A PHASE-I TRIAL OF BRYOSTATIN 1 IN PATIENTS WITH ADVANCED MALIGNANCY USING A 24-HOUR INTRAVENOUS-INFUSION

Bryostatin 1 is a macrocyclic lactone derived from the marine inverteb rate Bugula neritina. In vitro, bryostatin 1 activates protein kinase C (PKC), induces the differentiation of a number of cancer cell lineag es, exhibits anti-tumour activity and augments the response of haemopo ietic cells to certain growth factors. In vivo, bryostatin 1 is also i mmunomodulatory, but the range of tumours which respond to bryostatin 1 in xenograft tumour models is mostly the same as the in vitro tumour types, suggesting a direct mode of action. Nineteen patients with adv anced malignancy were entered into a phase I study in which bryostatin 1 was given as a 24 h intravenous infusion, weekly, for 8 weeks. Myal gia was the dose-limiting toxicity and the maximum tolerated dose was 25 mu g m(-2) per week. The myalgia was cumulative and dose related, a nd chiefly affected the thighs, calves and muscles of extraocular move ment. The mechanism of the myalgia is unknown. CTC grade 1 phlebitis a ffected every patient for at least one cycle and was caused by the dil uent, PET, which contains polyethylene glycol, ethanol and Tween 80. M ost patients experienced a 1 g dl(-1) decrease in haemoglobin within 1 h of commencing the infusion which was associated with a decrease in haematocrit. Radiolabelled red cell studies were performed in one pati ent to investigate the anaemia. The survival of radiolabelled red cell s during the week following treatment was the same as that seen in the week before treatment. However, there was a temporary accumulation of radiolabelled red cells in the liver during the first hour of treatme nt, suggesting that pooling of erythrocytes in the liver might account for the decrease in haematocrit. Total or activated PKC concentration s were measured in the peripheral blood mononuclear cells (PBMCs) of t hree patients for the first 4 h of treatment and during the last hour of the infusion. This showed that PKC activity was significantly modul ated during the infusion. Bryostatin 1 is immunomodulatory in vitro, a nd we have confirmed this activity in vivo. An investigation of the fi rst three cycles of treatment in seven patients showed an increased IL -2-induced proliferative response in peripheral blood lymphocytes and enhanced lymphokine activated killer (LAK) activity. A previously repo rted rise in serum levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF 1) was not confirmed in our study; of nine patients in this study, including patients at all dose levels, none showed an i ncrease in these cytokines. Responses were seen in four patients, incl uding two partial responses of 4 months' duration and two minor respon ses. The partial responses were seen in patients with ovarian carcinom a and low-grade non-Hodgkin's lymphoma (NHL). Two patients with ovaria n carcinoma, one with the partial response and the other with a minor response, were subsequently treated with tamoxifen, a PKC inhibitor, a nd the former had a partial response to tamoxifen of 14 months' durati on. The latter patient has clinically stable disease 10 months later. Bryostatin 1 is a novel anti-cancer agent which has shown clinical, bi ochemical and immunomodulatory activities in this phase I study. Phase II trials, in which bryostatin 1 is given as a 24 h infusion at 25 mu g m(-2) per week for 8 weeks, should be performed in ovarian carcinom a and low-grade NHL.