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Phase I and Pharmacokinetic Study of Lapatinib in Combination With Capecitabine in Patients With Advanced Solid Malignancies

Quincy S.C. Chu, Garry Schwartz, Johann de Bono, Deborah A. Smith, Kevin M. Koch, Melissa J. Versola, Lini Pandite, Nikita Arya, Jan Curtright, Ronald A. Fleming, Peter T.C. Ho, Eric K. Rowinsky

From the Institute for Drug Development, Cancer Therapy and Research Center; Brooke Army Medical Center, Fort Sam Houston, San Antonio, TX; and GlaxoSmithKline, Research Triangle Park, NC

Address reprint requests to Quincy S.C. Chu, MD, 11560 University Ave, Edmonton, Alberta T6G 1Z2, Canada; e-mail: quincchu{at}cancerboard.ab.ca

	ABSTRACT

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Purpose: This phase I trial (EGF10005) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies.

Patients and Methods: Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses.

Results: Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m²/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and -fluoro-ß-alanine, were not meaningfully altered by coadministration.

Conclusion: Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.

	INTRODUCTION

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erbB1 (epidermal growth factor/human epidermal growth factor receptor [HER] 1) and erbB2 (HER2/neu) are members of the type I receptor tyrosine kinase family (erbB). Kinase activation leads to interaction with other signal transduction molecules, initiating an intracellular signaling cascade, resulting in cellular proliferation or differentiation. Overexpression or gene amplification of some erbB receptors confers a poorer prognosis in breast and other cancers.^1-8 Overexpression of erbB family members in cells in vitro causes transformation and, in some cases, confers metastatic properties in vivo.^9-11 Inhibition of erbB kinases should block receptor-mediated signaling and, as a consequence, block transformation and inappropriate growth, leading to cell death or growth arrest.

Lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC) is a novel oral dual tyrosine kinase inhibitor with specificity for both the erbB1 and erbB2 receptors. Lapatinib simultaneously targets the following two major downstream pathways activated after stimulation of erbB receptors: the ERK1/2 pathway, which modulates cell proliferation, and the PI3K/Akt pathway, which regulates cell survival.^12,13Lapatinib binds reversibly to the cytoplasmic adenosine triphosphate–binding site of the kinase, preventing receptor phosphorylation and activation. Lapatinib induces growth arrest and/or apoptosis in erbB1- and erbB2-dependent tumor cell lines or xenografts.^12,13 A phase I trial of single-agent lapatinib in heavily pretreated patients with metastatic cancer has shown that it is well tolerated and clinically active.¹⁴

Because of the strong rationale supporting the development of lapatinib in breast, colorectal, and other cancers that commonly overexpress erbB1 and/or erbB2, this study sought to evaluate the feasibility of combining lapatinib and capecitabine (Xeloda; Roche Pharmaceuticals, Nutley, NJ), an orally administered fluoropyrimidine carbamate prodrug. This is further supported by the in vitro synergistic cytotoxicity between a lapatinib analog and the capecitabine metabolite 5'-deoxy-5-fluorouridine against breast cancer cell lines.¹⁵ The purpose of this study was to evaluate the safety, optimally tolerated regimen (OTR), pharmacokinetics, and preliminary clinical activity of lapatinib and capecitabine in combination in patients with advanced solid malignancies.

	PATIENTS AND METHODS

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Eligibility Criteria
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. Male and female patients 18 years old with histologically confirmed solid malignancies were eligible. Other eligibility criteria included Karnofsky performance status of 70%, platelets 100,000/µL, absolute granulocyte count 1,500/µL, hemoglobin 9 g/dL, serum creatinine 1.5 mg/dL, total bilirubin 1.5 mg/dL, AST/ALT 2x upper limit of normal (ULN; 5x ULN if patient had liver metastases), and prothrombin time/partial thromboplastin time 1.5x ULN. erbB1 or erbB2 tumor expression was not required for study inclusion. Additional eligibility criteria included the ability to swallow and retain oral medication, a life expectancy of at least 12 weeks, and signed informed consent.

