Dovitinib for Imatinib/Sumitinib-failed Gastrointestinal Stromal Tumors (GIST)
This study has been completed.
Information provided by (Responsible Party):
Yoon-Koo Kang, Asan Medical Center
First received: September 8, 2011
Last updated: January 13, 2014
Last verified: January 2014
With discovery of KIT mutations and the advent of KIT tyrosine kinase inhibitor imatinib (GlivecTM, Novartis), there has been substantial improvement in overall survival in patients with advanced and/or metastatic gastrointestinal tumors (GIST). Recently, sunitinib (SuteneTM, Pfizer) showed activity as second-line therapy in GIST patients after failure with imatinib. However, virtually all patients will eventually progress or become intolerable after the first-line imatinib and the second-line sunitinib. Dovitinib (TKI258, Novartis) is a multi-kinase inhibitor. TKI258 is a potent inhibitor of the VEGFR 1, 2, and 3, FGFR1, 2 and 3, PDGFRβ, Kit, RET, TrkA, CSF 1R, and FLT3 with inhibitory concentration 50% (IC50s) of less than 40nM. Stem cell factor (SCF) also termed KIT ligand, or steel factor has been shown to modulate tumor angiogenesis. In cultured human endothelial cells and Kit expressing cancer cells, TKI258 inhibits VEGF- and SCF-stimulated mitogenesis. .
Gastrointestinal Stromal Tumors
||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||A Phase II Trial of TKI258 in Patients With Metastatic or Advanced Gastrointestinal Stromal Tumors (GIST) After Failure to Imatinib and Sunitinib(CTKI258AKR01T)
Primary Outcome Measures:
- Disease Control Rate (DCR; OR + Stable Disease) [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]
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
This was evaluated with abdominal and pelvic dynamic CT scan every 4 weeks for the initial 8 weeks, and then every 8 weeks.
Secondary Outcome Measures:
- Overall Response Rate Using Both CT and PET Scans [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]
PET scan will be performed at baseline and at 4 weeks of treatment. Metabolic response was defined based on the PET response criteria of the European Organization for Research and Treatment of Cancer (EORTC); a metabolic partial response (mPR) was defined as a 25% reduction in average SUVmax; metabolic stable disease (mSD) between a 25% decrease and 25% increase in average SUVmax; metabolic progressive disease (mPD) as a 25% increase in average SUVmax or the appearance of new uptake in metastatic lesions.
- Efficacy According to the Primary Mutation Type [ Time Frame: Up to 24weeks ] [ Designated as safety issue: No ]
Correlation between efficacy results such as response, progression-free survival and overall survival, and primary mutation type including KIT exons 9, 11, 13, and 17 and PDGFRα exons 12 and 18.
- Efficacy According to the Concentrations of Circulating Growth Factors [ Time Frame: Up to 24weeks ] [ Designated as safety issue: No ]
Correlation between efficacy results, such as response, progression-free survival, and overall survival andcirculating growth factors (including vascular endothelial growth factor, fibroblast growth factor, interleukin‐8, placental growth factor, and fibroblast growth factor23), and soluble receptors (including soluble form of membrane bound vascular endothelial growth factor receptor-1 and -2).
- Number of Participants With Adverse Events [ Time Frame: Monitoring of adverse events will be continued for at least 28 days following the last dose of study treatment, up to 3 year. ] [ Designated as safety issue: Yes ]
Adverse events will be graded according to Common Terminology Criteria for Adverse events version 3.0, up to 3 year.
- Progression-free Survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
Progression-free survival is defined as the time from the first treatment to the onset of progressive disease per RECIST criteria or to the date of death whichever comes first. For patients who do not experience progressive disease or death, the progression-free survival duration will be right censored on the last disease assessment date.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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
- Overall Survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
Overall survival duration is calculated as time from the first treatment to the date of death. For patients who are still alive at the cut‐off date for statistical reporting, the overall survival duration will be right censored on the last known alive date.
| Study Start Date:
| Study Completion Date:
| Primary Completion Date:
||March 2013 (Final data collection date for primary outcome measure)
TKI258 at 500 mg/day on a 5 days on/2 days off dosing schedule
Other Name: A phase II study of TKI258
It is well known that KIT and PDGFR which can be inhibited by TKI258 have a crucial role in the development and proliferation of GIST, and in general FGFR has an important role in angiogenesis and tumor proliferation in many cancers. We assume that TKI258 can be also effective in patients with GIST. The objective of this study is to evaluate the safety and activity of TKI258 given as salvage treatment for GIST after failure to standard imatinib and sunitinib.
|Ages Eligible for Study:
||20 Years and older
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- Women of child-bearing potential who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control.
- Clinically significant cardiac disease (New York Heart Association, Class III or IV) or impaired cardiac function or clinically significant cardiac diseases,
- Uncontrolled infection.
- Diabetes mellitus (insulin dependent or independent disease, requiring chronic medication) with signs of clinically significant peripheral vascular disease.
- Previous pericarditis; clinically significant pleural effusion in the previous months or current ascites requiring two or more interventions/month.
- Known pre-existing clinically significant disorder of the hypothalamic-pituitary axis, adrenal or thyroid glands.
- Prior acute or chronic pancreatitis of any etiology.
- Acute and chronic liver disease and all chronic liver impairment.
- Malabsorption syndrome or uncontrolled gastrointestinal toxicities with toxicity greater than NCI CTCAE grade 2.
- Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality.
- Treatment with any of the medications that have a potential risk of prolonging the QT interval or inducing Torsades de Points and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
- Use of ketoconazole, erythromycin, carbamazepine, phenobarbital, rifampin, phenytoin and quinidine 2 weeks prior baseline.
- Major surgery ≤ 28 days prior to starting study drug or who have not recovered from side effects of such therapy.
- Known diagnosis of HIV infection .
- History of another primary malignancy that is currently clinically significant or currently requires active intervention.
- Patients with brain metastases as assessed by radiologic imaging
- Alcohol or substance abuse disorder.
- no other inhibitor of FGFR except sunitinib
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01440959
|Asan Medical Center, University of Ulsan College of Medicine
|Seoul,, Korea, Republic of, 138-736 |
Asan Medical Center
||Yoon-Koo Kang, MD, PhD
||Asan Medical Center
||Yoon-Koo Kang, Study Principal Investigator, Asan Medical Center
History of Changes
|Other Study ID Numbers:
|Study First Received:
||September 8, 2011
|Results First Received:
||November 12, 2013
||January 13, 2014
||Korea: Food and Drug Administration
Keywords provided by Asan Medical Center:
This is a single-center
open-label phase II study
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on May 02, 2016
Gastrointestinal Stromal Tumors
Digestive System Diseases
Digestive System Neoplasms
Neoplasms by Histologic Type
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue