Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 4, pp 673–683

Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors

Authors

  • Megumi Inada-Inoue
    • Department of Clinical Oncology and ChemotherapyNagoya University Hospital
    • Department of Clinical Oncology and ChemotherapyNagoya University Hospital
  • Kenji Kawada
    • Department of Clinical Oncology and ChemotherapyNagoya University Hospital
  • Ayako Mitsuma
    • Department of Clinical Oncology and ChemotherapyNagoya University Hospital
  • Masataka Sawaki
    • Department of Clinical Oncology and ChemotherapyNagoya University Hospital
  • Taro Yokoyama
    • Department of Palliative MedicineYokohama Municipal Citizen’s Hospital
  • Yu Sunakawa
    • Department of Internal MedicineShowa University Northern Yokohama Hospital
  • Hiroo Ishida
    • Department of MedicineShowa University Hospital
  • Kazuhiro Araki
    • Department of Breast OncologyThe Cancer Institute Hospital of JFCR
  • Keishi Yamashita
    • Kawagoe Gastroenterical Hospital
  • Keiko Mizuno
    • Department of Pulmonary Medicine, Graduate School of Medicine and Dental SciencesKagoshima University
  • Fumio Nagashima
    • Department of Internal Medicine, Medical OncologyKyorin University School of Medicine
  • Akiko Takekura
    • GlaxoSmithKline K.K.
  • Kazuo Nagamatsu
    • GlaxoSmithKline K.K.
  • Yasutsuna Sasaki
    • Department of MedicineShowa University Hospital
Original Article

DOI: 10.1007/s00280-014-2374-3

Cite this article as:
Inada-Inoue, M., Ando, Y., Kawada, K. et al. Cancer Chemother Pharmacol (2014) 73: 673. doi:10.1007/s00280-014-2374-3

Abstract

Purpose

A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors.

Methods

In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients).

Results

There was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 μg/mL).

Conclusions

The pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.

Keywords

PazopanibLapatinibJapanese patientsPhase 1Pharmacokinetics

Introduction

Pazopanib (GW786034, Votrient®, GlaxoSmithKline) is a potent, oral, small-molecule inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors (PDGFR)-alpha and -beta, and c-kit [1]. Clinical studies of pazopanib have demonstrated single-agent activity in patients with renal cell carcinoma and soft tissue sarcoma [24]. A previous phase 1 study of pazopanib in non-Japanese patients with solid tumors (VEG10003) showed that the drug was well tolerated up to 2,000 mg once daily, but the maximum tolerated dose (MTD) was not determined [5]. However, maximum plasma concentrations (Cmax) and areas under the plasma drug concentration–time curves (AUC) were similar after treatment with pazopanib 800–2,000 mg daily, suggesting that drug absorption is saturated at daily doses of 800 mg or higher. Moreover, the daily dose of pazopanib 800 mg achieved the target trough concentration of ≥17.5 μg/mL (40 μmol/L) required for optimal inhibition of tumor angiogenesis [6]. Based on the tolerable safety profile and plateau in steady-state systemic exposure at this dose level and achievement of the target trough concentration of pazopanib, the recommended dose for pazopanib monotherapy was determined to be 800 mg once daily for future studies. Pazopanib has been approved for the indications of soft tissue sarcoma and renal cell carcinoma in the United States, European Union, and other countries, and for the indication of soft tissue sarcoma in Japan. In phase 3 studies, pazopanib showed a statistically significant and clinically meaningful improvement in the primary end point of progression-free survival as compared with placebo in patients with ovarian cancer who did not have disease progression after first-line chemotherapy [7].

Lapatinib (Tykerb®, GlaxoSmithKline) is a potent, oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) [8]. This drug is used at a dose of 1,250 mg once daily for the treatment of HER2-positive advanced or metastatic breast cancer resistant to prior trastuzumab-based chemotherapy [9]. Lapatinib has been approved for the indication of breast cancer in Japan, the United States, European Union, and other countries.

