Gastrointestinal Stromal Tumors
Conditions
Brief summary
This is a 2-arm, randomized, open-label, international, multicenter study comparing the efficacy of ripretinib to sunitinib in GIST patients who progressed on or were intolerant to first-line anticancer treatment with imatinib. Approximately 426 patients will be randomized in a 1:1 ratio to ripretinib 150 mg once daily (continuous dosing for 6 week cycles) or sunitinib 50 mg once daily (6 week cycles, 4 weeks on, 2 weeks off).
Interventions
DRUGRipretinib
Oral KIT/PDGFRA kinase inhibitor
DRUGSunitinib
Oral receptor tyrosine kinase (RTK) inhibitor
Sponsors
Deciphera Pharmaceuticals, LLC
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
1. Patients ≥ 18 years of age at the time of informed consent. 2. Histologic diagnosis of GIST and must be able to provide an archival tumor tissue sample, otherwise, a fresh biopsy is required. 3. Molecular pathology report must be available. If molecular pathology report is not available or insufficient, an archival tumor tissue sample or fresh biopsy is required for mutation status confirmation by the central laboratory prior to randomization. 4. Patients must have progressed on imatinib or have documented intolerance to imatinib. 5. Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of ≤ 2 at screening. 6. Female patients of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening and negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug. 7. Patients of reproductive potential must agree to follow the contraception requirements outlined in the study protocol. 8. Patients must have at least 1 measurable lesion according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Version 1.1 (non nodal lesions must be ≥ 1.0 cm in the long axis or ≥ double the slice thickness in the long axis) within 21 days prior to the first dose of study drug. 9. Adequate organ function and bone marrow reserve as indicated by the central laboratory assessments performed at screening. 10. Resolution of all toxicities from prior therapy to ≤ Grade 1 (or patient baseline) within 1 week prior to the first dose of study drug (excluding alopecia and ≤ Grade 3 clinically asymptomatic lipase, amylase, and creatine phosphokinase laboratory abnormalities). 11. The patient is capable of understanding and complying with the protocol and the patient has signed the informed consent document. Signed informed consent form (ICF) must be obtained before any study-specific procedures are performed and the patient must agree to not participate in any other interventional clinical trial while on treatment in this clinical trial. Participation in a noninterventional study (including observational studies) is permitted.
Exclusion criteria
1. Treatment with any other line of therapy in addition to imatinib for advanced GIST. Imatinib-containing combination therapy in the first-line setting is not allowed. 2. Patients with a prior or concurrent malignancy whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical trial are not eligible. 3. Patient has known active central nervous system metastases. 4. New York Heart Association class II-IV heart disease, myocardial infarction within 6 months of cycle 1 day 1, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure. 5. Left ventricular ejection fraction (LVEF) \< 50% at screening. 6. Arterial thrombotic or embolic events such as cerebrovascular accident (including ischemic attacks) or hemoptysis within 6 months before the first dose of study drug. 7. Venous thrombotic events (e.g. deep vein thrombosis) or pulmonary arterial events (e.g. pulmonary embolism) within 1 month before the first dose of study drug. Patients on stable anticoagulation therapy for at least one month are eligible. 8. 12-lead ECG demonstrating QT interval corrected (QTc) by Fridericia's formula \> 450 ms in males or \> 470 ms in females at screening or history of long QTc syndrome 9. Use of known substrates or inhibitors of breast cancer resistance protein (BCRP) transporters within 14 days or 5 x the half-life (whichever is longer) prior to the first dose of study drug. 10. Major surgeries (e.g. abdominal laparotomy) within 4 weeks of the first dose of study drug. All major surgical wounds must be healed and free of infection or dehiscence before the first dose of study drug. 11. Any other clinically significant comorbidities. 