Gastrointestinal Stromal Tumors (GISTs)
Conditions
Brief summary
Randomized, placebo-controlled, phase III study of regorafenib 160 mg once daily on intermittent dosing schedule of 3 weeks on treatment followed by 1 weeks off demonstrated the significant benefit of regorafenib in terms of PFS in patients with GISTs who had failed to both imatinib and sunitinib. However, there are concerns that tumors and tumor-related symptoms may be progressed during off treatment period. Investigators hypothesize that continuous dosing schedule of regorafenib might be feasible and effective to prevent disease flare on off-treatment period. Based on the results of previous dose escalation study for continuous regorafenib dosing, we investigate the 100 mg daily dose of regorafenib in patients with TKI-refractory GISTs.
Interventions
DRUGRegorafenib
Regorafenib 100mg continuous dosing arm
Sponsors
Asan Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 20 years or older, at the time of acquisition of informed consent * Histologically confirmed metastatic and/or advanced (unresectable or recurrent) GIST with CD117(+), DOG-1(+), or mutation in KIT or PDGFRα gene * Disease progression or intolerance to imatinib as well as disease progression on sunitinib Disease progression is defined as (1) size increase \> 20% by RECIST version 1.1, (2) appearance of a definite new lesion (excluding small cystic new lesions in the liver within 6 months of starting TKIs), (3) new solid nodule within a cystic mass, or (4) increase of the size (\> 20%) of previously existing solid nodule within a cystic mass. Intolerance to previous TKIs is defined as (1) drug compliance \< 75% due to grade 2 or more non-hematologic toxicities despite dose reduction to one dose level below (300 mg per day for imatinib; 37.5 mg per day on a 4 weeks on and 2 weeks off schedule or 25 mg per day continuous dosing for sunitinib), (2) Febrile neutropenia, grade 4 neutropenia for more than 6 days, grade 4 thrombocytopenia, grade 3 thrombocytopenia with clinically significant bleeding, grade 3-4 or continuous intolerable grade 2 non-hematologic toxicities despite dose reduction to one dose level below as described above. * ECOG performance status of 0\ 1 * Resolution of all toxic effects of prior treatments to grade 0 or 1 by NCI-CTCAE version 4.03 * At least one measurable lesion as defined by RECIST version 1.1. * Adequate bone marrow, hepatic, renal, and other organ functions * Neutrophil \> 1,500/mm3 * Platelet \> 100,000/mm3 * Hemoglobin \> 9.0 g/dL * Total bilirubin \< 1.5 x upper limit of normal (ULN) * Lipase ≤ 1.5 x the ULN * AST/ALT \< 3.0 x ULN (or \< 5 x ULM in case of liver metastases) * Alkaline phosphatase (ALP) limit ≤ 2.5 x ULN (≤5 x ULN for patients with liver involvement of their cancer and /or have bone metastases). * Estimated creatinine clearance (CLcr) ≥ 30 mL/min as calculated using the Cockcroft-Gault equation. * International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g. heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care. * Electrolytes should be within normal limits. * Urine dipstick reading: Negative for proteinuria or, if documentation of +1 results for protein on dipstick reading, then total urinary protein ≤ 500 mg and measured creatinine clearance ≥ 30 mL/min/1.73m2 from a 24-hour urine collection * Life expectancy \> 12 weeks * Women with reproductive potential must have a negative serum or urine pregnancy test; and men and women of reproductive potential must practice an effective method of avoiding pregnancy while receiving study drug. * Provision of a signed written informed consent * Women of childbearing potential and men must agree to use adequate contraception before entering the program until at least 8 weeks after the last study drug administration. The investigator or a designated associate is requested to advise the subject on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care * Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment
Exclusion criteria
* Prior use of any VEGFR inhibitor other than sunitinib (e.g., sorafenib) * Subjects who have received: -any other approved tyrosine kinase inhibitor within 1 week or a minimum 5 drug half- lives, whichever is longer (i.e., within 7 days for imatinib or within 10 days for sunitinib) * any other investigational new drugs within 4 weeks or 5 drug half-lives (if drug half-life in subjects is known), whichever is shorter. * 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, including any one of the following: * LVEF \< 45% as determined by MUGA scan or echocardiogram * 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 (ventricular response \> 100 bpm). Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease control rate | at least 12 weeks | Disease control rate (CR + PR + SD) lasting for at least 12 weeks according to the RECIST v1.1 |
Secondary
| Measure | Time frame |
|---|---|
| Progression-free survival | up to 2 years |
| Overall survival | up to 2 years |
| Toxicity profile by the NCI-CTCAE v4.03 | up to 2 years |
Countries
South Korea
Outcome results
None listed