Several lines of evidence support the combined inhibition of VEGFR and EGFR in the management of some malignancies [10, 11]. A preclinical study showed that pazopanib and lapatinib act synergistically to induce apoptosis of non-small-cell lung cancer cells in vitro [12]. A previous phase 1 study of combination therapy with pazopanib and lapatinib in non-Japanese patients (VEG10006) showed that pazopanib and lapatinib could be administered concurrently at their respective single-agent doses with an acceptable safety profile [13].

Accordingly, the current phase 1 study evaluated the safety, tolerability, and pharmacokinetic (PK) profile of pazopanib alone and combining pazopanib and lapatinib in Japanese patients with solid tumors, as a first step to exploring the potential benefit of this combination regimen for the treatment of various cancer classes.

Patients and methods

Eligibility criteria

Eligible patients were at least 20 years of age with a histologic or cytologic diagnosis of solid tumor and an Eastern Cooperative Oncology Group performance status of 0 or 1. While the study was in progress, the protocol was amended to exclude patients with uterine cervical carcinoma from part B because a clinical trial in non-Japanese patients with uterine cervical carcinoma (VEG105281) showed that the potential benefits of combination therapy with pazopanib and lapatinib were outweighed by the risk of severe toxicity [14]. Eligible patients also had to have adequate hematologic and organ functions, including: absolute neutrophil count ≥1,500/mm3; platelet count ≥100,000/mm3; hemoglobin level ≥9.0 g/dL; prothrombin time or prothrombin time–international normalized ratio ≤1.2 × the upper limit of normal (ULN); creatinine clearance calculated by the Cockcroft–Gault formula ≥50 mL/min; urine protein:creatinine ratio <1; total bilirubin level ≤1.5 × ULN; and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN. In part B, patients additionally had to have a left ventricular ejection fraction of >50 %. Patients were excluded if they had central nervous system metastases, carcinomatous meningitis, clinically meaningful gastrointestinal abnormalities, uncontrolled infection, a corrected QT interval of >480 ms, a history of cardiovascular disease requiring cardiac angioplasty or stenting, or poorly controlled hypertension (≥140/90 mmHg). All patients provided written informed consent in accordance with the requirements of the review board of each participating institution.

Study design and treatment

This was a 2-center, open-label, non-randomized, dose-finding phase 1 study (VEG109693; NCT00516672) in Japanese patients with solid tumors who received pazopanib alone or in combination with lapatinib. The main objective was to assess the safety and tolerability of these oral tyrosine kinase inhibitors.

The study consisted of two parts: part A, in which patients received pazopanib monotherapy and part B, in which patients received combination therapy with pazopanib and lapatinib. Both parts were designed to evaluate safety, tolerability, and PK. Part A comprised an original cohort and an additional cohort, while part B comprised a dose-escalation cohort and a PK cohort (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs00280-014-2374-3/MediaObjects/280_2014_2374_Fig1_HTML.gif
Fig. 1

Schematic diagram of the study. In part A, pazopanib monotherapy was evaluated at a dose of 800 mg once daily (P800) in the original cohort. In the additional cohort, one group of patients received pazopanib 400 mg once daily on day 1, followed by pazopanib 800 mg from day 2 onward (P400/800), and another group of patients received pazopanib 1,000 mg once daily from day 1 onward (P1000). In part B, combination therapy with pazopanib and lapatinib was evaluated for pazopanib 400 mg plus lapatinib 1,000 mg once daily (P400/L1000), pazopanib 800 mg plus lapatinib 1,000 mg once daily (P800/L1000), and pazopanib 400 mg plus lapatinib 1,500 mg once daily (P400/L1500) in the dose-escalation cohort. Patients in the pharmacokinetic (PK) cohort received pazopanib 600 mg (P600) or lapatinib 1,250 mg (L1250) once daily for 15 days, followed by combination therapy with pazopanib 600 mg and lapatinib 1,250 mg once daily (P600/L1250) from day 16 onward. Dose-limiting toxicity was evaluated between day 1 and day 21 in the original (P800) and additional (P1000) cohorts of part A and the dose-escalation cohort of part B (P400/L1000, P800/L1000, and P400/L1500) or between day 16 and day 36 in the PK cohort of part B (P600/L1250)

