A phase I trial of bryostatin-1 in children with refractory solid tumors: A pediatric oncology group study

Bryostatin-1, a macrocyclic lactone, appears to elicit a wide range of biol ogical responses including modulation of protein kinase C (PKC), PKC, one o f the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor pro motion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase I trial of bryostatin-1 was performed in children wi th solid tumors to: (a) establish the dose-limiting toxicity (DLT) and maxi mum-tolerated dose (MTD); (b) establish the pharmacokinetic profile in chil dren; and (c) document any evidence of antitumor activity. A 1-h infusion of bryostatin-1 in a PET formulation (60% polyethylene glyco l 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks t o 22 children (age range, 2-21 Sears) with malignant solid tumors refractor y to conventional therapy. Doses ranged from 20 to 57 mu g/m(2)/ dose. Phar macokinetics were performed in at least three patients per dose level, The first course was used to determine the DLT and MTD. Twenty-two patients on five dose levels were evaluable for toxicities. At t he 57 mu g/m(2)/dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye p ain, and one experienced headache. Symptoms occurred in all patients within 24-72 h after the second dose of bryostatin-1 with resolution within 1 wee k of onset. Other observed toxicities (grades 1 and 2) included elevation i n liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The bryostatin-l infusion was typically well tolerated. Although stable disease was noted in several patients, no complete or partial responses were obser ved. The recommended Phase II dose of bryostatin-1 administered as a 1-h infusio n weekly for 3 of every 4 weeks to children with solid tumors is 44 mu g/m( 2)/dose, Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.