Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

Abstract

Telatinib is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor b tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t max of 3 hours or less. Geometric mean C max and AUC 0À12 increased in a less than doseproportional manner and plateaued in the 900 -1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC 0À12 of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.

A Phase I Dose–Escalation Study of Regorafenib (BAY 73–4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors

“…This AE profile is consistent with the mechanism of action of regorafenib and is broadly similar to that observed in phase I studies involving other multikinase inhibitors in development (21)(22)(23)(24)(25). Overall, treatment emergent AEs were manageable, although dose adjustments were necessary.…”

“…In cohort 1, patients received a single dose of 10 mg regorafenib oral solution on day 1 followed by 6 days off treatment (days 2-7), once daily dosing of regorafenib for 7 days (days [8][9][10][11][12][13][14], and 14 days off (days [15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Patients in cohort 1 were transferred to cohort 2 and continued to receive 10 mg regorafenib oral solution in repeating 28-day treatment cycles of 21 days on/seven days off.…”

Elevated Levels of Plasma Angiogenic Factors Are Associated with Human Lymphatic Filarial Infections

“…26 Although there is no information related to the utility of monitoring sVEGFR-2 levels in filarial infections, the inverse relationship between sVEGFR-2 and VEGF-A or VEGF-C is similar to that seen in other conditions. [27][28][29] Similarly, increased levels of VEGF and reduced levels of sVEGFR-2 have been shown with the use of inhibitors of cellular VEGF receptor tyrosine kinases VEGF RTKs, including sunitinib, 30 axitinib, 31 and telatinib, 32 suggesting a receptor downregulation-mediated increase in sVEGFR-2. Together with in vitro studies in which VEGFinduced endocytosis of VEGFR-2, resulting in lower levels of sVEGFR-2, 22 it seems possible that sVEGFR-2 levels in the plasma of filaria-infected individuals might influence levels of circulating VEGFs in filarial infections.…”

Clinical experience and critical evaluation of the role of sorafenib in renal cell carcinoma

“…33 Among 129 patients, confirmed partial response was observed in 16 patients (12.4%), stable disease was observed in sorafenib were progression free versus 6/33 in the placebo group (P = 0.008). An independent review of tumor response was undertaken in 152 patients, and the partial RR was 4% (8/202) (Figure 4).…”

“…The drug's pharmacokinetics has not been studied in patients with severe renal impairment (creatinine clearance ,30 mL/min) or in patients undergoing dialysis. [32][33][34] Steady state dosing of ketoconazole (400 mg), a potent inhibitor of CYP3A4, did not alter the mean AUC of an oral dose of sorafenib. Administration of sorafenib tablets did not alter the exposure of concomitantly given midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), or omeprazole (CYP2C19 substrate).…”