In the original cohort of part A, a minimum of 6 patients were assigned to receive pazopanib 800 mg once daily (P800), the recommended dose for non-Japanese patients, for assessing safety, tolerability, and PK in Japanese patients. Blood samples for PK analysis were taken during the 96 h after the first dose. From day 2 onward, the patients received additional doses of pazopanib 800 mg once daily. On day 22, blood samples for PK analysis were taken during the 24 h after dosing. If 2 or more of the 6 patients in the original cohort had dose-limiting toxicity (DLT), a lower dose of 600 mg/day was to be evaluated in 6 additional patients.

In the additional cohort of part A, a minimum of 3 patients received pazopanib 400 mg once daily on day 1 for assessing safety and PK, followed by pazopanib 800 mg once daily from day 2 (P400/800). A minimum of 3 other patients received pazopanib 1,000 mg once daily from day 1 onward (P1000) for assessing safety, tolerability, and PK. In both groups, blood samples for PK analysis were taken during the 96 h after the first dose of pazopanib. On day 22, blood samples for PK analysis were taken during the 24 h after dosing. If 1 of the 3 patients assigned to P1000 had DLT, 3 additional patients were enrolled, and if 2 of the first 3 patients or 2 or more of the 6 patients had DLT, the dose was considered to exceed the MTD.

In the dose-escalation cohort of part B, 3 patients were initially assigned to receive pazopanib 400 mg plus lapatinib 1,000 mg once daily (P400/L1000) for assessing safety, tolerability, and PK in Japanese patients. On day 1 and day 22, blood samples for PK analysis were taken during the 24 h after dosing. Then, 3 patients each received pazopanib 800 mg plus lapatinib 1,000 mg (P800/L1000) or pazopanib 400 mg plus lapatinib 1,500 mg (P400/L1500) once daily. If no DLT occurred among the first 3 patients who received P400/L1000, dose escalation proceeded to P800/L1000 and P400/L1500 in parallel, and patients were simultaneously enrolled. If 1 of the 3 patients had DLT, 3 additional patients were enrolled, and if 1 of the 6 patients had DLT, the dose was escalated. The dose at which 2 of the first 3 patients or 2 or more of 6 patients had DLT was considered to exceed the MTD. At the dose level of P800/L1000 and P400/L1500, MTD was considered by the same procedures as P400/L1000. If the MTD was not reached in the dose-escalation cohorts of part B (P400/L1000, P800/L1000, and P400/L1500), a minimum of 6 patients were assigned to the PK cohort of part B, designed to investigate potential PK interactions between pazopanib and lapatinib, for assessing safety, tolerability, and PK in Japanese patients. The originally planned doses for combination therapy in the PK cohort in part B were pazopanib 800 mg plus lapatinib 1,500 mg, based on the results of a phase 1 study (VEG10006) [13]. However, the doses were reduced during the study to pazopanib 600 mg (P600) and lapatinib 1,250 mg (L1250) because the interim analysis of a phase 2 study (VEG20007) in non-Japanese patients reported that intolerable toxicity occurred at doses of pazopanib 800 mg and lapatinib 1,500 mg [15].

A minimum of 3 patients in the PK cohort were assigned in each of the two groups receiving P600 once daily or L1250 once daily for 15 days. Patients in both groups then received pazopanib 600 mg plus lapatinib 1,250 mg once daily (P600/L1250) from day 16 onward. On day 15 and day 37, blood samples for PK analysis were taken during the 24 h after dosing. If 2 or more of the 6 patients had DLT, the dose was considered to exceed the MTD.

Patients in both part A and part B orally received pazopanib once daily, at least 1 h before or at least 2 h after breakfast. In part B, patients received lapatinib first, followed by pazopanib within a 15-min interval, at least 1 h before, or at least 2 h after breakfast.

