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

作者：Huyen Pham; Schwartz Benjamin M; Delmore James E; Reed Eddie; Cruickshank Scott; Drummond Leanne; Rodgers Kathleen E; Peterson Kainoa J; diZerega Gere S^*

来源：Cancer Chemotherapy and Pharmacology, 2013, 71(4): 965-972.

DOI：10.1007/s00280-013-2089-x

• A(1-7)
• Gemcitabine
• Carboplatin
• Cisplatin
• Thrombocytopenia
• Thrombocytosis

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.
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.
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.
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.

• 出版日期2013-4