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A Phase I trial of bryostatin-1 in children with refractory solid tumors: a Pediatric Oncology Group study
S Weitman1, A M Langevin, R L Berkow
1University of Texas Health Science Center at San Antonio 78284-3217, USA.
Abstract:
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.
Insights
Bryostatin-1, a novel cancer drug, showed potential in children with solid tumors. The recommended Phase II dose is 44 microg/m2, with dose-limiting toxicities including myalgia and photophobia.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Bryostatin-1 modulates protein kinase C (PKC), a key regulator of cell growth and differentiation.
- PKC plays a role in tumor promotion, making bryostatin-1 a potential anti-cancer agent.
- Solid tumors in children often become refractory to conventional therapies, necessitating novel treatment approaches.
Purpose of the Study:
- To determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of bryostatin-1 in pediatric patients.
- To characterize the pharmacokinetic profile of bryostatin-1 in children.
- To assess any evidence of antitumor activity in children with refractory solid tumors.
Main Methods:
- A Phase I clinical trial administered bryostatin-1 via a 1-hour infusion weekly for 3 weeks to 22 children (ages 2-21) with refractory malignant solid tumors.
- Doses ranged from 20 to 57 microg/m2, with pharmacokinetic assessments in at least three patients per dose level.
- Toxicity and antitumor activity were evaluated to establish the DLT, MTD, and recommended Phase II dose.
Main Results:
- The maximum-tolerated dose was determined to be 57 microg/m2, with dose-limiting toxicities including grade 3 myalgia, photophobia, eye pain, and headache.
- The recommended Phase II dose for pediatric solid tumors is 44 microg/m2 administered weekly for 3 of every 4 weeks.
- While stable disease was observed in some patients, no complete or partial responses were documented.
Conclusions:
- Bryostatin-1 can be administered safely in children with solid tumors at a recommended Phase II dose of 44 microg/m2.
- Myalgia and photophobia were identified as the primary dose-limiting toxicities.
- Further investigation is warranted to explore the potential antitumor efficacy of bryostatin-1 in pediatric oncology.