12. Known human immunodeficiency virus or hepatitis C infection only if the patient is taking medications that are excluded per protocol, active hepatitis B, or active hepatitis C infection. 13. If female, the patient is pregnant or lactating. 14. Known allergy or hypersensitivity to any component of the study drug. 15. Gastrointestinal abnormalities including but not limited to: * inability to take oral medication * malabsorption syndromes * requirement for intravenous (IV) alimentation 16. Any active bleeding excluding hemorrhoidal or gum bleeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) in the KIT Exon 11 Intent to Treat (ITT) Population | From date of randomization to earliest documented evidence of disease progression, or death due to any cause (up to 2.1 years) | PFS is defined as the interval between the date of randomization and the earliest documented evidence of disease progression based on the independent radiologic review using modified RECIST Version 1.1-(mRECIST 1.1) GIST specific, or death due to any cause. Per mRECIST 1.1, progression was defined using mRECIST 1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Progression Free Survival (PFS) in the All Patient (AP) Intent to Treat (ITT) Population | From date of randomization to earliest documented evidence of disease progression, or death due to any cause (up to 2.1 years) | PFS is defined as the interval between the date of randomization and the earliest documented evidence of disease progression based on the independent radiologic review using modified RECIST Version 1.1-(mRECIST 1.1) Gastrointestinal stromal tumor (GIST) specific, or death due to any cause. Per mRECIST 1.1, progression was defined using mRECIST 1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in the KIT Exon 11 Intent to Treat (ITT) Population Population | From confirmed CR or PR to disease progression (up to 1.74 years) | ORR was defined as the proportion of patients with confirmed complete response (CR) + confirmed partial response (PR) based on independent radiologic review using modified RECIST (mRECIST) criteria as best overall response. Per mRECIST 1.1 criteria, complete response is defined as disappearance of all target lesions; partial response is defined as \>=30% decrease in the sum of the longest diameter of target lesions. |
| Objective Response Rate (ORR) in the All Patient (AP) Intent to Treat (ITT) Population | From confirmed CR or PR to disease progression (up to 1.74 years) | ORR was defined as the proportion of patients with confirmed complete response (CR) + confirmed partial response (PR) based on independent radiologic review using modified RECIST (mRECIST) criteria as best overall response. Per mRECIST 1.1 criteria, complete response is defined as disappearance of all target lesions; partial response is defined as \>=30% decrease in the sum of the longest diameter of target lesions. |
| Overall Survival (OS) in the KIT Exon 11 Intent to Treat (ITT) Population | From date of randomization until death due to any cause (up to 3.33 years) | OS was defined as the time from the date of randomization until death due to any cause. |
| Overall Survival (OS) in the All Patient (AP) Intent to Treat (ITT) Population | From date of randomization until death due to any cause (up to 3.33 years) | OS was defined as the time from the date of randomization until death due to any cause. |
Countries
Argentina, Australia, Belgium, Canada, Chile, Czechia, France, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ripretinib Ripretinib (150 mg) once a day continuous dosing for 6-week (42 days) cycles | 226 |
| Sunitinib Sunitinib (50 mg) once a day in 6-week (42 days) cycles with 4 weeks continuous dosing followed by 2 week break. | 227 |
| Total | 453 |
Baseline characteristics
| Characteristic | Ripretinib | Sunitinib | Total |
|---|---|---|---|
| Age, Customized 18-64 years | 145 Participants | 143 Participants | 288 Participants |
| Age, Customized 65-74 years | 56 Participants | 66 Participants | 122 Participants |
| Age, Customized 75 years and older | 25 Participants | 18 Participants | 43 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score at Screening ECOG Score 0 | 131 Participants | 128 Participants | 259 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score at Screening ECOG Score 1 | 92 Participants | 98 Participants | 190 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score at Screening ECOG Score 2 | 3 Participants | 1 Participants | 4 Participants |
