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Safety and pharmacokinetic (PK) study of perifosine plus capecitabine (P-CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC)
Abstract   Open access   Peer reviewed

Safety and pharmacokinetic (PK) study of perifosine plus capecitabine (P-CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC)

F. A. Greco, J. R. Infante, H. A. Burris, S. F. Jones, J. Kolesar, L. R. Gardner, P. Sportelli and J. C. Bendell
Journal of clinical oncology, Vol.28(15_suppl), pp.e14086-e14086
05/20/2010
DOI: 10.1200/jco.2010.28.15_suppl.e14086
url
https://doi.org/10.1200/jco.2010.28.15_suppl.e14086View
Published (Version of record) Open Access

Abstract

Abstract only Background: Perifosine (P), a synthetic alkylphospholipid, inhibits or modifies multiple signal transduction pathways, including AKT, MAPK and JNK. A small randomized phase II study of P 50 mg PO QD d1-21 + CAP 825 mg/m2 PO BID d1-14 (P-CAP) vs. placebo + CAP 825 mg/m2 PO BID d1-14 in pts with advanced mCRC showed improved TTP and OS of P-CAP vs. placebo + CAP. A more commonly used dose of CAP in the U.S. is 1,000 mg/m2 PO BID. This study evaluated the safety and PK of P 50 mg PO QD d1-21 + CAP 1,000 mg/m2 BID d1-14. Methods: Pts with refractory mCRC received P 50 mg PO QD d 1-21 + CAP 1,000 mg/m2 BID d1- 14. Pts were enrolled in a 3+3 fashion, with a total of 9 patients treated if the dose was tolerated for further safety and PK data. PK of P and CAP were evaluated C1D1 and C1D11 (steady-state). Plasma concentrations were evaluated by a validated LCMS assay with PK parameters determined with Win Non Lin version 5.2. Results: 10 pts were enrolled. Median age 65 (54-72); 70% female. Median prior Rx = 3 (2-4). Prior Rx: FOLFOX (100%); FOLFIRI (100%); bevacizumab (100%); EGFR antibody (60%); progressed on prior 5-FU-based Rx (100%). 9 pts were evaluable for DLT; no DLTs were observed. 1 pt was inevaluable after stopping study drug after 2d for non-related AE. G 3/4 AE's ≥ 10%: dyspnea (10%), rash (10%), hyperkalemia (10%) and abdominal pain (10%). Perifosine PK results show a mean half-life of 5.66 ± 4.06 hours, Cmax of 2.66 ug/mL, AUC(0- 8) (C1D1) of 9.73 hr*ug/mL, CL of 5.66 mL/hr and a V of 26.5 L. Steady state AUC(0-8) was 21.8 hr*ug/mL. These data are consistent with single agent perifosine PK data, suggesting no perifosine PK change with the addition of capecitabine. Capecitabine PK evaluation is underway. As of Jan 2010, 3/10 pts have had one response assessment (9 wk scan). One pt had a 13% decrease in disease, and 1 pt had SD. 7/10 pts remain on study treatment. Conclusions: P 50 mg PO QD d1-21 + CAP 1,000 mg/m2 PO BID d 1-14 is a well-tolerated regimen for pts with mCRC. Updated PK, safety and efficacy results will be presented. A randomized phase III trial of P-CAP vs. placebo + CAP is planned for refractory colorectal cancer pts.

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