This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by El-Rayes, B. F. Articles by Philip, P. A. Search for Related Content PubMed PubMed Citation Articles by El-Rayes, B. F. Articles by Philip, P. A.

Phase I Study of Bryostatin 1 and Gemcitabine

Authors' Affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan

Requests for reprints: Basil F. El-Rayes, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI 48201. Phone: 313-576-8723; Fax: 313-576-8729; E-mail: elrayesb{at}karmanos.org.

Purpose: Bryostatin 1 is a macrocyclic lactone with protein kinase C inhibitory activity. Gemcitabine is a nucleotide analogue with a broad spectrum of anticancer activity. Bryostatin 1 enhanced the activity of antitumor agents including gemcitabine in preclinical models. The primary objective of this phase I study was to determine the recommended doses for phase II trials of bryostatin 1 and gemcitabine.

Experimental Design: Eligible patients had histologic or cytologic diagnosis of nonhematologic cancer refractory to conventional treatment; life expectancy of >3 months; normal renal, hepatic, and bone marrow function; and a Southwest Oncology Group performance status of 0 to 2. Gemcitabine was administered i.v. over 30 minutes and was followed by bryostatin 1 by i.v. infusion over 24 hours on days 1, 8, and 15 of a 28-day cycle. Bryostatin 1 (µg/m²) and gemcitabine (mg/m²) doses were escalated as follows: 25/600, 25/800, 25/1,000, 30/1,000, 35/1,000, and 45/1,000, respectively.

Results: Thirty-six patients (mean age, 57 years; male/female 15:21) were treated. The median number of treatment cycles per patient was 3 (range, 0-24). Four patients developed dose limiting toxicities: myalgia, 2; myelosuppression, 1; and elevation of serum alanine aminotransferase levels, 1. Ten grade 3 toxicities were observed (anemia, 2; neutropenia, 5; thrombocytopenia, 3). No treatment-related death was seen. The recommended doses for phase II trials for bryostatin 1 and gemcitabine were 35 µg/m² and 1,000 mg/m², respectively. Two heavily pretreated patients with breast and colon cancer experienced partial responses lasting 22 and 8 months, respectively. Eight patients had stable disease.

Conclusion: The combination of bryostatin 1 and gemcitabine seemed to be well tolerated with limited grade 3 toxicity. The recommended dose of bryostatin 1 in combination with full doses of gemcitabine was 35 µg/m².