Forearm blood flow and local responses to peptide vasodilators: A novel pharmacodynamic measure in the phase I trial of antagonist G, a neuropeptide growth factor antagonist

Purpose: Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH2, (Antagonist G), a substance P (SP 6-11) analogue, inhibits mitogenesis stimulated by a broad spectrum of neuropeptides and has demonstrated antitumor activity in vitro, and in vivo with IC50 concentrations of 10-20 muM in small cell lung cancer and other cell lines. Because neuropeptides are part of complex neurohumoral pathways , we have sought to develop novel pharmacodynamic approaches as part of the early clinical development of this potential anticancer drug. Experimental design: A Phase I trial was performed in two stages. In stage 1, Antagonist G was administered at 3-week intervals using an accelerated d ose-escalation strategy until the target maximum plasma concentration (C-ma x) of 10 muM was achieved. In stage 2, dose intensity was increased to week ly, and the inhibitory effect of Lv. Antagonist G was assessed by forearm b lood flow (FBF) using SP as a vasodilator, as measured by venous pletbysmog raphy. Results: In stage 1, dose was escalated from 2 to 300 mg/m(2) in 12 dose le vels using only 15 patients. In stage 2, nine patients were entered at thre e dose levels (300,350, and 400 mg/m(2)) and a C-max of 45 muM was achieved . Facial flushing was the only consistent toxicity but was not dose limitin g. FBF studies demonstrated that Antagonist G consistently inhibited the va sodilatory effects of SP (mean, 62 +/- 2% inhibition). Conclusions: Antagonist G can be safely administered up to 400 mg/m(2), ach ieving C(max)s > 20 muM by weekly 6-h i.v. infusion. FBF studies in patient s demonstrated that Antagonist G inhibits SP vasodilatory effects in vivo a t these doses in the absence of dose-limiting toxicity.