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Phase I and Pharmacokinetic Study of Lapatinib and Docetaxel in Patients With Advanced Cancer

Patricia M. LoRusso, Suzanne F. Jones, Kevin M. Koch, Nikita Arya, Ronald A. Fleming, Jill Loftiss, Lini Pandite, Shirish Gadgeel, Barbara L. Weber, Howard A. Burris, III

From the Karmanos Cancer Institute, Wayne State University, Detroit, MI; Sarah Cannon Research Institute, Nashville, TN; and GlaxoSmithKline, Research Triangle Park, NC

Corresponding author: Patricia M. LoRusso, DO, Division of Hematology-Oncology, 4100 John R 4HWCRC, Detroit, MI 48201; e-mail: lorussop{at}karmonos.org

	ABSTRACT

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Purpose This phase I study assessed the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of lapatinib and docetaxel in patients with advanced solid tumors.

Patients and Methods Doses of lapatinib (oral once daily, continuous) and docetaxel (intravenous, every 3 weeks) were escalated in cohorts of at least three patients based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. The protocol was amended to include pegfilgrastim because of dose-limiting toxicity (neutropenia), and a second dose-escalation phase was conducted to determine the OTR for the combination of docetaxel, lapatinib, and pegfilgrastim. After the determination of the OTR, the pharmacokinetics of lapatinib and docetaxel were determined to estimate the potential for an interaction between docetaxel and lapatinib at the OTR dose level.

Results Fifty-two patients with advanced solid tumors were enrolled. The OTR dose level for lapatinib and docetaxel with pegfilgrastim was 1,250 mg (once daily) and 75 mg/m² (once every 3 weeks), respectively. Overall, adverse events (AEs) were mild to moderate in severity. The drug-related AEs reported by most patients ( 25%) were diarrhea (56%), rash (52%), fatigue (27%), and nausea (25%). Of 43 patients assessable for clinical response, two patients had confirmed partial responses. The pharmacokinetics of lapatinib (area under the curve, maximum serum concentration) and docetaxel (area under the curve, clearance) in combination were not significantly different than when the drugs are administered separately.

Conclusion The combination of docetaxel and lapatinib with pegfilgrastim was well tolerated. No pharmacokinetic interaction was observed. Clinical activity was seen in this phase I drug combination trial.

	INTRODUCTION

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Lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC) is an oral, dual tyrosine kinase inhibitor with in vitro specificity for both the ErbB1 and ErbB2 receptors.¹ Lapatinib prevents receptor phosphorylation and activation by reversibly binding to the intracellular cytoplasmic adenosine triphosphate binding site of the kinase.² Lapatinib blocks the following two major downstream pathways that are activated after ErbB receptor stimulation: the ERK1/2 pathway, which modulates cell proliferation, and the PI3K/Akt pathway, which regulates cell survival.^1,3 Lapatinib both alone⁴ and in combination with capecitabine⁵ has demonstrated clinical activity against ErbB2-positive breast cancer.

Docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ) is a semisynthetic taxane that promotes the assembly and stabilization of microtubules causing cell cycle arrest and apoptosis.^6,7 Docetaxel has broad activity against a variety of tumors including breast, lung, ovarian, prostate, and other cancers.⁶ Over the last decade, docetaxel has emerged as a standard in the neoadjuvant, adjuvant, and metastatic treatment of breast cancer.⁸

As targeted agents such as lapatinib have entered into oncology clinical practice, investigators have sought to combine them with cytotoxic agents. Preclinical studies indicate that the combination of lapatinib and docetaxel has synergistic antitumor activity against ErbB2-positive breast cancer cells in vitro, and the combination of these agents in in vivo tumor models results in significantly longer tumor growth inhibition than either agent alone (GlaxoSmithKline Internal Data). Given the clinical activity of lapatinib and docetaxel in breast cancer and the preclinical activity of these agents in combination, it is rational to evaluate these agents in patients with cancer.

