Dovitinib Plus Docetaxel in Gastric Cancer

Study Overview
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Brief Summary
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Docetaxel is currently one of standard second-line therapy in patients with gastric cancer. As angiogenesis and FGFR pathway has been suggested to be associated with gastric cancer, dovitinib, dual VEGFR and FGFR inhibitor, may have the potential to improve the outcomes of patients with gastric cancer. Therefore, we investigated the combination regimen of docetaxel and dovitinib.

Official Title
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A Phase I-II Trial of Dovitinib Plus Docetaxel as Second-line Chemotherapy in Patients With Metastatic or Unresectable Gastric Cancer After Failure of First-line Chemotherapy

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: Dovitinib and docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically proven metastatic or unresectable adenocarcinoma of stomach or gastroesophageal junction Patients with progressive disease (radiological confirmation required) after one line of chemotherapy except taxane for advanced gastric cancer in palliative setting Presence of at least one evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Age of 18 to 74 years Estimated life expectancy of more than 3 months Eastern Cooperative Oncology Group (ECOG) performance status 0 2 Adequate bone marrow function (Absolute neutrophil counts ≥ 1,500/uL, hemoglobin ≥ 8.0g/dL, and platelet ≥ 100,000/uL) Adequate renal function (creatinine < 1.5mg/dL) Adequate hepatic function (total bilirubin < 1.5 mg/dL, transaminase < 3 times the upper normal limit [5 times for patients with liver metastasis]) No prior anti-angiogenic therapy (anti-VEGF or VEGFR tyrosine kinase inhibitor etc) or FGF/FGFR inhibitor No prior radiation therapy within 4 weeks of the study (Irradiated lesions should not be included in the evaluable lesions.) Written informed consent Exclusion Criteria: 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 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start Bowel obstruction Evidence of serious gastrointestinal bleeding Presence of central nervous system (CNS) metastasis History of significant neurologic or psychiatric disorders Significant cardiac disease within 6 months of the study (congestive heart failure uncontrollable by medication, symptomatic coronary heart disease, or arrhythmia, myocardial infarction) Left ventricular ejection fraction (LVEF) assessed by 2-D echocardiogram (ECHO) or multiple gated acquisition scan (MUGA), < 45% Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is allowed prior to study entry. QTc > 480 msec on screening ECG Proteinuria defined by NCI CTCAE grade > 1 at baseline as measured by a urine dipstick (2+ or greater) and confirmed by a 24 hour urine collection ( > 1g/24hrs). Subjects may be re-screened if blood pressure is shown to be controlled with or without intervention History of thrombotic or bleeding diathesis or coagulopathy Serious non-healing wound, peptic ulcer, or bone fracture Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months Pregnant or lactating women, women of childbearing potential not employing adequate contraception Other serious illness or medical conditions

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dovitinib plus docetaxel<br>In phase I portion of the study Docetaxel 45-75 mg/m2, intravenous, every 3 weeks Dovitinib 200-500 mg, oral, 5 days on/2 days off In phase II portion of the study Recommended dose of docetaxel and dovitinib in phase I portion will be used. | Drug: Dovitinib and docetaxel<br>* In phase I portion of the study Docetaxel 45-75 mg/m2, intravenous, every 3 weeks Dovitinib 200-500 mg, oral, 5 days on/2 days off In phase II portion of the study Recommended dose of docetaxel and dovitinib in phase I portion will be used.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | If dose limiting toxicities are experienced in two or more out of six patients in the cohort (more than 33% of patient cohort), that dose will be defined as the maximum tolerated dose. | 6 months | 
| Progression-free survival | Progression-free survival is defined as the time from the first treatment to the onset of progressive disease or to the date of death whichever comes first. | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Proportion of patients with complete and partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 | 2 year | 
| Toxicity | Adverse events caused by study drugs according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | 2 years | 
| Overall survival | Time from start of study treatment to any cause of death | 2 years | 
| Biomarker | FGFR2 copy number will be evaluated in blood and tumor tissue. Treatment efficacy including overall response rate, progression-free survival, and overall survival will be compared according to FGFR2 copy number determined by both FISH and real time PCR using TaqMan probe. | Baseline and 2 weeks after study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric cancer, Phase I/II, Second-line chemotherapy, Dovitinib, Docetaxel, Refractory to first-line chemotherapy