Study assessments

Baseline assessments on day 1 or within 72 h before treatment included medical history, physical examination, complete blood counts, serum chemical analysis, coagulation tests, urinalysis, pregnancy tests (for all women of childbearing potential), thyroid-stimulating hormone (TSH) levels, electrocardiography, left ventricular ejection fraction (LVEF; part B only), ErbB2 expression (part B only), and chest radiography. Assessments conducted on days 8, 15, and 22 (days 8, 15, 22, 29, and 37 in the PK cohort) and every 3 weeks thereafter included physical examination, complete blood counts, serum chemical analysis, and urinalysis. TSH levels were measured on day 22 (day 37 in the PK cohort) and every 3 weeks thereafter. Coagulation tests were performed every 9 weeks. Electrocardiography and LVEF measurements (part B only) were performed on day 22 (day 37 in the PK cohort) and every 9 weeks thereafter. Chest radiography (part B only) was performed on day 22 (day 29 in the PK cohort) and every 9 weeks thereafter. Toxicity was monitored continuously and graded according to the Common Terminology Criteria for Adverse Events, version 3.0 [16]. Disease assessments by investigator according to the Response Evaluation Criteria in Solid Tumors [17] were performed at baseline and every 9 weeks after starting the study medications until withdrawal from the study.

Dose-limiting toxicity was defined as at least 1 of the following events occurring between day 1 and day 21 in the original (P800) and additional (P1000) cohorts of part A and the dose-escalation cohort of part B (P400/L1000, P800/L1000, and P400/L1500) or between day 16 and day 36 in the PK cohort of part B (P600/L1250): grade 3 neutropenia persisting for at least 5 days, grade 4 neutropenia, febrile neutropenia, grade 3 or 4 thrombocytopenia, inability to resume treatment within 14 days of the scheduled date because of unresolved toxicity, inability to receive at least 75 % of the scheduled doses in a treatment period due to toxicity, any grade 3 or 4 clinically significant non-hematologic toxicity, and any grade 2 toxicity evaluated to be DLT by the investigator and medical monitor. However, grade 3 nausea, vomiting, or diarrhea in the absence of appropriate supportive therapy, grade 3 hypertension adequately controlled by antihypertensive therapy, and increased amylase/lipase levels unaccompanied by clinical symptoms were not considered DLT.

Pharmacokinetic assessments

Blood samples (3 mL) were collected for measurement of plasma pazopanib and lapatinib concentrations. In part A, blood samples were collected before treatment and 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, and 96 h after treatment on day 1, and before treatment and 0.5, 1, 2, 3, 4, 6, 8, and 24 h after treatment on day 22. The blood sample 24 h after treatment was collected within 1 h before the next treatment, to confirm that the trough plasma concentrations of pazopanib were above 20 μg/mL (i.e., high enough to inhibit VEGFR-2 activity). In the dose-escalation cohort of part B, blood samples were collected before treatment and 0.5, 1, 2, 3, 4, 6, 8, and 24 h after treatment on days 1 and 22. In the PK cohort of part B, blood samples were collected before treatment and 0.5, 1, 2, 3, 4, 6, 8, and 24 h after treatment on days 15 (monotherapy, steady state) and 37 (combination therapy). Concentrations of pazopanib and lapatinib were determined by protein precipitation of human plasma, followed by high-performance liquid chromatography–tandem mass spectrometry analysis. Quantification was performed by multiple reaction monitoring with TurboIonSpray® interface (AB Sciex, Concord, Ontario, Canada) in positive-ion mode. The calibration range was 100–50,000 ng/mL for pazopanib and 5–5,000 ng/mL for lapatinib in 20 and 25 μL of human plasma, respectively. The coefficient of variation (CV %) and accuracy bias (%) obtained with this method were both less than 15 %. WinNonlin Professional® software (Pharsight Corporation, Mountain View, California, USA) and standard non-compartmental methods were used to calculate the AUC, Cmax, time to maximum plasma concentration (tmax), and elimination half-life (t1/2).

