Phase 2
N=30
Dovitinib for Imatinib/Sumitinib-failed Gastrointestinal Stromal Tumors (GIST): TKI258
Gastrointestinal Stromal Tumors
Bottom Line
View on ClinicalTrials.gov: NCT01440959 ↗Enrolled (actual)
30
Serious AEs
26.7%
Results posted
Mar 2014
Primary outcome: Primary: Disease Control Rate (DCR; OR + Stable Disease) — 13 Percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- dovitinib (Drug)
- Age
- Adult, Older Adult · 20+ yrs
- Sex
- All
- Sponsor
- Asan Medical Center
- Primary completion
- Mar 2013
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Disease Control Rate (DCR; OR + Stable Disease) |
13 | — |
| SECONDARY Overall Response Rate Using Both CT and PET Scans |
3; 13 | — |
| SECONDARY Efficacy According to the Primary Mutation Type |
— | — |
| SECONDARY Efficacy According to the Concentrations of Circulating Growth Factors |
— | — |
| SECONDARY Number of Participants With Adverse Events |
30 | — |
| SECONDARY Progression-free Survival |
3.6 | — |
| SECONDARY Overall Survival |
9.7 | — |
Summary
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. .
Eligibility Criteria
Inclusion criteria
- Age 20 years or older
- Histologically confirmed metastatic and/or advanced GIST with CD117(+), DOG-1(+), or mutation in KIT or PDGFRα gene
- Failed (progressed and/or intolerable) after prior treatments for GIST, including at least both imatinib and sunitinib .
- ECOG performance status of 0~2
- Resolution of all toxic effects of prior treatments to grade 0 or 1 by NCI-CTCAE version 3.0
- At least one measurable lesion as defined by RECIST version 1.0.
- Adequate bone marrow, hepatic, renal, and other organ functions
- Neutrophil > 1,500/mm3
- Platelet > 75,000/mm3
- Hemoglobin > 8.0 g/dL
- Total bilirubin 12 weeks
- Women with reproductive potential must have a negative serum or urine pregnancy test
- Washout period of previous TKIs or chemotherapy for more than 4 times the half life.
- Provision of a signed written informed consent
Exclusion criteria
- 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
Data sourced from ClinicalTrials.gov (NCT01440959). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.