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

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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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Acknowledgment

The authors thank John Roboz for the GC/MS.

Author information

Authors and Affiliations

  1. New York University School of Medicine, New York University Cancer Institute, New York, NY, USA

    Anna C. Pavlick, Jennifer Wu, Mark A. Rosenthal, Anne Hamilton, Kathleen Farrell, Michelle Carr, David Fry, Ruth Oratz, Howard Hochster, Leonard Liebes & Franco Muggia

  2. Montefiore Medical Center, Bronx, NY, USA

    Scott Wadler

  3. Massey Cancer Center, Richmond, VA, USA

    John Roberts

  4. Cancer Therapy Evaluation Program, NCI, Bethesda, MD, USA

    Anthony J. Murgo

Authors
  1. Anna C. Pavlick
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  2. Jennifer Wu
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  8. Michelle Carr
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  11. Ruth Oratz
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  12. Howard Hochster
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  13. Leonard Liebes
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  14. Franco Muggia
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Corresponding author

Correspondence to Franco Muggia.

Additional information

The work was supported by U01 CA76642, P30 CA 16087 and GCRC MO1 RR00096.

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Pavlick, A.C., Wu, J., Roberts, J. et al. Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors. Cancer Chemother Pharmacol 64, 803–810 (2009). https://doi.org/10.1007/s00280-009-0931-y

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  • DOI: https://doi.org/10.1007/s00280-009-0931-y

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