Exclusion criteria included the following: more than three prior chemotherapy regimens, except for breast cancer; prior treatment with lapatinib; pregnant or lactating patients; uncontrolled brain metastases or leptomeningeal disease; other serious comorbidities; known contraindications to capecitabine; known hypersensitivity to drugs chemically related to lapatinib; left ventricular ejection fraction (LVEF) 40%; and participation in any investigational study within 28 days before study enrollment. Patients were ineligible if they had received hormonal therapy (other than replacement), radiotherapy, major surgery, or chemotherapy within 4 weeks of study entry (6 weeks for mitomycin or nitrosoureas).

Safety and Efficacy Assessments
At screening, a medical history and complete physical examination (including ECG and LVEF), Karnofsky performance status, hematology (CBC count with differentiation), clinical chemistry (electrolytes, AST, ALT, gamma-glutamyl transferase, lactate dehydrogenase, alkaline phosphatase, bilirubin, creatinine, blood urea nitrogen, albumin, total protein, and creatine phosphokinase), urinalysis, signs and symptoms of cancer, and disease assessment were performed. Vital signs, hematology, and clinical chemistry were assessed weekly during treatment cycles 1 and 2 and once every cycle thereafter. In the event of an absolute neutrophil count less than 750/µL, platelets less than 50,000/µL, or grade 3 clinical chemistry toxicity, these assessments were conducted every other day. LVEF assessment was performed every four cycles and at follow-up or study discontinuation. Safety was assessed by physical examination, laboratory and cardiac function tests, and review of adverse events, which were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Disease status was assessed after every two cycles and at study discontinuation using the Response Evaluation Criteria in Solid Tumors.¹⁶ Patients remained on study until the occurrence of unacceptable toxicities, disease progression, withdrawal of consent, or treatment delay of more than 2 weeks.

Study Treatments and Dose Escalation
This was an open-label, multiple-dose, dose-escalation study of oral lapatinib and oral capecitabine. Lapatinib was supplied as 250-mg tablets. Capecitabine was commercially available as 150- or 500-mg tablets. Patients received oral capecitabine (starting dose, 1,500 mg/m²/d) for 14 days on a 21-day cycle, administered on the standard twice-daily schedule, and once-daily oral lapatinib (starting dose, 1,250 mg/d) beginning the morning of cycle 1 day 1. At least three patients were entered at this initial dose level and monitored for dose-limiting toxicity (DLT) in cycle 1. If no DLT was observed, three additional patients were treated at the next higher dose level until DLT was observed or the maximum dose level was reached in the absence of DLT. The OTR was defined as the lapatinib and capecitabine doses at which no more than one of six patients experienced a DLT in the first treatment cycle. Additional patients were enrolled at the OTR dose level to further evaluate safety, tolerability, and anticancer activity.

DLTs were defined as grade 3 or 4 clinically significant nonhematologic toxicity (excluding nausea or alopecia); grade 4 granulocytopenia lasting more than 5 days; febrile neutropenia; grade 3 or greater thrombocytopenia (< 25,000/µL); inability to begin the next cycle of treatment within 2 weeks of scheduled dosing because of unresolved toxicity; grade 2 nonhematologic toxicity that persisted beyond cycle 1 or grade 2 renal, neurologic, or cardiovascular toxicity that, in the judgment of the investigator and medical monitor (sponsor), was a DLT; missing more than 25% of scheduled doses in a cycle as a result of toxicity; grade 3 or 4 diarrhea; or grade 3 or 4 nausea or vomiting in the presence of maximal support.

Pharmacokinetic Assessments
Additional patients were treated at the OTR dose level to characterize the pharmacokinetic profiles of lapatinib, capecitabine, fluorouracil (FU), and -fluoro-ß-alanine (FBAL) after administration of lapatinib alone, capecitabine alone, and both in combination. Patients were randomly assigned to three different treatment sequences with at least three individuals enrolled onto each sequence (an equal number in each). Blood samples (2 mL, collected in EDTA tubes) were taken before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 (lapatinib analysis only), and 24 (lapatinib analysis only) hours after dosing. The blood was centrifuged at 2,500 x g at 5°C for 10 minutes, and the plasma was separated and stored (–20°C) until analyzed. Pharmacokinetic parameters were determined using WinNonolin Professional software Version 4.1 (Pharsight Corp, Mountain View, CA). Analysis of variance of both area under the curve (AUC) and maximum concentration (C_max) were performed using a mixed model to estimate a point and a 90% CI estimate of the true difference in least square means between the test and reference treatments. Nonparametric methods were used to evaluate paired differences between treatments for time to maximum concentration and time to first measurable concentration (lapatinib only).