The objectives of this phase I dose-escalation study were to determine the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary anticancer activity of this combination in patients with advanced solid malignancies.

	PATIENTS AND METHODS

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Eligibility Criteria
Men or women 18 years of age with advanced or metastatic solid malignancies with no more than three prior chemotherapy regimens were eligible (patients with breast cancer were permitted > three prior regimens). Additional eligibility criteria included the following: life expectancy 12 weeks, Karnofsky performance score of 70, and adequate bone marrow (platelets 100,000/µL, absolute granulocyte count 1,500/µL, and hemoglobin 9 g/dL), liver function (total bilirubin 1.5 mg/dL and AST/ALT 2x upper limit of normal), kidney function (estimated creatinine clearance > 30 mL/min), and cardiac function (baseline left ventricular ejection fraction [LVEF] > 40%). All major surgery, hormonal therapy, chemotherapy, or radiotherapy was discontinued at least 4 weeks before study medication dosing.

Patients were excluded if they had peripheral neuropathy of greater than grade 1, uncontrolled brain or leptomeningeal metastases, or other serious medical conditions including clinically significant cardiac disease, angina pectoris, prior myocardial infarction, congestive heart failure, psychiatric disorder, or active infection. Patients with a malabsorption syndrome or disease that would significantly impact absorption of lapatinib were excluded. The study protocol was approved by the institutional review boards of the participating institutions and was conducted in accordance with the 1996 Declaration of Helsinki. Signed informed consent was obtained from all patients.

Study Treatments and Dose Escalation
Patients (in cohorts of at least three during dose escalation) received oral lapatinib once daily continuously with docetaxel (intravenous 1-hour infusion every 3 weeks). Lapatinib could be taken with a light, low-fat breakfast except on pharmacokinetic sampling days, when patients fasted for 4 hours before lapatinib dosing and 2 hours afterwards. Patients in the first dose-escalation cohort were administered starting doses of lapatinib 1,250 mg/d and docetaxel 60 mg/m². Planned maximum doses of lapatinib and docetaxel were 1,500 mg and 100 mg/m², respectively. If no dose-limiting toxicity (DLT) was observed during the first treatment cycle (one treatment cycle = 3 weeks), an additional three patients were entered at the next higher dose level with dose escalation continuing until DLT was observed. If one of three patients experienced a DLT at a particular dose level, an additional three patients were entered at that level. If two or more patients experienced a DLT at a given dose level, a lower dose level was explored to better define the OTR.

DLTs were defined as grade 3 or 4 clinically significant nonhematologic toxicity (excluding grade 3 nausea without maximal antiemetic support); grade 3 or 4 granulocytopenia with fever (ie, temperature > 38.5°C with absolute granulocyte count < 1,000/µL) or grade 4 granulocytopenia (absolute granulocyte count < 500/µL) lasting more than 5 days; thrombocytopenia 25,000/µL; inability to receive the next course of treatment within 2 weeks of scheduled dosing; any grade 2 toxicity considered a DLT by the clinical investigator; and any grade 2 nonhematologic toxicity that persisted beyond cycle 1 that was considered a DLT by the clinical investigator.

The OTR was defined as the dose of lapatinib and docetaxel at which no more than one of six patients experienced a DLT. Once the OTR was determined, additional patients were treated at the OTR to further evaluate the pharmacokinetics of lapatinib, docetaxel, and both in combination (details provided later).

Dose adjustments during the study were based on hematologic and nonhematologic toxicity in the preceding cycle. Docetaxel was reduced by 20% for grade 4 neutropenia (< 500/µL), grade 4 thrombocytopenia (< 10,000/µL), and grade 3 or 4 nonhematologic toxicity after resolution of toxicity to grade 1. For grade 2 or 3 neutropenia, grade 2 or 3 thrombocytopenia, and grade 2 nonhematologic toxicity, docetaxel was held until the toxicity resolved to grade 1. Lapatinib was reduced by 250 and 500 mg for grade 3 and 4 diarrhea, respectively. For other toxicities and their causality with lapatinib, dose modification was made after discussions among the study investigators.

