TY - JOUR
T1 - Evaluation of lapatinib and topotecan combination therapy
T2 - Tissue culture, murine xenograft, and phase i clinical trial data
AU - Molina, Julian R.
AU - Kaufmann, Scott H.
AU - Reid, Joel M.
AU - Rubin, Stephen D.
AU - Gálvez-Peralta, Marina
AU - Friedman, Robert
AU - Flatten, Karen S.
AU - Koch, Kevin M.
AU - Gilmer, Tona M.
AU - Mullin, Robert J.
AU - Jewell, Roxanne C.
AU - Felten, Sara J.
AU - Mandrekar, Sumithra
AU - Adjei, Alex A.
AU - Erlichman, Charles
PY - 2008/12/1
Y1 - 2008/12/1
N2 - Purpose: Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial. Experimental Design: The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2 + BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial. Results: Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2 + BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21 or 28 days with 3.2 mg/m 2 topotecan i.v. on days 1,8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization. Conclusions: The lapatinib/topotecan combination is well tolerated and warrants further study.
AB - Purpose: Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial. Experimental Design: The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2 + BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial. Results: Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2 + BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21 or 28 days with 3.2 mg/m 2 topotecan i.v. on days 1,8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization. Conclusions: The lapatinib/topotecan combination is well tolerated and warrants further study.
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U2 - 10.1158/1078-0432.CCR-08-0415
DO - 10.1158/1078-0432.CCR-08-0415
M3 - Article
C2 - 19047120
AN - SCOPUS:59449088659
SN - 1078-0432
VL - 14
SP - 7900
EP - 7908
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -