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

Primary Purpose

Gastrointestinal Stromal Tumors

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Nilotinib
Best Supportive Care (BSC) +/- imatinib or sunitinib
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gastrointestinal Stromal Tumors focused on measuring GIST, adults, imatinib resistant, sunitinib resistant, AMN107, nilotinib, treatment, Gastrointestinal stromal tumor (GIST)

Eligibility Criteria

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

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

Sites / Locations

  • UCLA's Jonsson Comprehensive Cancer Center
  • Washington Hospital Center - Washington Cancer Institute
  • H. Lee Moffitt Cancer Center
  • University of Chicago Hospital
  • Dana Farber Cancer Institute
  • Wayne State University/Wertz Clinical Cancer Center
  • Washington University School of Medicine - Siteman Cancer Center
  • St. Vincent's Comprehensive Cancer Center
  • Wake Forest University Health Sciences
  • Fox Chase Cancer Center
  • University of Texas/MD Anderson Cancer Center
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novrtis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Nilotinib

Control/cross-over to Nilotinib

Arm Description

400mg twice daily in core and extension phases 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.

Outcomes

Primary Outcome Measures

Progression-free Survival (PFS) From Central Radiology Review Based on Primary Analysis (Data Cut-off: June, 2008)
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.
Progression-free Survival (PFS) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set
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

Overall Survival Based on Primary Analysis (Data Cut-off:June, 2008)
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.
Overall Survival During Core and Extension Phases of the Study
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.
Overall Survival for Treatment Crossover Analysis Set
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.
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)
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).
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
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).
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)
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.
Overall Clinical Benefit (Complete Response [CR]/Partial Response [PR] or Stable Disease [SD]) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set
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.

Full Information

First Posted
April 26, 2007
Last Updated
June 5, 2012
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00471328
Brief Title
Efficacy and Safety of Nilotinib (AMN107) Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib
Acronym
ENEST
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 Type
Interventional

2. Study Status

Record Verification Date
June 2012
Overall Recruitment Status
Completed
Study Start Date
March 2007 (undefined)
Primary Completion Date
August 2008 (Actual)
Study Completion Date
June 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gastrointestinal Stromal Tumors
Keywords
GIST, adults, imatinib resistant, sunitinib resistant, AMN107, nilotinib, treatment, Gastrointestinal stromal tumor (GIST)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
248 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nilotinib
Arm Type
Experimental
Arm Description
400mg twice daily in core and extension phases of the study.
Arm Title
Control/cross-over to Nilotinib
Arm Type
Active Comparator
Arm 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 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.
Intervention Type
Drug
Intervention Name(s)
Nilotinib
Other Intervention Name(s)
AMN107, Tasigna®
Intervention Description
Nilotinib 400 mg twice daily (bid)
Intervention Type
Other
Intervention Name(s)
Best Supportive Care (BSC) +/- imatinib or sunitinib
Intervention Description
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.
Primary Outcome Measure Information:
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
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
Secondary Outcome Measure Information:
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
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)
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
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
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
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
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
UCLA's Jonsson Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Washington Hospital Center - Washington Cancer Institute
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010-2965
Country
United States
Facility Name
H. Lee Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
University of Chicago Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Wayne State University/Wertz Clinical Cancer Center
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Washington University School of Medicine - Siteman Cancer Center
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
St. Vincent's Comprehensive Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10011
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157-1082
Country
United States
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111-2497
Country
United States
Facility Name
University of Texas/MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-4009
Country
United States
Facility Name
Novartis Investigative Site
City
Auchenflower
State/Province
Queensland
ZIP/Postal Code
4066
Country
Australia
Facility Name
Novartis Investigative Site
City
East Melbourne
State/Province
Victoria
ZIP/Postal Code
3002
Country
Australia
Facility Name
Novartis Investigative Site
City
Vienna
Country
Austria
Facility Name
Novartis Investigative Site
City
Toronto
Country
Canada
Facility Name
Novartis Investigative Site
City
Praha 5
Country
Czech Republic
Facility Name
Novartis Investigative Site
City
Bordeaux
Country
France
Facility Name
Novartis Investigative Site
City
Lyon
Country
France
Facility Name
Novartis Investigative Site
City
Marseille
Country
France
Facility Name
Novartis Investigative Site
City
Berlin
Country
Germany
Facility Name
Novartis Investigative Site
City
Duesseldorf
Country
Germany
Facility Name
Novartis Investigative Site
City
Essen
Country
Germany
Facility Name
Novartis Investigative Site
City
Frankfurt
Country
Germany
Facility Name
Novartis Investigative Site
City
Hannover
Country
Germany
Facility Name
Novartis Investigative Site
City
Koln
Country
Germany
Facility Name
Novartis Investigative Site
City
Mannheim
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenchen
Country
Germany
Facility Name
Novartis Investigative Site
City
Tubingen
Country
Germany
Facility Name
Novrtis Investigative Site
City
Bologna
Country
Italy
Facility Name
Novartis Investigative Site
City
Milan
Country
Italy
Facility Name
Novartis Investigative Site
City
Seoul
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Leiden
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Warszawa
Country
Poland
Facility Name
Novartis Investigative Site
City
Madrid
Country
Spain
Facility Name
Novartis Investigative Site
City
Chur
Country
Switzerland

12. IPD Sharing Statement

Learn more about this trial

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

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