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Japanese Journal of Clinical Oncology Advance Access published online on December 3, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn135
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© The Author (2008). Published by Oxford University Press. All rights reserved

Phase I Dose-escalation and Pharmacokinetic Trial of Lapatinib (GW572016), a Selective Oral Dual Inhibitor of ErbB-1 and -2 Tyrosine Kinases, in Japanese Patients with Solid Tumors

Kazuhiko Nakagawa1, Hironobu Minami2,{dagger}, Masayuki Kanezaki3, Akihira Mukaiyama3, Yoshiyuki Minamide3, Hisao Uejima1, Takayasu Kurata1, Toshiji Nogami1, Kenji Kawada2, Hirofumi Mukai2, Yasutsuna Sasaki4 and Masahiro Fukuoka1

1 Kinki University School of Medicine, Osaka
2 National Cancer Center Hospital East, Chiba
3 GlaxoSmithKline, Tokyo
4 Saitama Medical School, Saitama, Japan

For reprints and all correspondence: Kazuhiko Nakagawa, Kinki University School of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-0014, Japan. E-mail: nakagawa{at}med.kindai.ac.jp

Received August 24, 2008; accepted October 30, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Acknowledgements
 References
 
Objective: The Phase I dose-escalation study was conducted to evaluate the safety and pharmacokinetics of lapatinib (GW572016), a dual ErbB-1 and -2 inhibitor, in Japanese patients with solid tumors that generally express ErbB-1 and/or overexpress ErbB-2.

Methods: Patients received oral lapatinib once daily until disease progression or in an event of unacceptable toxicity.

Results: Twenty-four patients received lapatinib at dose levels of 900, 1200, 1600 and 1800 mg/day; six subjects enrolled to each dose level. The majority of drug-related adverse events was mild (Grade 1–2); the most common events were diarrhea (16 of 24; 67%), rash (13 of 24; 54%) and dry skin (8 of 24; 33%). No Grade 4 adverse event was observed. There were four Grade 3 drug-related adverse events in three patients (i.e. two events of diarrhea at 1600 and 1800 mg/day each and {gamma}-glutamyl transpeptidase increase at 1800 mg/day). The maximum tolerated dose was 1800 mg/day. The pharmacokinetic profile of lapatinib in Japanese patients was comparable to that of western subjects.

Conclusions: Lapatinib was well tolerated at doses of 900–1600 mg/day in Japanese solid tumor patients. Overall, our findings were similar to those of overseas studies.

Key Words: ErbB-1 • ErbB-2 • lapatinib • phase I • tyrosine kinase inhibitor


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Acknowledgements
 References
 
Dysregulation of the human epidermal growth factor (ErbB) family of cell surface receptors has been noted in several solid tumors. Binding of extracellular ligand to ErbB receptors activates multiple intracellular signaling pathways that can promote tumor growth through processes, such as cell proliferation, differentiation and inhibition of apoptosis. ErbB-1 and ErbB-2 are implicated in the pathogenesis of several cancers (1), and their overexpression in epithelial tumors—including those of the lung, breast, head and neck, colon, stomach, ovary and prostate—often correlates with poor prognosis (2,3).

ErbB receptors present two rational targets for inhibition: blockade of the extracellular ligand-binding domain by monoclonal antibodies and inhibition of the intracellular tyrosine kinase domain by small molecules (4). Several anticancer agents target specific ErbB isoforms. For example, the small molecule tyrosine kinase inhibitors gefitinib (Iressa®) and erlotinib (Tarceva®) and the monoclonal antibody cetuximab (Erbitux®) all target ErbB-1 (5–7), and thus, they are indicated for the treatment of non-small cell lung cancer (NSCLC) and colorectal cancer (8,9). Furthermore, a monoclonal antibody directed against ErbB-2 (trastuzumab, Herceptin®) has been approved for patients with ErbB-2-overexpressing breast cancer (10). Sensitivity to some of these agents is strongly associated with the expression levels of ErbB-1 and -2 (2,3).

Since it has been suggested that tumors with ErbB-1 expression and ErbB-2 overexpression are more aggressive than those without expression of the receptors (11–13), it has been proposed that dual inhibition of ErbB-1 and -2 could be a useful approach in patients with overexpression of these receptors. Lapatinib (GW572016) is a potent, orally active, small molecule dual inhibitor of ErbB-1 and -2. Lapatinib markedly reduces autophosphorylation of ErbB-1 and -2, and inhibits activation of Erk1/2 and AKT, the downstream effectors of cell proliferation and cell survival, respectively (14–17). Lapatinib inhibits tumor cell proliferation in various human tumor cell lines expressing ErbB-1 and overexpressing ErbB-2, as well as in tumor xenograft models (14–17).

