TY - JOUR
T1 - A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib with Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients
AU - Ma, Wen Wee
AU - Xie, Hao
AU - Fetterly, Gerald
AU - Pitzonka, Laura
AU - Whitworth, Amy
AU - Levea, Charles
AU - Wilton, John
AU - Mantione, Krystin
AU - Schihl, Sarah
AU - Dy, Grace K.
AU - Boland, Patrick
AU - Iyer, Renuka
AU - Tan, Wei
AU - Brady, William
AU - Straubinger, Robert M.
AU - Adjei, Alex A.
N1 - Publisher Copyright:
© 2018 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Objectives: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. Materials and Methods: Patients received gemcitabine 1000 mg/m intravenously on days 1 and 8, capecitabine 1300 mg/m oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. Results: A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. Conclusions: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.
AB - Objectives: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. Materials and Methods: Patients received gemcitabine 1000 mg/m intravenously on days 1 and 8, capecitabine 1300 mg/m oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. Results: A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. Conclusions: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.
KW - FGFR/VEGFR inhibitor
KW - dovitinib
KW - pancreatic adenocarcinoma
UR - http://www.scopus.com/inward/record.url?scp=85056549699&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056549699&partnerID=8YFLogxK
U2 - 10.1097/COC.0000000000000492
DO - 10.1097/COC.0000000000000492
M3 - Article
C2 - 30418178
AN - SCOPUS:85056549699
SN - 0277-3732
VL - 42
SP - 184
EP - 189
JO - American Journal of Clinical Oncology: Cancer Clinical Trials
JF - American Journal of Clinical Oncology: Cancer Clinical Trials
IS - 2
ER -