Analysis of Samples for Lapatinib, Capecitabine, FU, and FBAL
Lapatinib plasma concentrations were determined as described.¹⁴ Capecitabine plasma concentrations were determined after solid-phase extraction and methanol elution by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) using a Turbo IonSpray interface (PE Sciex, Toronto, Canada) and multiple reaction monitoring in the positive ion mode with a sensitivity of 1 ng/mL. FU plasma concentrations were determined after protein precipitation with acetonitrile by LC/MS/MS using a Turbo IonSpray interface and multiple reaction monitoring in the negative ion mode with a sensitivity of 5 ng/mL. FBAL plasma concentrations were determined after protein precipitation with acetonitrile by LC/MS/MS using a Turbo IonSpray interface and multiple reaction monitoring in the positive ion mode with a sensitivity of 20 ng/mL.

	RESULTS

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Patient Characteristics
Forty-five patients were enrolled onto this study. Patient characteristics are listed in Table 1. Twenty-four patients (53%) had received at least two prior treatment regimens (includes cytotoxic, targeted therapies, hormonal therapy, and immunologic regimens). Eighteen patients were enrolled to determine the OTR. Three patients were treated at the OTR to further evaluate the safety at this dose level. In addition, three patients were treated at a higher capecitabine dose and lower lapatinib dose than the OTR. An additional 21 patients were treated at the OTR dose level to evaluate the pharmacokinetics of lapatinib and capecitabine.

Determination of the OTR
Three patients were enrolled at lapatinib 1,250 mg/d and capecitabine 1,500 mg/m²/d and completed cycle 1 without experiencing DLT. Two initial patients were enrolled at lapatinib 1,250 mg/d and capecitabine 2,000 mg/m²/d. One of these patients developed grade 3 mucositis and grade 2 diarrhea and discontinued treatment before completing cycle 1 because of disease progression. The second patient was also removed from study during cycle 1 as a result of adverse events related to disease progression and was not assessable for DLTs. Six additional patients were enrolled, and no DLTs were noted in cycle 1. Three patients were enrolled at lapatinib 1,500 mg/d and capecitabine 2,000 mg/m²/d. The third patient developed a grade 3 maculopapular rash during cycle 1. Four additional patients were enrolled, and the last patient developed grade 3 diarrhea during cycle 1. Because two patients experienced DLT in cycle 1 at this dose level, the OTR was exceeded. The OTR was determined to be lapatinib 1,250 mg/d and capecitabine 2,000 mg/m²/d.

An additional three patients were enrolled at the OTR to further evaluate safety, and no DLTs were observed in cycle 1. The safety of lapatinib 1,250 mg/d and capecitabine 2,500 mg/m²/d (the US Food and Drug Administration–approved capecitabine dose) was evaluated in three patients. One patient developed grade 3 diarrhea during cycle 1, and a second patient developed grade 2 bleeding stomatitis with weight loss during cycle 1. Because of these two toxicities, no additional patients were treated.

Safety and Tolerability
Most patients (96%) experienced at least one drug-related adverse event during the study (Table 2), with the majority of events being grade 1 to 2. Of the few grade 4 events reported, none were considered to be related to study medication. Drug-related grade 3 diarrhea and grade 3 palmar-plantar erythrodysesthesia (PPE) were reported in five patients each, and grade 3 neutropenia was reported in two patients. Additional drug-related grade 3 events that occurred in one patient each were anorexia, dehydration, fatigue, hyperbilirubinemia, increased international normalized ratio, mucositis, nausea, maculopapular rash, and vomiting.

