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Phase I Study of Bryostatin 1 and Fludarabine in Patients with Chronic Lymphocytic Leukemia and Indolent (Non-Hodgkin's) Lymphoma

Authors' Affiliations: ¹ Massey Cancer Center and the Departments of ² Internal Medicine, ³ Microbiology and Immunology, ⁴ Pharmacology and Toxicology, and ⁵ Biostatistics, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia; ⁶ Fox Chase Cancer Center, Department of Medical Oncology, Philadelphia, Pennsylvania; ⁷ Weill Medical College of Cornell University, New York, New York; ⁸ Mercy Cancer Center, Mason City, Iowa; ⁹ Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Steven Grant, Virginia Commonwealth University, P.O. Box 980230, Richmond, VA 23298-0230. Phone: 804-828-5211; Fax: 804-828-2174; E-mail: stgrant{at}vcu.edu.

Purpose: Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase II studies.

Experimental Design: Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events.

Results: Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m²/d x 5). The recommended bryostatin 1 phase II dose is 50 µg/m² for both sequences, bryostatin 1 fludarabine and fludarabine bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells.

Conclusions: Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration.