Gastrointestinal Stromal Tumors
Conditions
Keywords
Imatinib, Re-challenge
Brief summary
The objective of this study is to compare the clinical outcomes following resumption of dosing (re-challenge) with Imatinib plus best supportive care versus placebo plus best supportive care in patients with advanced/incurable Gastrointestinal Stromal Tumors following failure of prior imatinib and sunitinib therapies.
Interventions
DRUGImatinib
Patients will be randomly assigned to receive imatinib at a dose of 400mg/day, taken once daily with food, in the form of 100-mg tablets. The study medication will be administered until disease progression, unacceptable toxicity, or withdrawal of consent.
DRUGPlacebo
Patients will be randomly assigned to receive placebo at a dose of 400mg/day, taken once daily with food, in the form of 100-mg tablets. The study medication will be administered until disease progression or withdrawal of consent.
Sponsors
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients aged 18 years and older * Patients with metastatic or unresectable malignant gastrointestinal stromal tumour which has been histologically confirmed by the detection of CD117 on immunohistochemical staining or genetically confirmed by the detection of mutation in KIT or PDGFRα genes on direct sequencing of tumor DNA. * Prior benefit from 1st line imatinib defined as complete response, partial response, or stable disease at 6 months after the start of 1st line imatinib * Patients whose disease has progressed despite at least both prior imatinib therapy (400mg/day) and then subsequently also failure of prior sunitinib therapy. * ECOG(Eastern Cooperative Oncology Group) performance status 0 \ 3 * Adequate bone marrow function as defined by platelets ≥ 75 x 109/L and neutrophils ≥ 1.5 x 109/L * Adequate renal function, with serum creatinine \< 1.5 x upper limit of normal * Adequate hepatic function with serum total bilirubin \< 1.5 x upper limit of normal, alanine aminotransferase or aspartate aminotransferase \< 2.5 x upper limit of normal in the absence of liver metastases, or \< 5 x upper limit of normal in the presence of liver metastases. * Expected life expectancy of greater than 12 weeks in the absence of any intervention * No other malignant disease apart from non-melanotic skin cancer or carcinoma in situ of the uterine cervix or any other cancer except where treated with curative intent \> 5 years previously without evidence of relapse * Written, informed consent to the study
Exclusion criteria
* Medical or psychiatric conditions that compromise the patient's ability to give informed consent or to complete the protocol or a history of non- compliance * Last dose of radiotherapy received within 4 weeks before the start of study treatment, excluding palliative radiotherapy * Obstruction of gastrointestinal tract * Active gastrointestinal bleeding * Myocardial infarction within 6 months prior to the study medication, and other clinically significant heart disease (e.g., unstable angina, congestive heart failure or uncontrolled hypertension) * Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol * Female patients who are pregnant or breast-feeding. Female patients must have had a negative pregnancy test within one week before starting imatinib.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | up tp12 weeks | To compare the progression free survival (PFS) assessed by the blinded independent central review following resumption of dosing (re-challenge) with Imatinib plus best supportive care versus placebo plus best supportive care in patients with unresectable or metastatic GIST following failure of at least prior imatinib and sunitinib therapies |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival(OS) and Time to Progression(TTP) | Up to 3years | To compare the overall survival (OS) and time to progression (TTP) in both arms of the study |
| Disease Control Rate | up to 12 weeks | Inclusion of complete response, partial response or stable disease Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Progressive disease (PD), \>20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD), Insufficient change to qualify for PR or PD. |
| Progression Free Survival | up to 12 weeks | To compare PFS assessed by investigators |
| Response Rate | Up to 12weeks | Tumour responses were initially determined by the local investigators in accordance with RECIST 1.0.Treatment decisions were based on local onsite radiological review. All imaging data were subsequently collected, anonymised, and reviewed centrally in a double-blind manner by two external academic radiology reviewers. Response assessment was determined in a masked central review by use of RECIST1.1. |
| Safety and Tolerability of Imatinib | Up to 3years | percentage of patients who experienced toxicity from study treatment to evaluate the safety and tolerability of imatinib re-challenge in this patient population |
Countries
South Korea
Participant flow
Recruitment details
Between July 20, 2010, and Jan 17, 81 patients were enrolled in Asan Medical Center, Seoul, Korea.