View this table: [in this window] [in a new window]   Table 2. Patients With Drug-Related Adverse Events by Treatment Combination (occurring in 15% of treated patients)

Antitumor Activity
Of the 41 patients assessed for response, one had a confirmed complete response (CR), three had confirmed partial responses (PR), four had unconfirmed PRs on repeat radiologic assessments, and 20 had stable disease (SD; seven with SD > 16 weeks) as best response to their therapy. The summary of clinical activity in patients with confirmed clinical response is provided in Table 3.

View this table: [in this window] [in a new window]   Table 3. Summary of Patients With Confirmed Objective Responses and Patients With SD 16 Weeks

Patients with confirmed PRs (n = 3) as best response had breast cancer, cancer of the head and neck with skin involvement, and stomach cancer (Table 3). Patients with unconfirmed PRs (n = 4) had cancer of breast (n = 2), tongue, and tonsil. The 20 patients with SD as their best response had colorectal cancer (n = 6), lung cancer (n = 3), breast cancer (n = 2), cancer of the adenoids (n = 2), adenocarcinoma of unknown primary (n = 2), and cancer of the nasopharynx (n = 1), esophagus (n = 1), kidney (n = 1), head and neck (n = 1), and skin (n = 1). Of the seven patients with SD 16 weeks (Table 3), two patients with advanced colon cancer had received fluoropyrimidine-based regimens for metastatic disease with the best response being progressive disease. The largest proportion of patients in all three response categories (CR, PR, and SD) was receiving the OTR (lapatinib 1,250 mg/d and capecitabine 2,000 mg/m²/d).

Pharmacokinetics
Pharmacokinetic parameters for lapatinib and capecitabine and its metabolites are listed in Table 4 and Table 5, respectively. No statistically significant effects of capecitabine on the pharmacokinetics of lapatinib emerged from the variability in the data, although lapatinib AUC_tau and C_max tended to be higher (20% and 34%, respectively). There were no statistically significant effects of lapatinib on the pharmacokinetics of capecitabine, FU, or FBAL, apart from a statistically significant decrease in C_max for FU (30%). This reflected a tendency for lower C_max (28%) of capecitabine, but was not reflected by FBAL, in the presence of lapatinib.

	DISCUSSION

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In a second phase I study, lapatinib was administered once daily at doses of 500 to 1,600 mg to 67 patients with solid malignancies known to express erbB1 and/or erbB2.¹⁴ Lapatinib was well tolerated, with the most frequent drug-related toxicities being diarrhea (42%) and rash (31%). Four patients with breast cancer, including two with inflammatory breast cancer, experienced PRs (lapatinib doses of 650 to 1,200 mg).

The OTR in the current study was lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m²/d, which represents a slight reduction in the doses of lapatinib commonly used as monotherapy in phase II studies (ie, 1,500 mg/d) and the US Food and Drug Administration–approved dose of capecitabine as monotherapy (2,500 mg/m²/d).¹⁸ The combination was well tolerated, with most adverse events being grade 1 or grade 2. Diarrhea was the most common drug-related adverse event, occurring in 67% of patients, which is more frequent than the occurrence observed in the phase I trials of lapatinib as monotherapy and the occurrence observed with single-agent capecitabine 2,500 mg/m²/d (47% to 55%).¹⁸ However, most episodes (89%) were grade 1 or grade 2. Furthermore, the frequency of PPE in the current study was 40%, which is less than that reported for capecitabine monotherapy (54% to 60%) at 2,500 mg/m²/d.¹⁸ Five patients had grade 3 PPE. In patients requiring dose reductions or delays of capecitabine, PPE was the most common reason, consistent with capecitabine monotherapy. Forty-four percent of patients experienced drug-related rash, but the incidence of serious skin rash associated with the lapatinib/capecitabine combination was quite low (2%, grade 3).

The pharmacokinetics of lapatinib as well as capecitabine and its FU and FBAL metabolites were not meaningfully altered by coadministration. Although lapatinib concentrations tended to be higher and peak FU concentration was statistically significantly lower, these differences were of low magnitude and within the usual range of interpatient variability observed clinically.^14,19 The absence of any meaningful interaction is consistent with the independent mechanisms of metabolism and transport for these agents.

