A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan

Midgley, Rachel; Kerr, David J.; Flaherty, Keith T.; Stevenson, James P.; Pratap, Sarah; Koch, Kevin M.; Smith, Deborah A.; Versola, M.; Fleming, Ronald A.; Ward, Cynthia R.; O’Dwyer, Peter J.; Middleton, Mark R.

doi:10.1093/annonc/mdm366

Cited by 46 publications

(29 citation statements)

References 4 publications

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“…Despite the small numbers this trial compares favourably with historical response rates for 5-FU/irinotecan combinations in second-line treatment of advanced colorectal cancer (disease control rate 34%). The results suggest further study in a phase II trial [11].…”

Section: Clinical Trialsmentioning

confidence: 74%

Lapatinib: A Sword With Two Edges

Kopper

2008

Pathol. Oncol. Res.

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Lapatinib is an oral dual tyrosine kinase inhibitor targeting EGFR1 and EGFR2 (HER2). Phase I trials have shown that lapatinib is well tolerated, with mild diarrhea and skin rush as common adverse effects, and low cardiotoxicity. Phase II and III trials provided evidences on clinical effectiveness in advanced or metastatic breast cancer and potential against brain metastases. Lapatinib is active in combination with trastuzumab and in trastuzumab-resistant patients, moreover it has synergistic action with capecitabine. Several clinical trials are in progress to explore the effectiveness of lapatinib in other combinations and against several tumor types.

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Section: Clinical Trialsmentioning

confidence: 74%

Lapatinib: A Sword With Two Edges

Kopper

2008

Pathol. Oncol. Res.

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“…This is evident from phase I clinical data investigating lapatinib and irinotecan (SN-38 is the active metabolite of irinotecan) in combination, which showed that lapatinib significantly altered the pharmacokinetics of SN-38, with an increase in the area under the plasma concentration-time curve of SN-38 for the combination (26). The data presented here therefore have clinical implications, particularly as drug combinations are being given in large randomized studies, whereas unacceptable toxicity has been noted with other combinations (27,28).…”

Section: Discussionmentioning

confidence: 98%

A Synergistic Interaction between Lapatinib and Chemotherapy Agents in a Panel of Cell Lines Is Due to the Inhibition of the Efflux Pump BCRP

Perry

Ghazaly

Kitromilidou

et al. 2010

Molecular Cancer Therapeutics

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Lapatinib is a specific HER1 and 2 targeted tyrosine kinase inhibitor now widely used in combination with chemotherapy in the clinical setting. In this work, we investigated the interactions between lapatinib and specific chemotherapy agents (cisplatin, SN-38, topotecan) in a panel of cell lines [breast (n ¼ 2), lung (n ¼ 2), testis (n ¼ 4)]. A high-sensitivity cell proliferation/cytotoxicity ATP assay and flow cytometry were used to determine cell viability, apoptosis, and the effect of the drugs on cell-cycle distribution. CalcuSyn analysis was employed to formally identify synergistic interactions between drugs. Intracellular concentrations of SN-38 were measured using a novel high-performance liquid chromatography (HPLC) technique. Flow cytometry and HPLC techniques were used to identify the effect of lapatinib on drug influx and efflux pumps, using specific substrates and inhibitors of these pumps. Results showed significant synergy between SN-38, and lapatinib in the majority of cell lines (combination index < 0.75), associated with increased apoptosis. This synergy was not universal but, when observed (Susa S/R, H1975, H358, and MDA-MB-231 cell lines), was related to SN-38 intracellular accumulation (2.2-to 4.8-fold increase, P < 0.05 for each), attributable to the inhibition of the breast cancer-related protein (BCRP) efflux pump by lapatinib. Flow cytometry analysis showed that lapatinib (10 mmol/L) inhibited the efflux of mitoxantrone, a specific substrate of the BCRP pump, in a manner similar to fumitremorgin C, a known BCRP inhibitor, confirming lapatinib as a BCRP inhibitor. This work shows that lapatinib has a direct inhibitory effect on BCRP accounting for the synergistic findings. The synergy is cell line dependent and related to the activity of specific efflux pumps. Mol Cancer Ther; 9(12); 3322-9. Ó2010 AACR.

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“…Investigators have added lapatinib to chemotherapeutic agents such as paclitaxel (36), docetaxel (37), capecitabine (38), letrozole (39), and to combination regimens such as FOLFOX (40) and FOLFOX (41), with promising results. Although clinical trials in different tumor types are ongoing, the most mature data thus far have been in the treatment of breast cancer, particularly in trastuzumab-resistant patients (37).…”

Section: Discussionmentioning

confidence: 99%

Dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition exerts synergistic effect with conventional chemotherapy in pancreatic cancer

2012

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Abstract. Patient survival in pancreatic cancer remains poor with gemcitabine (GEM)-based regimens. The target specific molecular agent lapatinib, a dual ErbB1 and ErbB2 receptor tyrosine kinase inhibitor, has shown significant activity against ErbB1 and ErbB2-expressing tumors. Since pancreatic tumors frequently overexpress these proteins, we investigated its effects, both alone and in conjunction with 5-FU or GEM. The pancreatic cancer cell lines PANC-1 and AsPC were treated with varying doses of lapatinib in vitro. The effects on ErbB1/ ErbB2 protein phosphorylation and on the cell survival protein survivin were determined by western blotting. Cytotoxicity was determined by MTT assay and apoptosis was measured using the caspase-3 colorimetric assay. Similar dose-response lapatinib experiments were conducted with varying concentrations of 5-FU or GEM and isobolograms were constructed to evaluate therapeutic synergy. Lapatinib inhibited protein phosphorylation in the range of 4-16 µM, a clinically achievable concentration. The lapatinib-treated cells showed a dose-dependent inhibition of cell proliferation and induction of apoptosis at the same concentrations that blocked ErbB1/ ErbB2 phosphorylation. The addition of 5-FU or GEM to these cells resulted in synergistic effects. The lapatinib-treated cells also demonstrated downregulation of survivin. Simultaneous dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition with lapatinib results in significant reduction of pancreatic cancer cell growth and proliferation. These effects occur at clinically achievable concentrations and are synergistic with the effects of 5-FU or GEM. These findings support the potential role of lapatinib in the treatment of pancreatic cancer.

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A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan

Abstract: The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.

Cited by 46 publications

References 4 publications

Lapatinib: A Sword With Two Edges

Lapatinib: A Sword With Two Edges

A Synergistic Interaction between Lapatinib and Chemotherapy Agents in a Panel of Cell Lines Is Due to the Inhibition of the Efflux Pump BCRP

Dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition exerts synergistic effect with conventional chemotherapy in pancreatic cancer

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