Results

Patient characteristics

A total of 30 patients were enrolled between September 2007 and May 2010: 7 in the original cohort and 6 in the additional cohort of part A; 10 in the dose-escalation cohort and 7 in the PK cohort of part B. In addition to the initially planned numbers of patients (12 patients in part A and 15 patients in part B), 3 patients were additionally enrolled (1 each was assigned to P800 in part A and to P400/L1000 and P600/L1250 in part B) to compensate for patients who were ineligible for the evaluation of DLT. The most common tumor types were soft tissue sarcoma and colorectal cancer in part A and head and neck cancer in part B (Table 1). One patient in part A and 3 in part B were receiving the study treatment at the time of data cutoff (August 2010).
Table 1

Patient characteristics

 

Part A (n = 13)

Part B (n = 17)

Age, median years (range)

49 (39–74)

56 (27–74)

Gender, n

  

 Male

9

5

 Female

4

12

Prior chemotherapy regimens, n (%)

9 (69)

10 (59)

≥4 regimens

3 (23)

5 (29)

Tumor type

Soft tissue sarcoma, n = 4

Head and neck, n = 4

 

Colorectal, n = 4

Breast, n = 3

 

Head and neck, n = 2

Ovarian, n = 2

 

Othera, n = 3

Carcinoid, n = 2

  

Otherb, n = 6

aOther tumor types included thyroid cancer, gastrointestinal stromal tumor, and malignant melanoma

bOther tumor types included renal cell carcinoma, thyroid cancer, soft tissue sarcoma, bone sarcoma, gastric cancer, and central nervous system tumor (hemangiopericytoma)

Safety and tolerability

In part A, none of the 9 eligible patients (6 patients assigned to P800 and 3 assigned to P1000) had DLT. In part B, none of the 15 eligible patients (3 patients each assigned to P400/L1000, P800/L1000, and P400/L1500, and 6 patients assigned to P600/L1250) had DLT.

In part A, 12 (92 %) of the 13 patients had adverse events (AEs) associated with pazopanib, including leukopenia/white cell count decreased (62 %), neutropenia/neutrophil count decreased (62 %), thrombocytopenia/platelet count decreased (62 %), diarrhea (46 %), AST increased (38 %), hypertension (38 %), and lipase increased (38 %) (Table 2). Most AEs were manageable by dose reduction or treatment interruption. Five (42 %) of the 12 patients with AEs had drug-related AEs of grade 3 or worse, including neutropenia, hepatic function abnormal, hypertension, leukopenia, lymphopenia, hyperbilirubinemia, and lipase increased. The study treatment was discontinued because of AEs in 3 of these patients, 1 of whom had abnormal hepatic function (grade 4) related to pazopanib. The other 2 patients had AEs unrelated to pazopanib: 1 patient had abnormal hepatic function (grade 3) and lower respiratory tract infection (grade 2), and the other had ileus (grade 2). No patient died during the study.
Table 2

Summary of drug-related adverse events (at least 30 % in any part)

Adverse event

Part A

Total (n = 13)

P400/800 (n = 3)

P800 (n = 7)

P1000 (n = 3)

All Gr,

n (%)

Gr 3/4,

n (%)

All Gr

Gr 3/4

All Gr

Gr 3/4

All Gr

Gr 3/4

Any event

12 (92)

5 (38)

3

3

6

1

3

1

Leukopenia/white cell count decreased

8 (62)

1 (8)

3

0

4

0

1

1

Neutropenia/neutrophil count decreased

8 (62)

3 (23)

3

2

4

0

1

1

Thrombocytopenia/platelet count decreased

8 (62)

0

3

0

4

0

1

0

Diarrhea

6 (46)

0

1

0

3

0

2

0

Hypertension

5 (38)

1 (8)

3

1

1

0

1

0

AST increased

5 (38)

0

2

0

3

0

0

0

Lipase increased

5 (38)

1 (8)

2

0

2

1

1

0

Nausea

4 (31)

0

1

0

0

0

3

0

Rash

4 (31)

0

1

0

3

0

0

0

ALT increased

4 (31)

0

2

0

2

0

0

0

Fatigue

3 (23)

