The Global Programme to Eliminate Lymphatic Filariasis: Health Impact after 8 Years

Lymphatic filariasis (LF) is a vector-borne, chronically disabling parasitic infection causing elephantiasis, lymphedema, and hydrocele. The infection is endemic in 83 countries worldwide, with more than 1.2 billion people at risk and 120 million already infected. Since 1998, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) has targeted elimination of LF by 2020. In its first 8 operational years, the program has scaled-up to provide more than 1.9 billion treatments through annual, single-dose mass drug administration (MDA) to ∼570 million individuals living in 48 LF-endemic countries. Not only do the GPELF drugs prevent the spread of LF, they also stop the progression of disease in those already infected. In addition, since two of the three drugs used for LF elimination have broad anti-parasite properties, treated populations are freed from both intestinal worms and from skin infections with onchocerca, lice, and scabies. To better understand the public health benefit of this ongoing global health initiative, we undertook an analysis of Programme data made available to WHO by participating countries. Our conservative estimates show that the GPELF has had an unprecedented public health impact on both LF and other neglected tropical diseases; it justly deserves the accolade of ‘a best buy’ in global health

A Phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR in advanced hepatocellular carcinoma (HCC)

This journal suppl. is Abstract Book of The International Liver Congress™ 2011Poster SessionBACKGROUND AND AIMS: Foretinib is an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR. HGF/MET signaling plays a pivotal role in tumour cell proliferation, migration and invasion, and circulating levels of HGF correlate with poor prognosis in HCC. This phase I/II trial (MET111645) is evaluating oral foretinib as first line therapy in advanced Asian HCC patients. METHODS: Patients with measurable unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0–1, adequate organ function and Child–Pugh grade A are eligible for enrolment. Phase I is a standard 3+3 design using increasing doses of oral foretinib to evaluate safety and determine the maximum tolerated dose (MTD). Secondary objectives include antitumour activity and pharmacokinetics. RESULTS: As of November 16, 2010, 13 patients have been enrolled: median age 57 years (range 31–78 years), M/F = 9/4. BCLC stage 0/A/B/C at screening: 0/0/3/10. Prior lines of therapy including local treatment: unknown/1/2/3/4: 1/3/5/2/1. Drug-related adverse events (AE) were reported in 10 patients (77%). The most common AEs were hypertension (54%), diarrhoea (31%), thrombocytopenia (23%), and peripheral oedema (23%). Serious treatment-emergent toxicities were reported in 54% of patients. Two dose-limiting toxicities (renal failure, proteinuria) were observed in 2/6 patients at 45mg OD but no DLTs were observed in 6 patients at 30mg OD. Nine patients were evaluable for response according to RECIST 1.0; 2 patients had a best response of partial response (PR); objective response rate (ORR) 22%. When tumour response was assessed according to modified RECIST criteria for HCC, 1 patient showed a complete response and 3 patients had a PR; ORR 44%. Exposure of 30- and 45-mg OD foretinib was overlapping and similar to higher doses in other tumour types. CONCLUSION: The foretinib MTD was determined to be 30mg OD. The early promising signal of activity observed in this phase I trial needs to be confirmed in phase II.The 46th Annual Meeting of the European Association for the Study of the Liver (International Liver Congress 2011), Berlin, Germany, 30 March-3 April 2011. In Journal of Hepatology, 2011, v. 54 suppl. 1, p. S268, abstract no. 66

A phase I/II study of Foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR in advanced hepatocellular carcinoma (HCC)

Background: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in Asian advanced-HCC patients. Methods: Asian patients with measurable, unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0-1, adequate organ function and Child-Pugh grade A were recruited. The phase I was a standard 3+3 dose escalation design with a phase II cohort expansion. The primary endpoint was safety and tolerability at the maximum tolerated dose (MTD) and the secondary endpoints included antitumor activity (objective response rate [ORR], disease stabilization rate [DSR; confirmed CR/PR or SD for at least 12 weeks], and time to progression [TTP] evaluated by central review according to modified RECIST), and overall survival (OS) at the MTD, plus pharmacokinetics (PK). Results: Thirteen patients were enrolled in phase I. Two dose-limiting toxicities (DLT) (renal failure, proteinuria) were observed at 45 mg once daily (QD) but no DLTs were observed at 30 mg QD. Thus, the MTD was determined to be 30 mg QD. A further 32 patients were enrolled at the MTD, for a study total of 39 patients treated at 30 mg QD. The most common AEs, independent of causality,were hypertension (36%), decreased appetite (23%), and pyrexia (21%). The most common SAEs were hepatic encephalopathy (10%) and ascites (8%). Two patients discontinued foretinib due to AEs. No dose reductions were reported. Thirty-eight patients were evaluable for efficacy. The ORR was 24% (95% CI 11-40), DSR 79% (95% CI; 63-90), and the median TTP was 4.2 months (95% CI 2.7-7.5). Mature OS data will be presented. Mean steady-state exposures (AUC/Cmax) were comparable after administration of foretinib at 30 and 45 mg. Conclusions: Foretinib has an acceptable safety, tolerability, and PK profile in an Asian HCC population. It has demonstrated promising antitumor activity that warrants further testing in a randomized setting

A phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR in advanced hepatocellular carcinoma (HCC)

This journal suppl. contain 2012 ASCO Meeting AbstractsOpen Access JournalBACKGROUND: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in …link_to_OA_fulltex