Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors

Abstract

Purpose Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib. Methods Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1000 mg/m2 on days 1 and 8), cisplatin (70 mg/m2) or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1-5, 8-12 and 15-19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3+3 dose escalation rules. Results Fourteen patients with advanced solid tumors were enrolled, 5 to the cisplatin arm and 9 to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of 2 cycles of treatment (range, 1-5) and patients enrolled in the carboplatin arm received a median of 1 cycle of treatment (range, 1-4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia) and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort and the study was closed. No patients achieved an objective response to treatment. Conclusions Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression.

Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug–drug interaction

“…Thromboembolic events ( n = 2) have now been reported in another phase I study of dovitinib in combination with cisplatin and gemcitabine in patients with malignancies other than lung cancer. [25] Despite the toxicity, there were 2 patients in the study who had a significant decrease in target lesions after receiving the combination of dovitinib/erlotinib. One patient had a non-sensitizing EGFR mutation while the other had a suspected EGFR mutation with an unusually long survival of greater than 6 years from the time of diagnosis.…”

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

“…Foretinib or GSK1363089 was originally discovered by Exelixis and is currently under investigation by GlaxoSmithKline for various disease indications, such as RCC, GIST, HCC, NSCLC, breast and head and neck cancer [139,140]. As a multikinase inhibitor, its inhibitory activity has been known to be directed especially against VEGFR and MET, further against RON, AXL, Tie-2, c-KIT, Flt-3 and PDGFR.…”

“…A study by Galsky et al [140] followed a study protocol applying dovitinib with gemcitabine and cisplatin or carboplatin, both platinum-containing chemotherapeutics. Due to poor tolerance towards this dosing regimen, mainly myelosuppression, the study had to be discontinued and did not deliver sufficient pharmacokinetic data.…”

Interaction Potential of the Multitargeted Receptor Tyrosine Kinase Inhibitor Dovitinib with Drug Transporters and Drug Metabolising Enzymes Assessed in Vitro

“…Dovitinib (TKI-258) is an inhibitor of fibroblast growth factor receptors 1–3 (FGFR), vascular endothelial growth factor receptors 1–3 (VEGFR), platelet-derived growth factor receptor (PDGFR), and other class III receptor tyrosine kinases [ 1 ]. It is under development for the treatment of several neoplasias like renal cell carcinoma, advanced breast cancer, gastrointestinal stromal tumours, and hepatocellular carcinoma [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”