A Phase II Trial of Dovitinib Monotherapy as Salvage Treatment in Patients With Metastatic or Unresectable Gastric Cancer Harboring FGFR2(Fibroblast Growth Factor Receptor 2) Amplification After Failure of First or Second Line Chemotherapy
- Pathologically proven metastatic or unresectable adenocarcinoma of stomach or
- Patients with progressive disease (radiological confirmation required) after one or
two lines of chemotherapy in palliative setting for advanced gastric cancer. Adjuvant
or neoadjuvant chemotherapy is not counted as one line of prior chemotherapy.
- FGFR2 amplification (copy number > 3, identified by real time PCR using TaqMan probe)
by prescreening or screening procedure. Prescreening can be performed with Real Time
PCR for FGFR2 amplification any time during the prior chemotherapy. At least 18
patients should have 6 or more copy numbers of FGFR2 (see Statistical Methods and
- Presence of at least one measurable disease (for co-primary endpoint of overall
response rate in patients with FGFR2 copy number > 6) or one evaluable disease (for
co-primary endpoint of PFS in patients with FGFR2 copy number > 3) by Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Age of 18 years or older
- Expected life expectancy of more than 3 months
- ECOG performance status 0~2
- Resolution of all toxic effects of prior treatments to grade 0 or 1 by NCI-CTCAE
- Adequate bone marrow, hepatic, renal, and other organ functions ( Neutrophil >
1,500/mm3, Platelet > 75,000/mm3, Hemoglobin > 8.0 g/dL, Total bilirubin < 1.5 x
upper limit of normal (ULN), AST/ALT < 2.5 x ULN (or < 5 x ULM in case of liver
metastases), Creatinine < 1.5 x ULN, Amylase, lipase < ULN, 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 50 mL/min/1.73m2 from a 24-hour
- 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.
- Washout period of previous chemotherapy for more than 4 times the half life or at
least 2 weeks after completion of prior chemotherapy whichever comes first
- No prior FGF/FGFR inhibitor
- No prior radiation therapy within 2 weeks of the study (Irradiated lesions should not
be included in the evaluable lesions.)
- Written informed consent
- Past or concurrent history of neoplasm other than gastric adenocarcinoma, except for
curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix uteri
- Bowel obstruction
- Evidence of serious gastrointestinal bleeding
- 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. Oral, implantable, or
injectable contraceptives may be affected by cytochrome P450 interactions, and are
therefore not considered effective for this study. Women of child-bearing potential,
defined as sexually mature women who have not undergone a hysterectomy or who have
not been naturally postmenopausal for at least 12 consecutive months (i.e., who has
had menses any time in the preceding 12 consecutive months), must have a negative
serum pregnancy test 72 hours prior to starting TKI258.
- 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 exclusion criteria, Clinically
significant resting bradycardia (< 50 bpm), Uncontrolled hypertension (systolic blood
pressure 150 mmHg and/or diastolic blood pressure 100 mmHg, with or without
anti-hypertensive medication)., QTc > 480 msec on screening ECG, Right bundle branch block
+ left anterior hemiblock (Bifascicular block), Angina pectoris 3 months prior to starting
study drug, Acute Myocardial Infarction 3 months prior to starting study drug, Other
clinically significant heart disease (e.g., Congestive heart failure, history of labile
hypertension, or history of poor compliance with an antihypertensive regimen))
- 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 12
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 (nausea,
diarrhea,vomiting) with toxicity greater than NCI CTCAE grade 2.
- Other severe, acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or may interfere with the interpretation of study results and, in
the judgment of the investigator, would make the subject inappropriate for this
- 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 (HIV testing is not mandatory).
- Patients with brain metastases as assessed by radiologic imaging (e.g. CT, MRI)
- Alcohol or substance abuse disorder