Preclinical study of lapatinib revealed the agent to be well tolerated with an effective half-life of ~24 h, suggesting once-daily oral administration to be feasible (18). Clinical studies of the safety and efficacy of lapatinib in cancer patients are underway.

This was the first Japanese Phase I study of lapatinib in patients with solid tumors. This study was primarily designed to assess the safety of repeated oral doses of lapatinib in these patients and to investigate pharmacokinetics to see if they are comparable with those in western patients.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Acknowledgements
 References
 
Study Design
This was a non-randomized, open-label, multicenter, dose-escalation Phase I study conducted at two sites in Japan—Kinki University Hospital, Osaka and National Cancer Center Hospital East, Chiba.

The primary objectives were to assess the safety of repeated oral doses of lapatinib, to determine the maximum tolerated dose (MTD) in patients with solid tumors, to evaluate the pharmacokinetics (PK) of repeated oral doses of lapatinib and to compare the data from overseas studies and based on these data, to find the clinically recommended dose of lapatinib in Japanese patients enrolled in further studies.

Patient Eligibility
Adult patients aged 20–74 years with histologically or cytologically confirmed solid tumors that are generally known to express EGFR and/or overexpress ErbB-2 (including colorectal cancer, gastric cancer, NSCLC and breast cancer) were eligible for inclusion, provided that they had failed standard therapies or there were no other appropriate therapies available (19–40). Patients had to have normal function of major organs and adequate bone marrow, hepatic and renal functions defined as hemoglobin ≥9 g/dl, neutrophil count ≥1500/mm3 and platelets ≥100 000/mm3, AST and ALT ≤2.5 of upper limit of normal (ULN) and bilirubin ≤1.5 of ULN, and serum creatinine ≤1.5 of ULN, respectively. Left ventricular ejection fraction by echocardiography had to be ≥50% and in all patients an appropriate length of time since cessation of previous therapy was required (chemotherapy, radiotherapy, surgery or investigational products other than anticancer drugs, ≥4 weeks; nitrosourea compounds or mitomycin C, ≥6 weeks; biologic response modifiers or hormone therapy, ≥2 weeks). Patients were also to have an Eastern Cooperative Oncology Group performance status (PS) 0–2 and life expectancy ≥3 months after the start of lapatinib treatment.

Exclusion criteria were serious complications (Grade ≥3 according to the National Cancer Institute common toxicity criteria, NCI-CTC, version 2); pleural effusion, ascites and/or pericardial effusion requiring drainage by puncture, intracavital administration, or any other relevant treatment; systematic steroid use for ≥50 days or possible need for long-term use of systemic steroids; multiple active cancers; symptomatic brain metastases; malabsorption and/or total resection of the stomach or small intestine; corneal disorder; history of drug allergy; breast feeding; previous trastuzumab-induced impaired cardiac function; and previous acute pulmonary disorder or interstitial pneumonia induced by gefitinib.

All patients gave written informed consent before the start of study. The protocol was approved by the institutional review board of each study site. The study was conducted according to the World Medical Association Declaration of Helsinki (41) and Japanese good clinical practice guidelines (42).

Treatment
Based on the findings of overseas Phase I study (43), and in order to compare PK profiles with an overseas parallel Phase I study (44), patients were assigned to receive lapatinib 900, 1200 or 1600 mg/day for 21 consecutive days. Lapatinib was taken orally once daily with water after a light low-fat breakfast, except on Days 1 and 21 when it was administered in fasting state.

The dose levels started at 900 mg/day and increased to 1200 and 1600 mg/day, then increased by 200-mg increments until MTD was reached. MTD was defined as the dose at which dose-limiting toxicity (DLT), i.e. a drug-related adverse event of NCI-CTC Grade ≥3, occurred within 21 days after the initiation of dosage in two or more patients at each dose level with six subjects. When DLT was observed, the next dose for the patients was to be postponed, and could not restart until NCI-CTC grade became ≤2 within 14 days. In such cases, when NCI-CTC became Grade 2 or below, the dose was to be restarted at the previous dose level. When NCI-CTC did not reach Grade 2 or below after dose delays of 14 days, the treatment for the patients was to be discontinued. These dose delays and reductions were allowed to be performed only once.

