A Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor

Status: Recruiting
Phase: Phase 2
Diagnosis: Sarcoma
NCT ID: NCT01874665 (View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 13-190


The purpose of this study is to evaluate the efficacy and safety of ponatinib in patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) following failure of prior tyrosine kinase inhibitor (TKI) therapy.


Conducting Institutions:
Brigham and Women's Hospital, Dana-Farber Cancer Institute, Massachusetts General Hospital

Overall PI:
Suzanne George, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:
Edwin Choy, MD, Massachusetts General Hospital

Dana-Farber Cancer Institute: Melissa Hohos, mhohos@partners.org
Dana-Farber Cancer Institute: Mark Morley, mmorley@partners.org
Massachusetts General Hospital: Cancer Trials Call Center, 877-789-6100

Eligibility Criteria

Inclusion Criteria: 1. GIST with failure of at least 1 prior TKI therapy defined as: 1. Histologically confirmed metastatic and/or unresectable GIST after at least 1 failure of any prior treatment with a TKI. If prior TKI treatment was neoadjuvant therapy, then relapse must have occurred during the neoadjuvant therapy in order to consider it failed therapy 2. Patients in Cohort A must have evidence of activation mutations of exon 11 of KIT in their tumors. Demonstration of an exon 11 mutation may be based on prior assessment or on evaluation of a tumor sample after enrollment in this study. Patients in Cohort B must have GIST that lacks activating mutations in KIT exon 11, but may have evidence of another activating mutation such as in KIT exon 9 or PDGFR-α. Patients may be enrolled in the study prior to determination of appropriate cohort (as long as both cohorts are open for enrollment). 2. Measurable disease per modified RECIST 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 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 4. Adequate hepatic function as defined by the following criteria: 1. Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome 2. ALT ≤2.5×ULN or ≤5.0xULN if liver metastases are present 3. AST ≤2.5×ULN or ≤5.0xULN if liver metastases are present 5. Adequate renal function as defined by the following criterion: a. Serum creatinine <1.5×ULN 6. Adequate pancreatic function as defined by the following criterion: a. Serum lipase and amylase ≤1.5×ULN 7. Fully recovered (≤Grade 1 or returned to baseline or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug Exclusion Criteria: 1. Major surgery within 28 days prior to initiating therapy 2. History of bleeding disorder 3. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis 4. History of alcohol abuse 5. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL) 6. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: 1. Myocardial infarction (MI) within 6 months prior to enrollment 2. Unstable angina within 6 months prior to enrollment 3. Congestive heart failure within 6 months prior to enrollment, or LVEF less than lower limit of normal per local institutional standards 4. History of clinically significant (as determined by the treating physician) atrial arrhythmia 5. Any history of ventricular arrhythmia 6. Cerebrovascular accident or transient ischemic attack (TIA) within 6 months prior to enrollment 7. Any history of peripheral arterial occlusive disease requiring revascularization 8. Venous thromboembolism including deep venous thrombosis (DVT) or pulmonary embolism within 6 months prior to enrollment 7. Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control 8. Taking medications that are known to be associated with Torsades de Pointes 9. Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib 10. Ongoing or active infection. This includes, but is not limited to, the requirement for intravenous antibiotics 11. Known history of human immunodeficiency virus. Testing is not required in the absence of prior documentation or known history 12. Pregnant or breastfeeding 13. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs 14. Individuals with a history of a different malignancy, other than cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, are ineligible, except if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy OR if the other primary malignancy is neither currently clinically significant nor requiring active intervention. 15. Use of any approved TKIs or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is longer, prior to receiving study drug 16. Any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the drug
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