| Intolerance to Imatinib per Electronic Data Capture (EDC) No | 211 Participants | 208 Participants | 419 Participants |
| Intolerance to Imatinib per Electronic Data Capture (EDC) Yes | 15 Participants | 19 Participants | 34 Participants |
| Intolerance to Imatinib per Interactive Response Technology (IRT) No | 204 Participants | 204 Participants | 408 Participants |
| Intolerance to Imatinib per Interactive Response Technology (IRT) Yes | 22 Participants | 23 Participants | 45 Participants |
| Mutation Type per Electronic Data Capture (EDC) KIT Exon 11 | 167 Participants | 169 Participants | 336 Participants |
| Mutation Type per Electronic Data Capture (EDC) KIT Exon 9 | 31 Participants | 28 Participants | 59 Participants |
| Mutation Type per Electronic Data Capture (EDC) KIT/PDGFRA WT | 14 Participants | 16 Participants | 30 Participants |
| Mutation Type per Electronic Data Capture (EDC) Other KIT (absence of Exon 9 or 11)/PDGFRA | 14 Participants | 14 Participants | 28 Participants |
| Mutation Type per Interactive Response Technology (IRT) KIT Exon 11 | 163 Participants | 164 Participants | 327 Participants |
| Mutation Type per Interactive Response Technology (IRT) KIT Exon 9 | 31 Participants | 29 Participants | 60 Participants |
| Mutation Type per Interactive Response Technology (IRT) KIT/PDGFRA wild type (WT) | 15 Participants | 18 Participants | 33 Participants |
| Mutation Type per Interactive Response Technology (IRT) Other KIT (absence of Exon 9 or 11)/PDGFRA | 17 Participants | 16 Participants | 33 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 31 Participants | 27 Participants | 58 Participants |
| Race/Ethnicity, Customized Black or African American | 14 Participants | 14 Participants | 28 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Report | 30 Participants | 30 Participants | 60 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 148 Participants | 152 Participants | 300 Participants |
| Sex: Female, Male Female | 87 Participants | 85 Participants | 172 Participants |
| Sex: Female, Male Male | 139 Participants | 142 Participants | 281 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 90 / 223 | 95 / 221 |
| other Total, other adverse events | 221 / 223 | 219 / 221 |
| serious Total, serious adverse events | 64 / 223 | 61 / 221 |
Outcome results
Primary
Progression Free Survival (PFS) in the All Patient (AP) Intent to Treat (ITT) Population
PFS is defined as the interval between the date of randomization and the earliest documented evidence of disease progression based on the independent radiologic review using modified RECIST Version 1.1-(mRECIST 1.1) Gastrointestinal stromal tumor (GIST) specific, or death due to any cause. Per mRECIST 1.1, progression was defined using mRECIST 1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From date of randomization to earliest documented evidence of disease progression, or death due to any cause (up to 2.1 years)
Population: All patient (AP) Intent to Treat (ITT) Population is defined as all patients who are randomized. Patients in this population will be analyzed according to the treatment they were scheduled to receive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ripretinib | Progression Free Survival (PFS) in the All Patient (AP) Intent to Treat (ITT) Population | 8.0 months |
| Sunitinib | Progression Free Survival (PFS) in the All Patient (AP) Intent to Treat (ITT) Population | 8.3 months |
p-value: 0.715395% CI: [0.82, 1.33]Log Rank
Primary
Progression Free Survival (PFS) in the KIT Exon 11 Intent to Treat (ITT) Population
PFS is defined as the interval between the date of randomization and the earliest documented evidence of disease progression based on the independent radiologic review using modified RECIST Version 1.1-(mRECIST 1.1) GIST specific, or death due to any cause. Per mRECIST 1.1, progression was defined using mRECIST 1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From date of randomization to earliest documented evidence of disease progression, or death due to any cause (up to 2.1 years)
