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 biological responses including modulation of protein kinase C (PKC). PKC, one of the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor promotion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase I trial of bryostatin-1 was performed in children with solid tumors to: (a) establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); (b) establish the pharmacokinetic profile in children; and (c) document any evidence of antitumor activity. A 1-h infusion of bryostatin-1 in a PET formulation (60% polyethylene glycol 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks to 22 children (age range, 2-21 years) with malignant solid tumors refractory to conventional therapy. Doses ranged from 20 to 57 microg/m2/ dose. Pharmacokinetics 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 the 57 microg/m2/dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye pain, and one experienced headache. Symptoms occurred in all patients within 24-72 h after the second dose of bryostatin-1 with resolution within 1 week of onset. Other observed toxicities (grades 1 and 2) included elevation in liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The bryostatin-1 infusion was typically well tolerated. Although stable disease was noted in several patients, no complete or partial responses were observed. The recommended Phase II dose of bryostatin-1 administered as a 1-h infusion weekly for 3 of every 4 weeks to children with solid tumors is 44 microg/m2/dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.
Weitman
S
S
University of Texas Health Science Center at San Antonio 78284-3217, USA.
Langevin
A M
AM
Berkow
R L
RL
Thomas
P J
PJ
Hurwitz
C A
CA
Kraft
A S
AS
Dubowy
R L
RL
Smith
D L
DL
Bernstein
M
M
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054713:Bryostatins; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007783:Lactones / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018942:Macrolides; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013921:Thrombocytopenia / Q000139:chemically induced
D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1