Intravenous ghrelin for cancer-related anorexia/cachexia: A randomized, placebo-controlled, double-blind, double cross-over phase I/II study

Abstract

8619 Background: Ghrelin is a natural hormone with stimulatory effects on appetite and body weight. We assessed safety, tolerability, pharmacokinetics, and preliminary efficacy of intravenous ghrelin in patients (pts) with cancer-related anorexia/cachexia. Methods: In a cross-over study 21 pts (median age 68 [44, 79]) were randomized for ghrelin (Merck Biosciences, Switzerland) given over 60 min before lunch or placebo on d1 and d8, or d4 and d11. Ten pts received low dose ghrelin (LD) 2mcg/kg, 11 pts high dose ghrelin (HD) 8mcg/kg. Safety and tolerability were assessed using CTC-Toxicity Criteria, cardiac examination, tumour measurement, and IGF-1. Pts preference for ghrelin or placebo was assessed at d8 and d17/18. Nutritional intake of lunch at treatment days (NIL) was measured in the hospital and thereafter daily by pts. Eating-related symptoms and blood levels of hormones were monitored during treatment days. Results: Adverse events possible or probable related to study drug, including 1 SAE (apoplectiform deafness, placebo), did not differ between ghrelin and placebo in pts on LD (7 vs. 14) and HD (19 vs. 13). Of 8 pts with SD at study entry, 1 had PD, 1 dropped out, and 6 pts remained SD during study. Of 12 pts with PD at study entry, 1 remained PD, 10 were SD, and 1 dropped out. 1 pat with PR at study entry had SD. Ghrelin treatment was preferred at d8 by 8/10 pts of LD and 9/11 of HD, and at d17/18 by 6/9 pts of LD and 6/10 of HD. Variability of nutritional intake and eating-related symptoms were high. They did overall not statistically differ between ghrelin (LD, HD) and placebo. At study start NIL was 642 kcal (SD 284) for LD and 424 (196) for HD. Weight remained unchanged. Total ghrelin levels were higher (p<0.05) for HD at d17/18 (3580pg/ml) than study start (990), not for LD (950/1000). Active ghrelin, GH, or IGF-1 did not increase at d17/18 compared to study start. Conclusions: Ghrelin is well tolerated and safe in pts with far advanced cancer and anorexia/cachexia. More patients preferred ghrelin than placebo, without significant changes in nutritional intake or symptoms. Higher levels of total ghrelin at study end may suggest carry-over effects. Further research will explore schedule and dose modifications and mechanisms of ghrelin resistance. [Table: see text]