In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 2591-2591
Abstract:
2591 Background: A phenotypic probe is a test that can be administered to a patient as a potential indicator of a drug’s PK/PD which can then be used to individualize therapy. Since nanoparticles are cleared via the MPS, including blood monocytes (MO), we hypothesize that circulating MO could potentially play a major role in, and be a surrogate marker of nanoparticle clearance (CL). Furthermore, we postulate that the ability to measure MO functional activity in blood samples can be used to predict CL and subsequently PD endpoints such as progression free survival (PFS) and hand-foot syndrome (HFS), in patients (pt). Methods: PLD 30/40 mg/m 2 IV x 1 with or without carboplatin (AUC = 5 mg/mL/min) was administered to pts (n=10) with recurrent ovarian cancer. Serial PK samples were obtained at time 0 to day 28 post dose. Plasma was processed to measure encapsulated and released doxorubicin using solid phase separation and HPLC. Data was analyzed with WinNonlin to obtain PK parameters. MO and granulocyte phagocytic function (uptake of FITC-labeled opsonized E. Coli) and oxidative burst activity (intracellular oxidation of dihydrorhodamine 123) were assessed via flow cytometry at 0, 48, 96 h, and on day 28. For both assays, changes in mean fluorescence intensity of the gated MO population, following incubation of whole blood with the appropriate substrate, served as an index of activity. Pts were followed from the first dose of PLD until time of disease progression. Results: There was a direct linear relationship between encapsulated doxorubicin CL and both phagocytosis (R 2 = 0.87) and oxidative burst activity (R 2 = 0.64) in blood MO. Similarly, phagocytosis (R 2 = 0.77) and oxidative burst probes correlated with PFS (R 2 = 0.67) in the 4 pts who progressed while on PLD. Oxidative burst also correlated with degree of HFS (R 2 = 0.56). There was no relationship between phagocytosis and oxidative burst in granulocytes and PK/PD of PLD. Conclusions: These findings indicate that probes of MPS function predict PLD CL, HFS and PFS and thus may be useful for individualizing PLD therapy in ovarian cancer and other malignancies.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.2591
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