Safety and Efficacy Assessments
Screening assessments consisted of a complete physical examination, medical history, current medication history, disease assessment, multiple-gated acquisition scan (MUGA) or echocardiogram, 12-lead ECG, CBCs, clinical chemistry, and urinalysis. Before each treatment cycle, tests for clinical chemistry and hematology were performed. During the first treatment cycle, clinical chemistry and hematology tests were performed weekly. Cardiac function was monitored closely; a MUGA or echocardiogram was performed at the end of every three treatment cycles. Approximately 28 days after the last dose of study medication or discontinuation from treatment, physical examination, vital signs, hematology, clinical chemistry, MUGA, and assessment of adverse events (AEs) were performed. All AEs were graded by the National Cancer Institute Common Toxicity Criteria, version 2.0. Tumor response was assessed on completion of treatment cycle 3 (9 weeks from the beginning of drug therapy) and every 9 weeks thereafter or at the discretion of the investigator. Response was assessed using the Response Evaluation Criteria in Solid Tumors guidelines.⁹ All patients continued on study until disease progression, unacceptable toxicity, or withdrawal of consent.

Pharmacokinetic Methods
Blood was collected to measure plasma drug concentrations in the dose-escalation cohorts (sparse sampling, four samples of 4 mL each, collected over 24 hours) to guide dose adjustment in the event of a profound interaction; blood was also collected in the pharmacokinetic cohort at the OTR (intensive sampling, 15 samples of 4 mL each, collected over 24 hours) to quantify any such interaction. The pharmacokinetic cohort involved random assignment to one of two sequences within one of two groups (Fig 1), each involving two 24-hour periods of serial blood sampling. After the pharmacokinetic assessments, these patients could remain on study receiving the OTR dose level until disease progression, unacceptable toxicity, or withdrawal of consent. Lapatinib plasma concentrations were determined using a previously reported method.¹⁰ Docetaxel plasma concentrations were determined after solvent extraction using liquid chromatography/mass spectrometry/mass spectrometry. Precision and accuracy of either method were within 15% of nominal. Plasma concentration data were analyzed by noncompartmental methods (WinNonlin version 4.1; Pharsight Corp, Mountain View, CA). Pharmacokinetic parameters were compared by analysis of variance using a mixed model to estimate the least squares mean and 90% CI for the true difference between treatments. Relationships between drug exposure and toxicity were explored using various regression models.

View larger version (26K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Pharmacokinetic cohort: scheduled days of dosing (tan) and dosing plus blood sampling (blue) for lapatinib (L) and docetaxel (D).

	RESULTS

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Dose escalation with pegfilgrastim. Three patients received lapatinib 1,000 mg/d and docetaxel 60 mg/m² (dose level 0) plus pegfilgrastim (6 mg by subcutaneous administration 24 hours after each docetaxel infusion, administered at all cycles), and no DLTs were reported in the first treatment cycle. Four patients received lapatinib 1,000 mg/d and docetaxel 75 mg/m² (dose level +1) plus pegfilgrastim, and no DLTs were reported in the first treatment cycle. Seven patients received lapatinib 1,250 mg/d and docetaxel 75 mg/m² (dose level +2) plus pegfilgrastim. One patient developed grade 3 rash and grade 3 diarrhea during cycle 1, but no other patients experienced DLTs. Five patients received lapatinib 1,500 mg/d and docetaxel 75 mg/m² (dose level +3) plus pegfilgrastim. Two patients developed grade 3 rash during cycle 1, thus exceeding the OTR. The OTR was defined as lapatinib 1,250 mg/d and docetaxel 75 mg/m² plus pegfilgrastim.