Although appropriate supportive care and symptomatic treatment were allowed, prophylactic use (including antiemetics) was not permitted between screening and Day 21 of the treatment period. Anticancer therapy of any kind, medications that may affect the absorption or metabolism of lapatinib, and other investigational drugs were prohibited throughout the study. Also, to prevent PK interactions, patients were instructed to avoid grapefruit, grapefruit juice and St John’s Wort (Hypericum perforatum) throughout the study.

Safety Assessments
Assessments including clinical laboratory tests, vital signs, PS and body weight were performed at screening, at baseline (i.e. within 3 days before the first dose), on Days 7, 14 and 21, every 4 weeks thereafter, on cessation of treatment, and on the last day of observation (i.e. 28 days after the final dose or immediately before the start of next anticancer therapy). Chest X-ray, 12-lead electrocardiogram and echocardiography were performed at screening, once between Days 14 and 21, and on the last observation day. Toxicity was graded according to the NCI-CTC version 2.

Pharmacokinetic Analysis
For PK evaluation, 3-ml blood samples were collected at 1 h pre-dosing and at 1, 2, 3, 4, 6, 8, 10, 12 and 24 h after dosing on Days 1 and 21 and at pre-dosing on Days 7 and 14. Urine samples were collected before dosing on Day 1 and 0–24 h after dosing on Days 1 and 21.

Serum concentrations of lapatinib were measured by liquid chromatography tandem mass spectrometry with a lower limit of quantitation of 1 ng/ml.

The calculated PK parameters were maximum serum concentration (Cmax), time to Cmax (tmax), area under the plasma drug concentration–time curve from 0 to 24 h (AUC0–24) and terminal half-life (t1/2). Renal clearance was calculated from urine concentrations of lapatinib.

Efficacy Assessments
For efficacy assessment [i.e. tumor response as determined by X-ray, computed tomography (CT), magnetic resonance imaging (MRI) and/or other objective measurements according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (45)], evaluations were performed at screening (i.e. 4 weeks before the first dose of lapatinib), once during Days 14–21, every 4 weeks thereafter, and on the last day of observation. Target and non-target lesions were assessed in the same manner before and after dosing. Consistency of efficacy evaluation by the study investigators was assessed by extramural review committee.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Conflict of interest statement
 Acknowledgements
 References
 
Patients
Twenty-four patients were enrolled; all had received prior chemotherapy. Table 1 shows their baseline characteristics. The median age was 60 years (range, 37–73), and they had a median PS of 1. NSCLC was the main tumor type. Six patients at four dose levels, 900, 1200, 1600 and 1800 mg/day each, received lapatinib. Eight patients received lapatinib for >3 months and four for >6 months.


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  		Table 1. Baseline characteristics of patients

 
All patients completed the initial 21-day treatment period, although one of the patients had dose reduction (overall compliance, 90.5%) due to the onset of a Grade 3 drug-related adverse event (diarrhea) during this period. Four patients (three at 1200 mg dose level and one at 1600 mg dose level) withdrew from study due to disease progression and four (one each at 900 and 1600 mg dose level and two at 1800 mg dose level) were withdrawn at their own request. Mean durations of study treatment in the 900, 1200, 1600 and 1800 mg groups were 131, 68.2, 117 and 49.3 days, respectively. No patient withdrew due to adverse events.

Safety
All 24 patients were eligible for safety analysis. Table 2 lists the drug-related adverse events experienced by ≥20% of patients at each dose level. The majority of events was mild (Grade 1–2); the most common events were skin reactions (mostly rash and dry skin) observed in 22 patients (92%) and gastrointestinal disorders (mostly diarrhea) in 18 patients (75%). The most severe drug-related adverse events were Grade 3 diarrhea observed in one patient at 1600 mg dose level and two patients at 1800 mg dose level. One of these also had Grade 3 {gamma}-GTP increase. All diarrhea resolved with routine symptomatic treatment during or after withdrawal of lapatinib therapy, {gamma}-GTP increase resolved without further treatment after completion of lapatinib therapy.


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  		Table 2. No. of patients with drug-related adverse events that occurred in ≥20% of patients receiving lapatinib

 
Grade 1/2 drug-related nausea and vomiting were experienced only by patients at higher dose levels of lapatinib [1/6 (17%) at 1600 mg/day and 3/6 (50%) at 1800 mg/day], with Grade 2 symptoms only seen at the 1800 mg dose level.

