The objective of this study is to determine the recommended dose of combination of dovitinib and imatinib in phase I study.
combination of dovitinib and imatinib could lead to additive or synergistic effect in patients who had failure of standard TKI therapies including imatinib, sunitinib, and/or regorafenib. In this phase I-II study of dovitinib plus imatinib, we aim to determine a recommended dose of dovitinib plus imatinib and to evaluate the safety and activity of the combination at the recommended dose as a 3rd or more line of treatment in metastatic or unresectable GIST.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Dovitinib once daily on a 5 days on/2 days off dosing schedule, and imatinib once daily on a continuous dosing schedule
Maximal tolerated dose and recommended dose
Initially three patients will be treated at each dose level. If one out of three patients experiences a DLT, three additional patients will be entered at that dose level. Dose escalation will be continued until DLTs are experienced in two or more out of six patients (more than 33% of patient cohort), which will be defined as the MTD.If more than 33% of patients experience a DLT in a dose level, one doe level below will be the RD
Time frame: 3 years
Disease control rate
response + stable disease evaluated with abdominal and pelvic spiral CT scan every 4 weeks for the first 8 weeks, and then every 8 weeks, using RECIST criteria v1.1
Time frame: 3 years
Overall response rate
response + stable disease evaluated with abdominal and pelvic spiral CT scan every 4 weeks for the first 8 weeks, and then every 8 weeks, using RECIST criteria v1.1
Time frame: 3 years
Number of Participants with Adverse Events as a Measure of Safety
Safety by NCI CTCAE version 4.0
Time frame: 3 years
Progression-free survival
response + stable disease evaluated with abdominal and pelvic spiral CT scan every 4 weeks for the first 8 weeks, and then every 8 weeks, using RECIST criteria v1.1
Time frame: 3 years
Overall survival (OS)
OS assessment dates will be the time point when 6 months have passed after the enrollment of the last patient
Time frame: 3 years
optionally, correlation of efficacy with potential biomarkers
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mutational analysis of KIT exons 9, 11, 13, and 17, and PDGFRα exons 12, 14, and 18 with direct sequencing using DNA extracted from archival tissues and/or newly obtained tissues at baseline, and with BEAMing assay using ctDNA extracted from plasma at baseline and every time when follow-up CT scans are conducted; optionally circulating growth factors including but not limited to VEGF, bFGF, IL-8, PLGF, FGFR2, and FGF23, and soluble receptors including but not limited to sVEGFR1 and 2 with plasma collected at baseline and on Cycle 1 Week 4 Day 5
Time frame: 3 years
next generation sequencing will be performed in newly obtained tissues at baseline to find out new genetic changes after failure of previous standard TKIs
Time frame: 3 years
Optionally, activation of FGFR signaling will be analyzed using the reverse phase protein microarray and/or immunohistochemistry including but not limited to pFRS2 and pFGFR in archival tissues and/or newly obtained tissues at baseline
Time frame: 3 years
Imatinib and dovitinib plasma concentrations vs time profile, and basic pharmacokinetics parameters
PK samples will be taken at 0 hour (pre-dose) and at 1, 2, 3, 4, 6, and 8 hours (post-dose) after administration of dovitinib and imatinib on Cycle 1 Week 1 Day 1, Cycle 1 Week 1 Day 5, and Cycle 1 Week 4 Day 5
Time frame: 3 years