A PHASE-I STUDY OF INTRAVENOUS BRYOSTATIN-1 IN PATIENTS WITH ADVANCEDCANCER

Bryostatin 1 is a novel antitumour agent derived from Bugula neritina of the marine phylum Ectoprocta. Nineteen patients with advanced solid tumours were entered into a phase I study to evaluate the toxicity an d biological effects of bryostatin 1. Bryostatin 1 was given as a one hour intravenous infusion at the beginning of each 2 week treatment cy cle. A maximum of three treatment cycles were given. Doses were escala ted in steps from 5 to 65 mug m-2 in successive patient groups. The ma ximum tolerated dose was 50 mug m-2. Myalgia was the dose limiting tox icity and was of WHO grade 3 in all three patients treated at 65 mug m -2. Flu-like symptoms were common but were of maximum WHO grade 2. Hyp otension, of maximum WHO grade 1, occurred in six patients treated at doses up to and including 20 mug M-2 and may not have been attributabl e to treatment with bryostatin 1. Cellulitis and thrombophlebitis occu rred at the bryostatin 1 infusion site of patients treated at all dose levels up to 50 mug m-2, attributable to the 60% ethanol diluent in t he bryostatin 1 infusion. Subsequent patients treated at 50 and 65 mug m-2 received treatment with an intravenous normal saline flush and th ey did not develop these complications. Significant decreases of the p latelet count and total leucocyte, neutrophil and lymphocyte counts we re seen in the first 24 h after treatment at the dose of 65 mug m-2. I mmediate decreases in haemoglobin of up to 1.9g dl-1 were also noted i n patients treated with 65 mug m-2, in the absence of clinical evidenc e of bleeding or haemodynamic compromise. No effect was observed on th e incidence of haemopoietic progenitor cells in the marrow. Some patie nts' neutrophils demonstrated enhanced superoxide radical formation in response to in vitro stimulation with opsonised zymosan (a bacterial polysaccharide) but in the absence of this additional stimulus, no bry ostatin 1 effect was observed. Lymphocyte natural killing activity was decreased 2 h after treatment with bryostatin 1, but the effect was n ot consistently seen 24 h or 7 days later. With the dose schedule exam ined no antitumour effects were observed. We recommend that bryostatin 1 is used at a dose of 35 to 50 mug m -2 two weekly in phase II studi es in patients with malignancies including lymphoma, leukaemia, melano ma or hypernephroma, for which pre-clinical investigations suggest ant itumour activity.