For other adverse events, no clear drug relation was found. The most frequent events included decreased body weight and serum alkaline phosphatase increase, each observed in 10 patients (42%). Grade 1 drug-related decreases in left ventricular ejection fraction were found in three of the six patients at the 1200 mg dose level. No clinically relevant changes in vital signs, 12-lead electrocardiogram or echocardiography were noted.

Hypoxemia and pneumonia were reported at the 900-mg dose level in another patient with NSCLC on Day 35. After hypoxemia occurred, the patient continued to receive study drug medication until Day 40. We attributed hypoxemia to bronchostenosis caused by the primary disease. Oxygen inhalation and erythromycin were given and hypoxemia improved while the pneumonia was resolved on Day 41 before the patient died from progression of primary disease 3 months after the events were resolved. Chest X-rays and CT findings for this patient were inconsistent with those for interstitial pneumonia associated with other tyrosine kinase inhibitors; therefore a drug relation with lapatinib was denied.

Maximum Tolerated Dose
Dose escalation was stopped at 1800 mg/day, where two patients experienced DLT (Grade 3 diarrhea). One of these patients also experienced Grade 3 {gamma}-GTP increase. Thus, 1800 mg/day was determined as the MTD.

Pharmacokinetics
Table 3 shows the PK parameters derived from data on 23 patients (data from one patient received lapatinib for only 19 days and are not included).


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  		Table 3. Derived pharmacokinetic parameters of lapatinib (including 95% confidence intervals)

 
Serum concentrations of lapatinib at each dose level on Days 1 and 21 are shown in Fig. 1. Repeated doses of lapatinib (900–1800 mg/day) for 21 days resulted in dose-related increases in mean Cmax (range, 1715–3111 ng/ml) and mean AUC0–24 (range, 25 680–51 099 ng·h/ml) (Table 3). Large inter-patient variations were found in mean Cmax and mean AUC0–24. After a single dose of lapatinib, tmax was ~4 h, although values varied greatly among patients. After 21 days of treatment, tmax values were similar to those observed after the single dosing on Day 1.


Figure 1
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  		Figure 1. Serum concentrations of lapatinib at each dose level as detected on (A) Day 1 and (B) Day 21.

 
Steady-state serum concentrations of lapatinib generally increased with dose, 820 ± 448 ng/ml at 1200 mg dose level and 1899 ± 1356 ng/ml at 1600 mg dose level (Table 3). Both concentrations exceeded the half maximal inhibitory concentration values for in vitro tumor growth (14). The median t1/2 after repeat dose was 16.9 h (range, 15.1–34.3) at 1200 mg dose level and 26.2 h (range, 12.9–48.3) at 1600 mg dose level.

The fraction of urinary excretion of lapatinib was <0.1% of the dose, suggesting that none or negligible amount of drug is excreted in urine.

Comparison of on-treatment Cmax and AUC0–24 values obtained in Japanese and western patients are shown in Fig. 2 (43,44).


Figure 2
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  		Figure 2. Relation between dose of lapatinib and exposure: comparison of (A) maximum serum concentration (Cmax) and (B) area under the plasma drug concentration–time curve from 0 to 24 h (AUC0–24) after dosing on Day 21 (our study, Japanese patients) and Days 14 and 20 (US studies, western patients).

 
Efficacy
Among 24 patients, the best overall response was assessed as partial response (PR) in two patients (8.3%), stable disease (SD) in 12 patients (50.0%), progressive disease in eight patients (33.3%) and indeterminate in two patients (8.3%).

Of the two patients with PR, the first was a 73-year-old man with NSCLC (squamous cell carcinoma) with prior docetaxel and gemcitabine treatment, who received lapatinib 900 mg/day. PR was assessed by CT scan with 41% shrinkage on Day 49. Time to progression was 191 days. The second patient was a 55-year-old woman with trastuzumab-resistant breast cancer (invasive ductal carcinoma; hormone receptor-negative, ErbB-2 3+). Disease progressed after doxorubicin and cyclophosphamide/docetaxel therapy, was stable with doxifluridine, and progressed with trastuzumab. Following treatment with lapatinib 1600 mg/day, the tumor shrank by 41% on Day 21. Time to progression was 133 days.

Among the patients with SD, three (two with NSCLC and one with colorectal cancer) were stabilized for >6 months and three (two with NSCLC and one with cervical cancer) were stabilized for 3–6 months and therefore were considered as having a durable response.