Pre-assignment details
Randomization was done in a double-blind manner and stratified by performance status (0-1 vs 2-3) and by the number of previous lines of tyrosine-kinase inhibitor therapy (2 or less vs more than 2).
Participants by arm
| Arm | Count |
|---|---|
| Imatinib Patients will be randomly assigned to receive imatinib at a dose of 400mg/day, taken once daily with food, in the form of 100-mg tablets. The study medication will be administered until disease progression, unacceptable toxicity, or withdrawal of consent. | 41 |
| Placebo Patients will be randomly assigned to receive placebo at a dose of 400mg/day, taken once daily with food, in the form of 100-mg tablets. The study medication will be administered until disease progression or withdrawal of consent. | 40 |
| Total | 81 |
Baseline characteristics
| Characteristic | Placebo | Imatinib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 12 Participants | 27 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 29 Participants | 54 Participants |
| Age, Continuous | 59.6 years STANDARD_DEVIATION 10.6 | 57.9 years STANDARD_DEVIATION 10.4 | 58.7 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment Korea, Republic of | 40 participants | 41 participants | 81 participants |
| Sex: Female, Male Female | 14 Participants | 12 Participants | 26 Participants |
| Sex: Female, Male Male | 26 Participants | 29 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 41 / 41 | 39 / 40 |
| serious Total, serious adverse events | 1 / 41 | 2 / 40 |
Outcome results
Primary
Progression-free Survival
To compare the progression free survival (PFS) assessed by the blinded independent central review following resumption of dosing (re-challenge) with Imatinib plus best supportive care versus placebo plus best supportive care in patients with unresectable or metastatic GIST following failure of at least prior imatinib and sunitinib therapies
Time frame: up tp12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib | Progression-free Survival | 1.8 Months |
| Placebo | Progression-free Survival | 0.9 Months |
Secondary
Disease Control Rate
Inclusion of complete response, partial response or stable disease Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Progressive disease (PD), \>20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD), Insufficient change to qualify for PR or PD.
Time frame: up to 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib | Disease Control Rate | 32 percentage of participants |
| Placebo | Disease Control Rate | 5 percentage of participants |
Secondary
Overall Survival(OS) and Time to Progression(TTP)
To compare the overall survival (OS) and time to progression (TTP) in both arms of the study
Time frame: Up to 3years
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imatinib | Overall Survival(OS) and Time to Progression(TTP) | Overall survival | 8.2 Months |
| Imatinib | Overall Survival(OS) and Time to Progression(TTP) | Time to progression | 1.8 Months |
| Placebo | Overall Survival(OS) and Time to Progression(TTP) | Overall survival | 7.5 Months |
| Placebo | Overall Survival(OS) and Time to Progression(TTP) | Time to progression | 0.9 Months |
Secondary
Progression Free Survival
To compare PFS assessed by investigators
Time frame: up to 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib | Progression Free Survival | 1.8 Months |
| Placebo | Progression Free Survival | 1.7 Months |
Secondary
Response Rate
Tumour responses were initially determined by the local investigators in accordance with RECIST 1.0.Treatment decisions were based on local onsite radiological review. All imaging data were subsequently collected, anonymised, and reviewed centrally in a double-blind manner by two external academic radiology reviewers. Response assessment was determined in a masked central review by use of RECIST1.1.
Time frame: Up to 12weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib | Response Rate | 0 percentage of participants |
| Placebo | Response Rate | 0 percentage of participants |
Secondary
Safety and Tolerability of Imatinib
percentage of patients who experienced toxicity from study treatment to evaluate the safety and tolerability of imatinib re-challenge in this patient population
Time frame: Up to 3years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib | Safety and Tolerability of Imatinib | 100 percentage of participants |
| Placebo | Safety and Tolerability of Imatinib | 98 percentage of participants |