Gastrointestinal Stromal Tumors
Conditions
Keywords
Gastrointestinal stromal cancer, GIST, multikinase inhibitor
Brief summary
A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib. The study is composed of 3 periods: A Screening Period, a Treatment Period, and a Survival Follow up Period. Subjects randomized to be treated with regorafenib will receive 160 mg po od for 3 weeks of every 4 week (28 day) cycle (ie, 3 weeks on/1 week off). In addition subjects will receive best supportive care which excludes any disease specific anti cancer therapy such as any kinase inhibitor, chemotherapy, radiation therapy, or surgery. Tumor assessment will be every 4 weeks for the first 3 months, every 6 weeks for the next 3 months (through month 6), and every 8 weeks until the end of treatment, or more frequently if clinically indicated. Tumor assessments include CT or MRI and will be performed until tumor progression is seen in a central radiology review. Subjects receiving placebo who experience disease progression may be offered active treatment. Subjects who experience progression during regorafenib treatment may continue open label treatment. All subjects will enter the Survival Follow-up Period upon discontinuation of randomized study treatment.
Interventions
DRUGRegorafenib (Stivarga, BAY73-4506)
160 mg po once daily (od), 3 weeks on/1 week off. Route of administration: oral
DRUGPlacebo
once daily (od), 3 weeks on/1 week off. Route of administration: oral
DRUGBest supportive care
Best supportive care includes any method to preserve the comfort and dignity of the patients, and excludes any disease-specific anti-neoplastic therapy such as any kinase inhibitor, chemotherapy, radiation therapy, or surgical intervention.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects 18 years of age. * Subjects with histologically confirmed metastatic and/or unresectable GIST. * At least imatinib and sunitinib as prior treatment regimens, with objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib therapy. Additionally, disease progression or intolerance to other systemic therapies, as well as investigational new agents, is allowed, except prior treatment with any other vascular endothelial growth factor receptor (VEGFR) inhibitor. * Subjects must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrollment. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. * Adequate bone marrow, liver, and renal function as assessed by laboratory parameters. Recovery to NCI-CTCAE v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure-related toxicity (except alopecia and anemia).
Exclusion criteria
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication. * Congestive heart failure New York Heart Association (NYHA) class 2. * Unstable angina (angina symptoms at rest, new-onset angina, ie, within the last 3 months) or myocardial infarction (MI) within the past 6 months before start of study medication. * Uncontrolled hypertension (systolic blood pressure 140 mmHg or diastolic pressure 90 mmHg despite optimal medical management). Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of study drug or venous thrombotic events such as deep vein thrombosis within the 3 months before start of study drug. * Ongoing infection grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Symptomatic metastatic brain or meningeal tumors. * Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event NCI-CTCAE version 4.0 grade 3 or higher within 4 weeks prior to the start of study drug. Non-healing wound, ulcer, or bone fracture. * Persistent proteinuria of NCI-CTCAE version 4.0 grade 3 or higher (3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From randomization of the first subject until approximately 144 progression-free survival events had occurred (study duration approximately one year) | Progression-free Survival (PFS) was defined as the time from date of randomization to radiological disease progression or death due to any cause, whichever occurs first. PFS was based on central radiological assessment using modified RECIST (Response Evaluation Criteria in Solid Tumors) v.1.1. Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | From randomization of the first subject until until date of database cutoff (26 Jan 2012); study duration approximately 1 year | Time to progression (TTP) was defined as the time from date of randomization to disease progression (based on central radiological assessment using modified RECIST \[Response Evaluation Criteria in Solid Tumors\] v.1.1). Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation. |
| Tumor Response | From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year | Tumor Response of a subject was defined as the best tumor response (Complete Response \[CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).\], Partial Response \[PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.\], Stable Disease \[SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.\], or Progressive Disease \[PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.\]) observed during the trial period and assessed according to RECIST v1.1 criteria. Results are based on central evaluation. |
| Overall Survival | From randomization of the first subject until date of database cutoff (08 Jun 2015) | Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their date of last contact. Median OS was not observed at the time of PFS analysis and first analysis of OS, therefore only the proportion of death events was reported in the results posting system. This approach was maintained for the subsequent updates in the results posting system. |
| Disease Control Rate (DCR) | From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year | Disease Control Rate (DCR) was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or Stable Disease (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST v1.1 criteria. SD had to be maintained for at least 12 weeks from the first demonstration of that rating. Results are based on central evaluation. |
| Duration of Response (DOR) | From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year | Duration of Response was defined as the time from date of first response (Complete Response \[CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).\] or Partial Response \[PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.\]) to the date when Progressive Disease (PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.) is first documented, or to the date of death, whichever occurs first, according to RECIST v1.1. Subjects still having CR or PR and have not died at the time of analysis were censored at their last date of tumor evaluation. Duration of response defined for responders only, i.e CR or PR. Results are based on central evaluation. |
| Objective Response Rate | From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year. | Objective response rate was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Results are based on central evaluation. |
Countries
Austria, Belgium, Canada, China, Finland, France, Germany, Israel, Italy, Japan, Netherlands, Poland, Singapore, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 240 participants with metastatic and/or unresectable GIST whose disease had progressed despite prior treatments with at least imatinib and sunitinib were screened; 199 were randomized. Patients must have shown objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib treatment.