Dose Administration and Modification
The median number of treatment cycles administered for all patients and those receiving pegfilgrastim was two (range, one to 13 cycles) and three (range, one to 13 cycles), respectively. The docetaxel dose was reduced by 20% in six patients as a result of grade 4 neutropenia in five patients and grade 3 diarrhea and fatigue in one patient. Only one of these patients (one patient with neutropenia) received pegfilgrastim. The lapatinib dose was reduced in 10 patients for the following reasons: four patients had rash (two grade 2 and two grade 3), four patients had diarrhea (three grade 3 and one grade 1), one patient had grade 1 nausea and anorexia, and one patient had grade 3 elevated serum creatinine. Treatment cycles were delayed in four patients as a result of toxicity; one patient had grade 4 febrile neutropenia (same patient as above who had dose reduction for grade 4 neutropenia), one patient had grade 3 diarrhea and fatigue (same patient as above who had dose reduction), one patient had grade 1 mucositis, and one patient had grade 3 elevated serum creatinine (same patient as above who had dose reduction).

Safety and Tolerability
All 52 patients were assessable for toxicity. Of the 52 patients enrolled, 49 (94%) reported drug-related AEs. The drug-related AEs reported by 10% of patients and by grade are listed in Table 2. Grade 3 and 4 drug-related toxicities were infrequent. Grade 3 and grade 4 neutropenia occurred in two and five patients, respectively, with all of these events occurring in the two dose cohorts without pegfilgrastim except for one patient receiving lapatinib 1,250 mg/d and docetaxel 75 mg/m² plus pegfilgrastim. One of the patients receiving lapatinib 1,250 mg/d and docetaxel 50 mg/m² (no pegfilgrastim) had febrile neutropenia. The most frequent nonhematologic, drug-related grade 3 toxicities included diarrhea (three patients), rash (three patients), fatigue (two patients), and increased serum creatinine (one patient). One patient receiving lapatinib 1,250 mg/d and docetaxel 75 mg/m² plus pegfilgrastim experienced asymptomatic declines in LVEF of 23% and 20% from baseline at weeks 10 and 12 (baseline value of 75% by MUGA), respectively, and was at 65% (14% decrease) at week 18. The patient remained on drug therapy during this period. Two patients died on study as a result of disease progression. One patient receiving lapatinib 1,250 mg/d and docetaxel 60 mg/m² with no pegfilgrastim withdrew from study as a result of grade 1 chest pain, insomnia, irritability, muscle spasms, nausea, palpitations, rash, vomiting, and grade 2 dyspnea, which the investigator assigned as drug-related toxicities.

View this table: [in this window] [in a new window]   Table 2. Frequency of All Drug-Related Adverse Events by Maximum Toxicity Grade Occurring in 10% of All Patients

Pharmacokinetics
Mean plasma concentration versus time curves for each drug alone and in combination were nearly superimposable (Fig 2). Statistical analysis of derived pharmacokinetic parameters (Tables 3 and 4) indicated no effect on either drug of sufficient magnitude to achieve statistical significance that emerged from the inherent variability in this small cohort.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Median plasma concentration-time curves of (A) lapatinib and (B) docetaxel.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Percent change in neutrophil count in relation to docetaxel concentration (upper curve, the concentration producing half of the maximal effect [EC50] 118 nmol/L docetaxel) showing the effect of lapatinib concentration (lower curve, Ki 129 nmol/L lapatinib). Adding lapatinib improved the fit (r2 = 0.774) and decreased the EC50 approximately 20-fold from 118 to 6 nmol/L. ANC, absolute neutrophil count; Ki, the half-maximal inhibitory concentration.

