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

• Published in: Clinical cancer research Vol. 5; no. 9; pp. 2344 - 2348
• Main Authors: WEITMAN, S, LANGEVIN, A.-M, BERKOW, R. L, THOMAS, P. J, HURWITZ, C. A, KRAFT, A. S, DUBOWY, R. L, SMITH, D. L, BERNSTEIN, M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.1999
• Subjects: Adolescent; Adult; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Bryostatins; Chemotherapy; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Lactones - adverse effects; Lactones - pharmacokinetics; Lactones - therapeutic use; Macrolides; Male; Medical sciences; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Thrombocytopenia - chemically induced; Human; Antineoplastic agent; Solid tumor; Intravenous administration; Toxicity; Lactone; Malignant tumor; Biological activity; Macrocycle; Chemotherapy; Limit dose; Treatment; Phase I trial; Pharmacokinetics; Child
• ISSN: 1078-0432; 1557-3265

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/m 2 /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/m 2 /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/m 2 /dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.