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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 Antagonist¹

Imperial Cancer Research Fund Medical Oncology Unit [S. C., A. M., A. Y., B. B., J. F. S., D. I. J.] and Clinical Pharmacology Unit and Research Centre, University of Edinburgh [D. J. W.], Western General Hospital, Edinburgh EH4 2XU, and Drug Development Office, Cancer Research Campaign, London NW1 4JL [L. R.], United Kingdom

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 µM 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 dose-escalation strategy until the target maximum plasma concentration (C_max) of 10 µM was achieved. In stage 2, dose intensity was increased to weekly, and the inhibitory effect of i.v. Antagonist G was assessed by forearm blood flow (FBF) using SP as a vasodilator, as measured by venous plethysmography.

Results: In stage 1, dose was escalated from 2 to 300 mg/m² in 12 dose levels using only 15 patients. In stage 2, nine patients were entered at three dose levels (300, 350, and 400 mg/m²) and a C_max of 45 µM was achieved. Facial flushing was the only consistent toxicity but was not dose limiting. FBF studies demonstrated that Antagonist G consistently inhibited the vasodilatory effects of SP (mean, 62 ± 2% inhibition).

Conclusions: Antagonist G can be safely administered up to 400 mg/m², achieving C_maxs >20 µM by weekly 6-h i.v. infusion. FBF studies in patients demonstrated that Antagonist G inhibits SP vasodilatory effects in vivo at these doses in the absence of dose-limiting toxicity.

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