Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy.
OBJECTIVE
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.
Livingston Laboratory, Keck School of Medicine at USC, 1321 N Mission Rd, Los Angeles, CA 90033, USA.
Huyen
H
Pham
Benjamin M
BM
Schwartz
James E
JE
Delmore
Eddie
E
Reed
Scott
S
Cruickshank
Leanne
L
Drummond
Kathleen E
KE
Rodgers
Kainoa J
KJ
Peterson
Gere S
GS
diZerega
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000803:Angiotensin I / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010446:Peptide Fragments / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000517:prevention & control*; D000093542:Gemcitabine
D010446:Peptide Fragments; D003841:Deoxycytidine; D000803:Angiotensin I; D016190:Carboplatin; C118790:angiotensin I (1-7); D002945:Cisplatin; D000093542:Gemcitabine