Population: The KIT Exon 11 Intent to Treat (ITT) Population is defined as all patients who are designated as having a mutation in KIT Exon 11 at the time of randomization. Patients in this population will be analyzed according to the treatment they were scheduled to receive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ripretinib | Progression Free Survival (PFS) in the KIT Exon 11 Intent to Treat (ITT) Population | 8.3 months |
| Sunitinib | Progression Free Survival (PFS) in the KIT Exon 11 Intent to Treat (ITT) Population | 7.0 months |
p-value: 0.359895% CI: [0.66, 1.16]Log Rank
Secondary
Objective Response Rate (ORR) in the All Patient (AP) Intent to Treat (ITT) Population
ORR was defined as the proportion of patients with confirmed complete response (CR) + confirmed partial response (PR) based on independent radiologic review using modified RECIST (mRECIST) criteria as best overall response. Per mRECIST 1.1 criteria, complete response is defined as disappearance of all target lesions; partial response is defined as \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: From confirmed CR or PR to disease progression (up to 1.74 years)
Population: All patient (AP) Intent to Treat (ITT) Population is defined as all patients who are randomized. Patients in this population will be analyzed according to the treatment they were scheduled to receive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ripretinib | Objective Response Rate (ORR) in the All Patient (AP) Intent to Treat (ITT) Population | 21.7 percentage of participants |
| Sunitinib | Objective Response Rate (ORR) in the All Patient (AP) Intent to Treat (ITT) Population | 17.6 percentage of participants |
p-value: 0.2681Cochran-Mantel-Haenszel
Secondary
Objective Response Rate (ORR) in the KIT Exon 11 Intent to Treat (ITT) Population Population
ORR was defined as the proportion of patients with confirmed complete response (CR) + confirmed partial response (PR) based on independent radiologic review using modified RECIST (mRECIST) criteria as best overall response. Per mRECIST 1.1 criteria, complete response is defined as disappearance of all target lesions; partial response is defined as \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: From confirmed CR or PR to disease progression (up to 1.74 years)
Population: The KIT Exon 11 Intent to Treat (ITT) Population is defined as all patients who are designated as having a mutation in KIT Exon 11 at the time of randomization. Patients in this population will be analyzed according to the treatment they were scheduled to receive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ripretinib | Objective Response Rate (ORR) in the KIT Exon 11 Intent to Treat (ITT) Population Population | 23.9 percentage of participants |
| Sunitinib | Objective Response Rate (ORR) in the KIT Exon 11 Intent to Treat (ITT) Population Population | 14.6 percentage of participants |
p-value: 0.0333Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS) in the All Patient (AP) Intent to Treat (ITT) Population
OS was defined as the time from the date of randomization until death due to any cause.
Time frame: From date of randomization until death due to any cause (up to 3.33 years)
Population: All patient (AP) Intent to Treat (ITT) Population is defined as all patients who are randomized. Patients in this population will be analyzed according to the treatment they were scheduled to receive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ripretinib | Overall Survival (OS) in the All Patient (AP) Intent to Treat (ITT) Population | 35.5 months |
| Sunitinib | Overall Survival (OS) in the All Patient (AP) Intent to Treat (ITT) Population | 30.9 months |
p-value: 0.392895% CI: [0.66, 1.18]Log Rank
Secondary
Overall Survival (OS) in the KIT Exon 11 Intent to Treat (ITT) Population
OS was defined as the time from the date of randomization until death due to any cause.
Time frame: From date of randomization until death due to any cause (up to 3.33 years)
Population: The KIT Exon 11 Intent to Treat (ITT) Population is defined as all patients who are designated as having a mutation in KIT Exon 11 at the time of randomization. Patients in this population will be analyzed according to the treatment they were scheduled to receive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ripretinib | Overall Survival (OS) in the KIT Exon 11 Intent to Treat (ITT) Population | 34.0 months |
| Sunitinib | Overall Survival (OS) in the KIT Exon 11 Intent to Treat (ITT) Population | 31.5 months |
p-value: 0.773395% CI: [0.75, 1.48]Log Rank