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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2009

01-09-2009 | Original Article

Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors

Authors: Anna C. Pavlick, Jennifer Wu, John Roberts, Mark A. Rosenthal, Anne Hamilton, Scott Wadler, Kathleen Farrell, Michelle Carr, David Fry, Anthony J. Murgo, Ruth Oratz, Howard Hochster, Leonard Liebes, Franco Muggia

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2009

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Abstract

Purpose

Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence.

Methods

Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50  and 75 mg/m2; the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles.

Results

Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m2 its recommended phase II dose was 30 μg/m2. In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo’s erratic extraction. Consistent inhibition of PKC isoform eta (η) in peripheral blood mononuclear cells was observed following bryo.

Conclusions

Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved.
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Metadata
Title
Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors
Authors
Anna C. Pavlick
Jennifer Wu
John Roberts
Mark A. Rosenthal
Anne Hamilton
Scott Wadler
Kathleen Farrell
Michelle Carr
David Fry
Anthony J. Murgo
Ruth Oratz
Howard Hochster
Leonard Liebes
Franco Muggia
Publication date
01-09-2009
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-009-0931-y

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