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01-04-2013 | Original Article

Pharmacodynamic stimulation of thrombogenesis by angiotensin (1–7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy

Authors: Huyen Pham, Benjamin M. Schwartz, James E. Delmore, Eddie Reed, Scott Cruickshank, Leanne Drummond, Kathleen E. Rodgers, Kainoa J. Peterson, Gere S. diZerega

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2013

Abstract

Purpose

This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1–7) for reduction in Grade 3–4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1–7) in platelet production and retention of scheduled dose intensity were also determined.

Methods

Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated. Patients were randomized to receive study drug subcutaneously at 100 mcg/kg (n = 11), 300 mcg/kg (n = 13), or placebo (n = 10) following chemotherapy for up to six cycles. Hematologic variables were obtained throughout each treatment cycle.

Results

There were no drug-related safety issues. There were no instances of Grade 4 thrombocytopenia in patients who received 100 mcg/kg treatment compared to 6 % of chemotherapy cycles for patients receiving placebo (p = 0.07). The maximal percentage increase in platelet concentration from baseline was higher for patients who received 100 mcg/kg A(1–7) compared to placebo (p = 0.02). This increase was accompanied by a reduction in the nadir absolute neutrophil count (p = 0.04). Relative dose intensity for the combination chemotherapy was higher for patients who received 100 mcg/kg A(1–7) compared to placebo (p = 0.04). There were no differences in outcomes for patients receiving 300 mcg/kg dose compared to placebo.

Conclusions

A 100 mcg/kg dose of A(1–7) was shown to produce pharmacodynamic effects on peripheral blood platelet counts, preserve planned dose intensity, and reduce Grade 3–4 thrombocytopenia following gemcitabine and platinum chemotherapy. These findings are consistent with A(1–7)-induced stimulation of thrombogenesis in the bone marrow following marrow-toxic chemotherapy.

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Title: Pharmacodynamic stimulation of thrombogenesis by angiotensin (1–7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy
Authors: Huyen Pham
Benjamin M. Schwartz
James E. Delmore
Eddie Reed
Scott Cruickshank
Leanne Drummond
Kathleen E. Rodgers
Kainoa J. Peterson
Gere S. diZerega
Publication date: 01-04-2013
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2089-x

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