	DISCUSSION

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Neutropenia, a frequent toxicity associated with docetaxel,¹² occurred during the current study (4% grade 3, 10% grade 4) and necessitated the addition of pegfilgrastim to the dose-escalation cohorts. After the addition of pegfilgrastim, the doses of docetaxel and lapatinib were escalated until DLT of grade 3 rash led to docetaxel 75 mg/m² and lapatinib 1,250 mg being identified as the OTR dose level. Rash was a frequent AE (52%), but the majority of events were of grade 1 to 2 severity (42% grade 1, 4% grade 2, and 6% grade 3). Gomez et al⁴ have reported a 28% frequency of rash (all grade 1 or 2) in patients receiving monotherapy lapatinib (1,500 mg once daily). The frequency of diarrhea in the current study was higher (56% overall, 6% grade 3) than observed with monotherapy lapatinib 1,500 mg (35% overall, 1% grade 3).⁴ However, diarrhea is also an AE associated with administration of docetaxel; 36% of patients (1% grade 3) have diarrhea when administered docetaxel 75 mg/m² every 3 weeks¹³ The increased frequency of diarrhea may be a result of overlapping toxicities of these two agents. Dose reductions because of diarrhea were infrequent, and patients were typically managed with dose delays or with antidiarrheal medications.

Of the 52 patients, only one patient had a decrease in LVEF of more than 20% relative to the baseline assessment and below the lower limit of normal for LVEF at the patient's institution. This patient remained on lapatinib. In a recent analysis of 3,127 cancer patients receiving lapatinib, a 1.3% incidence of decreased LVEF was reported (National Cancer Institute Common Toxicity Criteria grade 3 or 4 or asymptomatic LVEF decline of 20% relative to baseline and below the institution's lower limit of normal). Only 0.1% of patients had symptomatic LVEF dysfunction, and this was generally reversible or nonprogressive.¹⁴

The pharmacokinetics of lapatinib and docetaxel in the current study were similar to those previously reported for both agents.^15,16 Lapatinib has been shown in vitro to inhibit CYP3A4,¹⁷ an enzyme responsible for the metabolism of docetaxel.¹⁵ In addition, lapatinib (GlaxoSmithKline Internal Data) and docetaxel are highly bound to plasma albumin and alpha ₁-acid glycoprotein (AAG), suggesting the potential for a displacement interaction. However, neither of these mechanisms seemed to be altered in vivo, which is consistent with the observation that lapatinib plasma concentrations did not exceed those producing in vitro inhibition and in vitro experiments demonstrating the absence of any protein binding displacement (GlaxoSmithKline Internal Data).

The effect of lapatinib on the relationship between neutropenia and docetaxel concentration suggests that lapatinib increased sensitivity to this toxicity, consistent with the clinical observations described earlier. Although speculative, this might result from lapatinib inhibition of Pgp-mediated efflux of docetaxel from bone marrow stem cells.

In summary, the results of this study indicate that the combination of lapatinib, docetaxel, and pegfilgrastim is clinically feasible, well tolerated, and clinically active. Despite the lack of a pharmacokinetic interaction, increased neutropenia suggests a pharmacodynamic interaction between these two agents.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Kevin M. Koch, GlaxoSmithKline (C); Nikita Arya, GlaxoSmithKline (C); Ronald A. Fleming, GlaxoSmithKline (C); Jill Loftiss, GlaxoSmithKline (C); Lini Pandite, GlaxoSmithKline (C); Barbara L. Weber, GlaxoSmithKline (C) Consultant or Advisory Role: Patricia M. LoRusso, GlaxoSmithKline (C) Stock Ownership: Kevin M. Koch, GlaxoSmithKline; Nikita Arya, GlaxoSmithKline; Ronald A. Fleming, GlaxoSmithKline; Jill Loftiss, GlaxoSmithKline; Lini Pandite, GlaxoSmithKline; Barbara L. Weber, GlaxoSmithKline Honoraria: Patricia M. LoRusso, GlaxoSmithKline; Shirish Gadgeel, GlaxoSmithKline; Howard A. Burris III, Sanofi, GlaxoSmithKline Research Funding: Patricia M. LoRusso, GlaxoSmithKline Expert Testimony: None Other Remuneration: Patricia M. LoRusso, GlaxoSmithKline

	AUTHOR CONTRIBUTIONS

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Conception and design: Patricia M. LoRusso, Kevin M. Koch, Nikita Arya, Howard A. Burris III

Provision of study materials or patients: Suzanne F. Jones, Nikita Arya, Jill Loftiss, Shirish Gadgeel, Howard A. Burris