Pre-assignment details
Participants were randomized in a 2:1 ratio to receive either regorafenib (133 patients) or placebo (66 patients). Randomization was stratified according 3rd vs. 4th line of therapy (at least 50% of patients were to be 3rd line), and geographical region (Asia vs.rest of world).
Participants by arm
| Arm | Count |
|---|---|
| Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks | 133 |
| Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks | 66 |
| Total | 199 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Treatment | Adverse Event | 9 | 4 |
| Double Blind Treatment | Death | 2 | 0 |
| Double Blind Treatment | Lack of Efficacy | 1 | 0 |
| Double Blind Treatment | Non compliance with study drug | 2 | 0 |
| Double Blind Treatment | Progressive disease | 23 | 3 |
| Double Blind Treatment | receive no study drug | 1 | 0 |
| Double Blind Treatment | Withdrawal by Subject | 4 | 1 |
| Open Label Treatment | Adverse Event | 14 | 8 |
| Open Label Treatment | Death | 6 | 5 |
| Open Label Treatment | Non-compliance with study drug | 1 | 0 |
| Open Label Treatment | Physician Decision | 2 | 0 |
| Open Label Treatment | Progressive disease | 59 | 32 |
| Open Label Treatment | Protocol Violation | 0 | 1 |
| Open Label Treatment | Switching to other therapy | 2 | 1 |
| Open Label Treatment | transferred to rollover study | 1 | 0 |
| Open Label Treatment | Withdrawal by Subject | 6 | 11 |
| Safety Follow-up | Death | 11 | 7 |
| Safety Follow-up | No follow-up | 1 | 1 |
| Safety Follow-up | Not analyzed after cutoff 08Jun2015 | 3 | 4 |
| Safety Follow-up | Progressive disease | 1 | 0 |
| Safety Follow-up | Protocol Violation | 1 | 1 |
| Safety Follow-up | Withdrawal by Subject | 4 | 2 |
| Survival Follow-up | Not analyzed after cutoff 08Jun2015 | 15 | 6 |
Baseline characteristics
| Characteristic | Regorafenib (Stivarga, BAY73-4506) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.2 Years STANDARD_DEVIATION 12.5 | 58.1 Years STANDARD_DEVIATION 13.9 | 58.2 Years STANDARD_DEVIATION 12.9 |
| ECOG Performance Status (PS)] Missing | 0 Participants | 0 Participants | 0 Participants |
| ECOG Performance Status (PS)] PS 0 | 73 Participants | 37 Participants | 110 Participants |
| ECOG Performance Status (PS)] PS 1 | 60 Participants | 29 Participants | 89 Participants |
| ECOG Performance Status (PS)] PS 2 | 0 Participants | 0 Participants | 0 Participants |
| Prior anti-cancer drug group 3rd line | 74 Participants | 39 Participants | 113 Participants |
| Prior anti-cancer drug group 4th line and beyond | 59 Participants | 27 Participants | 86 Participants |
| Sex: Female, Male Female | 48 Participants | 24 Participants | 72 Participants |
| Sex: Female, Male Male | 85 Participants | 42 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 40 / 41 | 7 / 8 | 47 / 58 | 155 / 190 | 48 / 75 |
| other Total, other adverse events | 40 / 41 | 7 / 8 | 58 / 58 | 189 / 190 | 75 / 75 |
| serious Total, serious adverse events | 23 / 41 | 8 / 8 | 31 / 58 | 103 / 190 | 39 / 75 |
Outcome results
Primary
Progression-free Survival
Progression-free Survival (PFS) was defined as the time from date of randomization to radiological disease progression or death due to any cause, whichever occurs first. PFS was based on central radiological assessment using modified RECIST (Response Evaluation Criteria in Solid Tumors) v.1.1. Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation.
