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A Phase I Trial of Bryostatin-1 in Children with Refractory Solid Tumors: A Pediatric Oncology Group Study

University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-3217 [S. W., A-M. L., P. J. T.]; University of Alabama, Birmingham, Alabama [R. L. B.]; Maine Children’s Cancer Program, Barbara Bush Children’s Hospital of the Maine Medical Center, Portland, Maine [C. A. H.]; University of Colorado Health Science Center, Denver, Colorado [A. S. K.]; SUNY-Health Science Center at Syracuse, Syracuse, New York [R. L. D.]; University of Kansas Medical Center, Kansas City, Kansas [D. L. S.]; and McGill University, Montreal, Quebec, Canada [M. B.]

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 µg/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 µg/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 µg/m²/dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.

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