A Trial of Dovitinib in Combination With Imatinib in Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors After Failure to Imatinib and Sunitinib
Overview
- Phase
- Phase 1
- Intervention
- dovitinib plus imatinib
- Conditions
- Gastrointestinal Stromal Tumors
- Sponsor
- Asan Medical Center
- Primary Endpoint
- Maximal tolerated dose and recommended dose
- Status
- Withdrawn
- Last Updated
- 10 years ago
Overview
Brief Summary
The objective of this study is to determine the recommended dose of combination of dovitinib and imatinib in phase I study.
Detailed Description
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.
Investigators
Yoon-Koo Kang
Professor
Asan Medical Center
Eligibility Criteria
Inclusion Criteria
- •Age 19 years or older
- •Histologically confirmed metastatic or unresectable GIST with CD117(+), DOG-1(+), or mutation in KIT or PDGFRα gene
- •Disease control (response or stabilization for at least 6 months with first-line imatinib and failure of prior treatments for GIST, including at least both imatinib and sunitinib and/or regorafenib. However, patients with imatinib rechallenge will not be accrued.
- •ECOG performance status of 0\~2
- •Resolution of all toxic effects of prior treatments to grade 0 or 1
- •At least one evaluable or measurable lesion for phase I study
- •Adequate bone marrow, hepatic, renal, and other organ functions
- •Neutrophil \> 1,500/mm3
- •Platelet \> 75,000/mm3
- •Hemoglobin \> 8.0 g/dL
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. Barrier contraceptives must be used throughout the trial in both sexes.
- •Clinically significant cardiac disease or impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
- •LVEF \< 45%
- •Complete left bundle branch block
- •Obligate use of a cardiac pacemaker
- •Congenital long QT syndrome
- •History or presence of ventricular tachyarrhythmia
- •Presence of unstable atrial fibrillation .
- •Clinically significant resting bradycardia
- •Uncontrolled hypertension
Arms & Interventions
Dovitinib plus Imatinib
Dovitinib once daily on a 5 days on/2 days off dosing schedule, and imatinib once daily on a continuous dosing schedule
Intervention: dovitinib plus imatinib
Outcomes
Primary Outcomes
Maximal tolerated dose and recommended dose
Time Frame: 3 years
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
Secondary Outcomes
- Disease control rate(3 years)
- Number of Participants with Adverse Events as a Measure of Safety(3 years)
- optionally, correlation of efficacy with potential biomarkers(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(3 years)
- Progression-free survival(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(3 years)
- Overall survival (OS)(3 years)
- Imatinib and dovitinib plasma concentrations vs time profile, and basic pharmacokinetics parameters(3 years)
- Overall response rate(3 years)