Clinical anticancer activity was observed in the current study, with four confirmed responses (one CR and three PRs) and four unconfirmed PRs. It is noteworthy that the CR occurred in a patient with breast cancer who had experienced progression on two previous chemotherapy regimens in the metastatic setting including one containing trastuzumab. Furthermore, 20 patients had SD as their best response, with seven persisting for 16 weeks.

In vitro data have shown that tyrosine kinase inhibitors can modulate key enzymes linked to fluoropyrimidine activity, which may portend favorable therapeutic implications.²⁰ In breast cancer cell lines treated with the capecitabine metabolite 5'-deoxy-5-fluorouridine and a lapatinib analog in vitro, synergistic cytotoxicity was observed, along with reduced thymidylate synthase (TS) gene expression.¹⁵ Decreased TS gene expression has been linked to increased fluoropyrimidine sensitivity in both preclinical and clinical evaluations.²¹ Thus, in addition to its anticancer effects, lapatinib may modulate key enzymes important to the pharmacology of fluoropyrimidines at the tumoral level. These observations may, in part, account for the longer median time to progression (8.4 months for lapatinib plus capecitabine v 4.4 months for capecitabine alone) noted in a phase III trial (EGF100151) in which patients with breast cancer were randomly assigned to either lapatinib plus capecitabine or capecitabine (hazard ratio = 0.49; 95% CI, 0.34 to 0.71; log-rank, one-sided P < .001).²²

The combination of lapatinib and capecitabine was well tolerated at relevant single-agent doses of both agents, and clinical activity was observed in heavily pretreated patients. These results support further investigations of the combination in breast, GI, and other malignancies.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: Deborah A. Smith, GlaxoSmithKine; Kevin M. Koch, GlaxoSmithKline; Melissa J. Versola, GlaxoSmithKline; Lini Pandite, GlaxoSmithKline; Nikita Arya, GlaxoSmithKline; Ronald A. Fleming, GlaxoSmithKline; Peter T.C. Ho, GlaxoSmithKline; Eric K. Rowinsky, ImClone Systems Inc Leadership: N/A Consultant: N/A Stock: Deborah A. Smith, GlaxoSmithKline; Kevin M. Koch, GlaxoSmithKline; Melissa J. Versola, GlaxoSmithKline; Lini Pandite, GlaxoSmithKline; Nikita Arya, GlaxoSmithKline; Ronald A. Fleming, GlaxoSmithKline; Peter T.C. Ho, GlaxoSmithKline Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Quincy S.C. Chu, Johann de Bono, Deborah A. Smith, Kevin M. Koch, Melissa J. Versola, Lini Pandite, Nikita Arya, Peter T.C. Ho, Eric K. Rowinsky

Financial support: Peter T.C. Ho

Provision of study materials or patients: Quincy S.C. Chu, Garry Schwartz, Johann de Bono, Jan Curtright, Eric K. Rowinsky

Collection and assembly of data: Quincy S.C. Chu, Garry Schwartz, Johann de Bono, Kevin M. Koch, Melissa J. Versola, Nikita Arya, Jan Curtright, Ronald A. Fleming, Eric K. Rowinsky

Data analysis and interpretation: Quincy S.C. Chu, Garry Schwartz, Deborah A. Smith, Kevin M. Koch, Melissa J. Versola, Lini Pandite, Nikita Arya, Ronald A. Fleming, Peter T.C. Ho, Eric K. Rowinsky

Manuscript writing: Quincy S.C. Chu, Garry Schwartz, Johann de Bono, Deborah A. Smith, Kevin M. Koch, Lini Pandite, Ronald A. Fleming, Peter T.C. Ho, Eric K. Rowinsky

Final approval of manuscript: Quincy S.C. Chu, Garry Schwartz, Johann de Bono, Deborah A. Smith, Kevin M. Koch, Lini Pandite, Peter T.C. Ho, Eric K. Rowinsky

Other: Lini N. Pandite [Medical governance of the study as the GlaxoSmithKline medical director]

	ACKNOWLEDGMENTS

 
We thank the patients who participated in this study and their families.

	NOTES

 
Supported by a grant from GlaxoSmithKline.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2004, New Orleans, LA.

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

	REFERENCES

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Submitted March 5, 2007; accepted June 18, 2007.

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