Collection and assembly of data: Patricia M. LoRusso, Suzanne F. Jones, Kevin M. Koch, Nikita Arya, Jill Loftiss, Lini Pandite, Howard A. Burris III

Data analysis and interpretation: Patricia M. LoRusso, Suzanne F. Jones, Kevin M. Koch, Nikita Arya, Ronald A. Fleming, Jill Loftiss, Lini Pandite, Barbara L. Weber, Howard A. Burris III

Manuscript writing: Patricia M. LoRusso, Kevin M. Koch, Ronald A. Fleming, Lini Pandite

Final approval of manuscript: Patricia M. LoRusso, Suzanne F. Jones, Kevin M. Koch, Nikita Arya, Ronald A. Fleming, Jill Loftiss, Lini Pandite, Shirish Gadgeel, Barbara L. Weber, Howard A. Burris III

	NOTES

 
Supported by a grant from GlaxoSmithKline.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Rusnak DW, Lackey K, Affleck K, et al: The effects of the novel, reversible epidermal growth factor receptor/ErbB2 tyrosine kinase inhibitor, GW572016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 1:85-94, 2001[Abstract/Free Full Text]

2. Wood ER, Truesdale AT, McDonald OB, et al: A unique structure for epidermal growth factor receptor bound to GW572016 (lapatinib): Relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64:6652-6659, 2004[Abstract/Free Full Text]

3. Xia W, Mullin RJ, Keith BR, et al: Anti-tumor activity of GW572016: A dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21:6255-6263, 2002[CrossRef][Medline]

4. Gomez HL, Chavez MA, Doval DC, et al: Updated biomarker results from a phase II randomized study of lapatinib as first-line treatment for patients with erbB2-amplified advanced or metastatic breast cancer. Breast Cancer Res Treat 100:S68, 2006 (suppl 1)

5. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006[Abstract/Free Full Text]

6. Montero A, Fossella F, Hortobagyi G, et al: Docetaxel for treatment of solid tumours: A systematic review of clinical data. Lancet Oncol 6:229-239, 2005[CrossRef][Medline]

7. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643-2655, 1995[Abstract]

8. Nabholtz JM, Gligorov J: The role of taxanes in the treatment of breast cancer. Expert Opin Pharmacother 6:1073-1094, 2005[CrossRef][Medline]

9. Therasse P, Arbuch SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

10. Hsieh S, Tobien T, Koch K, et al: Increasing throughput of parallel on-line extraction liquid chromatography/electrospray ionization tandem mass spectroscopy system for GLP quantitative bioanalysis in drug development. Rapid Commun Mass Spectrom 18:285-292, 2004[CrossRef][Medline]

11. Burris HA: Dual kinase inhibition in the treatment of breast cancer: Initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9:10-15, 2004 (suppl 3)[Abstract/Free Full Text]

12. Sanofi-Aventis: Taxotere (docetaxel) prescribing information. http://www.taxotere.com/

13. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000[Abstract/Free Full Text]

14. Perez EA, Byrne JA: Results of an analysis of cardiac function in 3127 patients treated with lapatinib. J Clin Oncol 24:23s, 2006 (suppl; abstr 583)[CrossRef]

15. Baker SD, Sparreboom A, Verweij J: Clinical pharmacokinetics of docetaxel: Recent developments. Clin Pharmacokinet 45:235-252, 2006[CrossRef][Medline]

16. Burris HA, Hurwitz HI, Dees EC, et al: Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305-5313, 2005[Abstract/Free Full Text]

17. GlaxoSmithKline: Tykerb (lapatinib) prescribing information. http://www.tykerb.com/

Submitted October 18, 2007; accepted February 28, 2008.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by LoRusso, P. M. Articles by Burris, H. A. Search for Related Content PubMed PubMed Citation Articles by LoRusso, P. M. Articles by Burris, H. A., III Related Articles Related Correspondence Social Bookmarking                            What's this?