Time frame: From randomization of the first subject until approximately 144 progression-free survival events had occurred (study duration approximately one year)
Population: Full Analysis Set (FAS) - defined as all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506) | Progression-free Survival | 147 Days |
| Placebo | Progression-free Survival | 28 Days |
Comparison: The two treatment groups were compared using a stratified log rank test with a one-sided alpha of 0.01 stratified by (3rd vs 4th-line; and geographical region). The null hypothesis that both treatment arms have the same PFS distribution was tested against the alternative hypothesis that the distribution of PFS in the regorafenib arm is different from the control arm according to a proportional hazards relation between the treatment arms.p-value: <0.000001Log Rank
Comparison: Hazard ratio and its 95% CI (Confidence Interval) was based on stratified Cox Regression Model95% CI: [0.185, 0.388]Regression, Cox
Secondary
Disease Control Rate (DCR)
Disease Control Rate (DCR) was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or Stable Disease (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST v1.1 criteria. SD had to be maintained for at least 12 weeks from the first demonstration of that rating. Results are based on central evaluation.
Time frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506) | Disease Control Rate (DCR) | 52.6 Percentage of Participants |
| Placebo | Disease Control Rate (DCR) | 9.1 Percentage of Participants |
Secondary
Duration of Response (DOR)
Duration of Response was defined as the time from date of first response (Complete Response \[CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).\] or Partial Response \[PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.\]) to the date when Progressive Disease (PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.) is first documented, or to the date of death, whichever occurs first, according to RECIST v1.1. Subjects still having CR or PR and have not died at the time of analysis were censored at their last date of tumor evaluation. Duration of response defined for responders only, i.e CR or PR. Results are based on central evaluation.
Time frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year
Population: Full Analysis Set with response participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506) | Duration of Response (DOR) | 99 Days |
| Placebo | Duration of Response (DOR) | 30 Days |
Secondary
Objective Response Rate
Objective response rate was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Results are based on central evaluation.
Time frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year.
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506) | Objective Response Rate | 4.5 Percentage of Participants |
| Placebo | Objective Response Rate | 1.5 Percentage of Participants |
Secondary
Overall Survival
Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their date of last contact. Median OS was not observed at the time of PFS analysis and first analysis of OS, therefore only the proportion of death events was reported in the results posting system. This approach was maintained for the subsequent updates in the results posting system.
Time frame: From randomization of the first subject until date of database cutoff (08 Jun 2015)
Population: Full Analysis Set (FAS). 58 (87.9%) patients in placebo group and 91 (68.4%) patients in regorafenib had started open-label treatment with regorafenib before time of final database cutoff 08 Jun 2015
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506) | Overall Survival | 82.0 Percentage of patients with death |
| Placebo | Overall Survival | 80.3 Percentage of patients with death |
p-value: 0.285777Log Rank
Comparison: Hazard ratio and its 95% CI was based on stratified Cox Regression Model95% CI: [0.653, 1.265]Regression, Cox
Secondary
Time to Progression (TTP)
Time to progression (TTP) was defined as the time from date of randomization to disease progression (based on central radiological assessment using modified RECIST \[Response Evaluation Criteria in Solid Tumors\] v.1.1). Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation.
Time frame: From randomization of the first subject until until date of database cutoff (26 Jan 2012); study duration approximately 1 year
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506) | Time to Progression (TTP) | 165 Days |
| Placebo | Time to Progression (TTP) | 28 Days |
p-value: <0.000001Log Rank
95% CI: [0.17, 0.364]Regression, Cox
Secondary
Tumor Response
Tumor Response of a subject was defined as the best tumor response (Complete Response \[CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).\], Partial Response \[PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.\], Stable Disease \[SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.\], or Progressive Disease \[PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.\]) observed during the trial period and assessed according to RECIST v1.1 criteria. Results are based on central evaluation.
Time frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib (Stivarga, BAY73-4506) | Tumor Response | Partial Response (PR) | 4.5 Percentage of Participants |
| Regorafenib (Stivarga, BAY73-4506) | Tumor Response | Stable Disease (SD) | 71.4 Percentage of Participants |
| Regorafenib (Stivarga, BAY73-4506) | Tumor Response | Complete Response (CR) | 0 Percentage of Participants |
| Regorafenib (Stivarga, BAY73-4506) | Tumor Response | Not Assessable | 3.0 Percentage of Participants |
| Regorafenib (Stivarga, BAY73-4506) | Tumor Response | Progressive Disease (PD) | 21.1 Percentage of Participants |
| Placebo | Tumor Response | Not Assessable | 1.5 Percentage of Participants |
| Placebo | Tumor Response | Progressive Disease (PD) | 63.6 Percentage of Participants |
| Placebo | Tumor Response | Complete Response (CR) | 0 Percentage of Participants |
| Placebo | Tumor Response | Stable Disease (SD) | 33.3 Percentage of Participants |
| Placebo | Tumor Response | Partial Response (PR) | 1.5 Percentage of Participants |