Gastrointestinal Stromal Tumors
Conditions
Keywords
GIST, adults, imatinib resistant, sunitinib resistant, AMN107, nilotinib, treatment, Gastrointestinal stromal tumor (GIST)
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.
Interventions
DRUGNilotinib
Nilotinib 400 mg twice daily (bid)
OTHERBest 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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
Countries
Australia, Austria, Canada, Czechia, France, Germany, Italy, Netherlands, Poland, South Korea, Spain, Switzerland, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Nilotinib 400 mg was taken orally twice daily in core and extension phase of the study | 165 |
| 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. | 83 |
| Total | 248 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Phase | Abnormal laboratory value | 1 | 0 |
| Core Phase | Administrative Problem | 0 | 1 |
| Core Phase | Adverse Event | 18 | 6 |
| Core Phase | Death | 8 | 4 |
| Core Phase | Disease Progression | 78 | 53 |
| Core Phase | Protocol Deviation | 0 | 1 |
| Core Phase | Withdrawal by Subject | 2 | 2 |
| Extension Phase | Administrative Problem | 1 | 0 |
| Extension Phase | Adverse Event | 3 | 12 |
| Extension Phase | Death | 1 | 7 |
| Extension Phase | Disease Progression | 32 | 44 |
| Extension Phase | New cancer Therapy | 1 | 0 |
| Extension Phase | Protocol Deviation | 3 | 1 |
| Extension Phase | Treatment duration as per protocol | 0 | 1 |
| Extension Phase | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Nilotinib | Control/Cross Over to Nilotinib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 47 Participants | 26 Participants | 73 Participants |
| Age, Categorical Between 18 and 65 years | 118 Participants | 57 Participants | 175 Participants |
| Age Continuous | 57.4 years STANDARD_DEVIATION 12.69 | 58.6 years STANDARD_DEVIATION 10.57 | 57.8 years STANDARD_DEVIATION 12.01 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 11 Participants | 32 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) White | 134 Participants | 67 Participants | 201 Participants |
| Sex: Female, Male Female | 64 Participants | 36 Participants | 100 Participants |
| Sex: Female, Male Male | 101 Participants | 47 Participants | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 159 / 165 | 73 / 83 | 58 / 67 |
| serious Total, serious adverse events | 81 / 165 | 27 / 83 | 32 / 67 |
Outcome results
Primary
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.
Time frame: Up to 16 months
Population: The intent to treat (ITT) population was defined as all randomized patients and was used as the primary efficacy population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Progression-free Survival (PFS) From Central Radiology Review Based on Primary Analysis (Data Cut-off: June, 2008) | 109.0 days |
| Control/Cross Over to Nilotinib | Progression-free Survival (PFS) From Central Radiology Review Based on Primary Analysis (Data Cut-off: June, 2008) | 111.0 days |
Primary
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.
Time frame: Up to 34 months
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Progression-free Survival (PFS) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set | 84 days |
Secondary
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).
Time frame: Up to 16 months
Population: The intent to treat (ITT) population was defined as all randomized patients and was used as the primary efficacy population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | 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) | 1 Participants |
| Control/Cross Over to Nilotinib | 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) | 0 Participants |
Secondary
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).
Time frame: Up to 34 months
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | 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 | 1 Participants |
Secondary
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.
Time frame: Up to 16 months
Population: The intent to treat (ITT) population was defined as all randomized patients and was used as the primary efficacy population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nilotinib | 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) | CR/PR/SD | 52.7 Percentage of Participants |
| Nilotinib | 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) | CR/PR/SD lasting > 6 months | 7.3 Percentage of Participants |
| Nilotinib | 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) | CR/PR/SD lasting > 12 months | 0.6 Percentage of Participants |
| Control/Cross Over to Nilotinib | 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) | CR/PR/SD | 44.6 Percentage of Participants |
| Control/Cross Over to Nilotinib | 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) | CR/PR/SD lasting > 6 months | 1.2 Percentage of Participants |
| Control/Cross Over to Nilotinib | 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) | CR/PR/SD lasting > 12 months | 0 Percentage of Participants |
Secondary
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.
Time frame: Up to 34 months
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nilotinib | Overall Clinical Benefit (Complete Response [CR]/Partial Response [PR] or Stable Disease [SD]) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set | CR/PR/SD | 37.3 Percentage of Participants |
| Nilotinib | Overall Clinical Benefit (Complete Response [CR]/Partial Response [PR] or Stable Disease [SD]) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set | CR/PR/SD lasting > 6 months | 7.5 Percentage of Participants |
| Nilotinib | Overall Clinical Benefit (Complete Response [CR]/Partial Response [PR] or Stable Disease [SD]) From Local Investigator's Assessment Based on Treatment Crossover Analysis Set | CR/PR/SD lasting > 12 months | 6.0 Percentage of Participants |
Secondary
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.
Time frame: Up to 16 months
Population: The intent to treat (ITT) population was defined as all randomized participants and was used as the primary efficacy population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Overall Survival Based on Primary Analysis (Data Cut-off:June, 2008) | 332.0 days |
| Control/Cross Over to Nilotinib | Overall Survival Based on Primary Analysis (Data Cut-off:June, 2008) | 280.0 days |
Secondary
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.
Time frame: Up to 50 months (including core, extension and follow up period)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Overall Survival During Core and Extension Phases of the Study | 361 days |
| Control/Cross Over to Nilotinib | Overall Survival During Core and Extension Phases of the Study | 300 days |
Secondary
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.
Time frame: Up to 34 months
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Overall Survival for Treatment Crossover Analysis Set | 231 days |