   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Conflict of interest statement
 Acknowledgements
 References
 
The dual ErbB-1/-2 inhibitor lapatinib taken orally once daily for ≥21 days was well tolerated at doses of 900–1600 mg in Japanese solid tumor patients. Adverse events were mostly mild in nature, and only four grade ≥3 drug-related adverse events were noted, in three patients (three events of Grade 3 diarrhea and one Grade 3 {gamma}-GTP increase). No NCI-CTC Grade 4 adverse events were observed. Grade 1–2 diarrhea occurred in some patients other than those who experienced Grade 3 diarrhea; for these, supportive therapy was given and fully recovered in all cases. Grade 1/2 drug-related nausea and vomiting were experienced only by patients at higher dose levels of lapatinib, with Grade 2 symptoms only seen at 1800 mg dose level.

The types and incidences of drug-related adverse events in Japanese patients were similar to those reported from studies conducted in healthy volunteers (18) and two overseas Phase I studies, the latter including a parallel study in western patients that used similar dose administration and dose-escalation schedules (43,44). In that study as well as in ours, diarrhea and rash were the most frequently noted drug-related adverse events. Adverse events were generally mild (Grade 1–2), transient and reversible on dose delay or interruption. Headache, which was common in western patients (18), was reported only by one patient at 1600 mg dose level. 1800 mg/day was considered as MTD, at which Grade 3 diarrhea and {gamma}-GTP increase were observed.

Skin-related adverse events of lapatinib were similar to those reported for other agents that target ErbB-1; rash is also a common adverse event associated with the ErbB-1 tyrosine kinase inhibitors gefitinib (46–49) and erlotinib (7,50), as well as the anti-ErbB-1 antibody cetuximab (51). Patients who received these medications also experienced diarrhea (7,46–50). These adverse events occurred at a similar frequency in our study as in two overseas Phase I studies (43,44).

Apart from one event of {gamma}-GTP increase, no Grade ≥3 abnormal laboratory test suggestive of liver dysfunction was noted. Therefore, drug-related liver abnormality was generally less frequently seen with lapatinib compared with gefitinib (48,49).

Hematologic toxicity was uncommon and limited to cases of anemia. This finding is similar to those of the Phase I biomarker study (44) and studies of gefitinib (48,49,52).

None of the patients developed interstitial lung disease, which is an adverse event reportedly associated with gefitinib (53,54) and occurs in 5.8% of Japanese patients (55). However, because of the limited number of patients in our study, further studies are required to assess safety of lapatinib in this regard.

Cardiotoxicity is a known adverse event associated with trastuzumab therapy and might be related to ErbB-2 inhibition (2,56); however, we found no evidence of drug-related cardiac dysfunction in our study.

PK parameters such as Cmax and AUC0–24 in this study were analyzed and their means and 95% confidence intervals compared with those obtained at similar doses (900–1800 mg) in two overseas Phase I studies (43,44). As can be seen in Fig. 2, the values were comparable among the three studies. However, large inter-patient variations were noted, especially in Japanese patients, and these might have contributed to higher mean values. On the other hand, no clear pharmacokinetic differences were apparent between Japanese and non-Japanese subjects, suggesting that values obtained overseas can be extrapolated to the Japanese population.

The dose recommended for further clinical studies outside Japan, 1500 mg/day, can be used for Phase II studies in Japan. We base this recommendation on the similar PK profiles of lapatinib in Japanese and western patients, evidence of antitumor activity at doses of ≥900 mg/day, and an MTD of 1800 mg/day.

To conclude, lapatinib, taken continuously as once-daily oral therapy at 900–1600 mg, was well tolerated in Japanese patients with solid tumors. The safety and PK profiles shown in this study are similar to those in Phase I studies conducted in western patients. Phase II studies to determine the efficacy of lapatinib against a range of tumors are now in progress.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Conflict of interest statement
 Acknowledgements
 References
 
This study was sponsored by GlaxoSmithKline K.K.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
Acknowledgements
 References
 
The author, Hironobu Minami, receives honoraria from GlaxoSmithKline. The authors, Masayuki Kanezaki, Akihira Mukaiyama, and Yoshiyuki Minamide are employed by GlaxoSmithKline.


   Acknowledgements
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Acknowledgements
References
 
We thank all the patients who participated in this study, their families, and all the investigators (Dr K. Araki, Dr M. Fukuda, Dr M. Ikeda, Dr H. Kaneda, Dr T. Sato, Dr M. Tahara and Dr K. Tamura), research nurses, and study coordinators at study sites.


   Footnotes
 
{dagger} Present address: Kobe University Hospital and Graduate School of Medicine, Hyogo, Japan Back


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Acknowledgements
 References
 
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