Drug preparation and dose escalation
toxicity, toxicities
OVARY, STERILE
hrBMP4 was purified from a working cell bank of CHO (Chinese Hamster Ovary) DGG cells (GEQA1058-2 cell line), producing hrBMP4 via a proprietary expression vector (pPGIX) by IBI Lorenzini (Aprilia; Italy). GMP certification for human use was obtained by AIFA (Authorization aM-188/2015). The study drug solution was prepared by dissolving hrBMP4 in sterile saline (NaCl 0·9%) up to a volume of 44–66 ml. Gadobutrol 1·0 mM was added to determine the study drug distribution in MRI scans. Increasing hrBMP4 doses were infused in five cohorts of three patients, from 0·5 to 18 mg from the first to the last cohort. The total volume was infused via CED catheters over 4 or 6 days (11 ml/day; 6 days for the 18 mg dose) with flow rates between 2·55 and 7·6 µL/minute, depending on dose level and number of catheters. If toxicity was observed in one out of three patients in a dose level, the other three patients would be treated with the same dose. In the absence of new toxicities, the next dose level would be assessed; if another toxicity occurred, the dose below would deemed to be the maximum tolerated dose (MTD).