A Phase I Pharmacokinetic and Pharmacodynamic Study of TKI258, an Oral, Multitargeted Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

Abstract

OBJECTIVE: To assess evidence from randomized controlled trials (RCTs) on the safety of isotonic versus hypotonic intravenous (IV) maintenance fluids in hospitalized children. METHODS:We searched PubMed, Embase, Cochrane Library, and clinicaltrials.gov (up to April 11, 2013) for RCTs that compared isotonic to hypotonic maintenance IV fluid therapy in hospitalized children. Relative risk (RR), weighted mean differences, and 95% confidence intervals (CIs) were calculated based on the effects on plasma sodium (pNa). The risk of developing hyponatremia (pNa ,136 mmol/L), severe hyponatremia (pNa ,130 mmol/L), and hypernatremia (pNa .145 mmol/L) was evaluated. We adopted a random-effects model in all meta-analyses. Sensitivity analyses by missing data were also performed.RESULTS: Ten RCTs were included in this review. The meta-analysis showed significantly higher risk of hypotonic IV fluids for developing hyponatremia (RR 2.24, 95% CI 1.52 to 3.31) and severe hyponatremia (RR 5.29, 95% CI 1.74 to 16.06). There was a significantly greater fall in pNa in children who received hypotonic IV fluids (-3.49 mmol/L versus isotonic IV fluids, 95% CI -5.63 to -1.35). No significant difference was found between the 2 interventions in the risk of hypernatremia (RR 0.73, 95% CI 0.22 to 2.48). None of the findings was sensitive to imputation of missing data.CONCLUSIONS: Isotonic fluids are safer than hypotonic fluids in hospitalized children requiring maintenance IV fluid therapy in terms of pNa. Pediatrics 2014;133:105-113

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

“…These include 4 ATP-competitive VEGFR2 inhibitors that are in various stages of clinical development as antiangiogenic agents, dovitinib, cediranib, BIBF 1120, and brivanib, which have also been shown to have activity against FGFRs in preclinical models (29)(30)(31)(32)(33)(34)(35). Here, using a Ba/F3 system transduced with activated forms of FGFR1-4, we show that ponatinib was at least 4-to 29-fold more potent than dovitinib and cediranib and at least 25-fold more potent than BIBF 1120 and brivanib.…”

“…For comparison, the in vitro kinase and cellular activities of 4 other multitargeted TKIs that have been reported to have anti-FGFR activity (and whose structures were published at the time of these studies), dovitinib, cediranib, BIBF 1120, and brivanib (29)(30)(31)(32)(33)(34)(35), were also examined. By both measures, ponatinib was found to be the most potent inhibitor of each of the 4 FGFRs ( Fig.…”

“…Brivanib (BMS-540215) targets FGFR1 (32) and selectively inhibits growth of breast cancer cell lines with FGFR1 gene amplification (33). Finally, dovitinib (TKI258) inhibits the kinase activity of FGFR1, FGFR2, and FGFR3 and the cellular activity of FGFR3 in models of multiple myeloma (34,35). Ponatinib (AP24534) is an oral multitargeted kinase inhibitor that potently inhibits native and mutant forms of BCR-ABL (36)(37)(38) and is currently being investigated in a phase II pivotal trial in patients with chronic myelogenous leukemia (CML; Clinicaltrials.gov: NCT01207440).…”

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…One melanoma patient had a partial response (PR) to the treatment, and 2 patients achieved stable disease (SD) status for more than 6 months. Interestingly, 5 of 14 evaluable patients had a modulation of phosphorylated extracellular signal-regulated kinase (ERK) levels in peripheral blood mononuclear cells ( 76 ). Forty-seven previously treated patients with advanced melanoma were included in a phase I/II dose-escalation study evaluating dovitinib.…”

Vascular endothelial growth factor receptor tyrosine kinase inhibitors in metastatic renal cell cancer: latest results and clinical implications

“…Further assessment of regorafenib should exploit its ability to inhibit mechanisms of escape from anti-angiogenic treatment with a focus on biomarker-defined subsets of patients with evidence of angiopoetin or fibroblast growth factor (FGF) pathway upregulation. Dovitinib is a potent oral angiogenesis inhibitor with a wide spectrum of therapeutic targets including FGFR-1 as well as the VEGFRs [Sarker et al 2008]. It showed substantial activity in a recent phase II trial in mRCC patients previously treated with a VEGFR TKI and/or an mTOR inhibitor, with an ORR of 8%, a PFS of 6.1 months and an OS of 16 months [Angevin et al 2011].…”