.4%)		2/67 (3%)
Hypoalbuminaemia	8/165 (4.8%)		3/83 (3.6%)		4/67 (6%)
Hypocalcaemia	7/165 (4.2%)		5/83 (6%)		2/67 (3%)
Hypokalaemia	9/165 (5.5%)		3/83 (3.6%)		4/67 (6%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/165 (6.1%)		3/83 (3.6%)		1/67 (1.5%)
Back pain	24/165 (14.5%)		5/83 (6%)		6/67 (9%)
Muscle spasms	9/165 (5.5%)		4/83 (4.8%)		3/67 (4.5%)
Musculoskeletal chest pain	10/165 (6.1%)		1/83 (1.2%)		2/67 (3%)
Myalgia	20/165 (12.1%)		4/83 (4.8%)		4/67 (6%)
Pain in extremity	6/165 (3.6%)		3/83 (3.6%)		5/67 (7.5%)
Nervous system disorders
Dysgeusia	9/165 (5.5%)		1/83 (1.2%)		0/67 (0%)
Headache	34/165 (20.6%)		8/83 (9.6%)		4/67 (6%)
Psychiatric disorders
Insomnia	13/165 (7.9%)		1/83 (1.2%)		2/67 (3%)
Respiratory, thoracic and mediastinal disorders
Cough	19/165 (11.5%)		6/83 (7.2%)		4/67 (6%)
Dyspnoea	22/165 (13.3%)		11/83 (13.3%)		8/67 (11.9%)
Pleural effusion	3/165 (1.8%)		2/83 (2.4%)		5/67 (7.5%)
Skin and subcutaneous tissue disorders
Erythema	10/165 (6.1%)		1/83 (1.2%)		3/67 (4.5%)
Palmar-plantar erythrodysaesthesia syndrome	3/165 (1.8%)		6/83 (7.2%)		1/67 (1.5%)
Pruritus	19/165 (11.5%)		2/83 (2.4%)		4/67 (6%)
Rash	26/165 (15.8%)		7/83 (8.4%)		4/67 (6%)
Vascular disorders
Hypertension	8/165 (4.8%)		5/83 (6%)		1/67 (1.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.