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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00471328
First received: April 26, 2007
Last updated: June 5, 2012
Last verified: June 2012
  Purpose

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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Progression-free Survival (PFS) From Central Radiology Review Based on Primary Analysis (Data Cut-off: June, 2008) [ Time Frame: Up to 16 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 34 months ] [ Designated as safety issue: No ]
    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) [ Time Frame: Up to 16 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 50 months (including core, extension and follow up period) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 34 months ] [ Designated as safety issue: No ]
    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) [ Time Frame: Up to 16 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 34 months ] [ Designated as safety issue: No ]
    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) [ Time Frame: Up to 16 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 34 months ] [ Designated as safety issue: No ]
    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.


Enrollment: 248
Study Start Date: March 2007
Study Completion Date: June 2011
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nilotinib
400mg twice daily in core and extension phases of the study.
Drug: Nilotinib
Nilotinib 400 mg twice daily (bid)
Other Name: 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 Name: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00471328

  Show 35 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00471328     History of Changes
Obsolete Identifiers: NCT00488150
Other Study ID Numbers: CAMN107A2201, 2006-002267-11
Study First Received: April 26, 2007
Results First Received: January 12, 2011
Last Updated: June 5, 2012
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Czech Republic: State Institute for Drug Control
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
South Korea: Korea Food and Drug Administration (KFDA)
Italy: The Italian Medicines Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Spain: Ministry of Health and Consumption
Switzerland: Swissmedic
Taiwan: Department of Health
United States: Food and Drug Administration

Keywords provided by Novartis:
GIST
adults
imatinib resistant
sunitinib resistant
AMN107
nilotinib
treatment
Gastrointestinal stromal tumor (GIST)

Additional relevant MeSH terms:
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Imatinib
Sunitinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors

ClinicalTrials.gov processed this record on August 27, 2014