0

0

0

1

0

2

0

Skin hypopigmentation

3 (23)

0

2

0

0

0

1

0

Lymphopenia

3 (23)

1 (8)

2

0

1

1

0

0

Serum TSH increased

3 (23)

0

2

0

1

0

0

0

Hair color changes

2 (15)

0

0

0

2

0

0

0

Proteinuria

2 (15)

0

1

0

1

0

0

0

Decreased appetite

1 (8)

0

1

0

0

0

0

0

Dysgeusia

1 (8)

0

1

0

0

0

0

0

Adverse event

Part B

Total (n = 17)

P400/L1000 (n = 4)

P800/L1000 (n = 3)

P400/L1500 (n = 3)

P600/L1250 (n = 7)

All Gr

n (%)

Gr 3/4,

n (%)

All Gr

Gr 3/4

All Gr

Gr 3/4

All Gr

Gr 3/4

All Gr

Gr 3/4

Any event

17 (100)

9 (53)

4

2

3

2

3

1

7

4

Leukopenia/white cell count decreased

11 (65)

1 (6)

2

0

3

1

1

0

5

0

Neutropenia/neutrophil count decreased

12 (71)

0

3

0

3

0

2

0

4

0

Thrombocytopenia/platelet count decreased

12 (71)

0

3

0

2

0

1

0

6

0

Diarrhea

16 (94)

1 (6)

3

0

3

0

3

0

7

1

Hypertension

8 (47)

2 (12)

1

1

1

0

2

0

4

1

AST increased

5 (29)

0

1

0

1

0

3

0

0

0

Lipase increased

4 (24)

4 (24)

2

2

0

0

1

1

1

1

Nausea

7 (41)

0

1

0

1

0

2

0

3

0

Rash

11 (65)

0

3

0

1

0

2

0

5

0

ALT increased

7 (41)

0

1

0

1

0

3

0

2

0

Fatigue

9 (53)

0

1

0

2

0

2

0

4

0

Skin hypopigmentation

7 (41)

0

2

0

2

0

1

0

2

0

Lymphopenia

7 (41)

1 (6)

2

0

1

0

1

0

3

1

Serum TSH increased

10 (59)

0

1

0

3

0

1

0

5

0

Hair color changes

6 (35)

0

1

0

1

0

0

0

4

0

Proteinuria

6 (35)

0

1

0

2

0

1

0

2

0

Decreased appetite

11 (65)

0

3

0

1

0

2

0

5

0

Dysgeusia

9 (53)

0

1

0

1

0

3

0

4

0

Weight decreased

7 (41)

1 (6)

3

1

1

0

1

0

2

0

Stomatitis

7 (41)

1 (6)

0

0

1

0

2

0

4

1

AST aspartate aminotransferase, ALT alanine aminotransferase, Gr grade, L lapatinib, P pazopanib, TSH thyroid-stimulating hormone

In part B, all 17 patients had AEs related to the study drugs, including diarrhea (94 %), neutropenia/neutrophil count decreased (71 %), thrombocytopenia/platelet count decreased (71 %), leukopenia/white cell count decreased (65 %), rash (65 %), decreased appetite (65 %), and increased serum TSH level (59 %) (Table 2). Most of these AEs were manageable by dose reduction or treatment interruption. Nine (53 %) of the 17 patients had drug-related AEs of grade 3 or worse, including lipase increased, hypertension, diarrhea, weight decreased, stomatitis, blood amylase increased, vomiting, pyrexia, hepatic function abnormal, pneumonia, lymphopenia, and leukopenia. The study treatment was discontinued because of AEs in 3 patients, 2 of whom had AEs related to the study drugs: 1 had ALT increased (grade 2), AST increased (grade 2), and fatigue (grade 1), and the other had abnormal hepatic function (grade 3) and pneumonia (grade 3). The third patient had ileus (grade 2) unrelated to the study drugs. One patient with head and neck cancer who received P800/L1000 died of disease progression 47 days after the last dose of the study drugs. This disease progression was not considered to be related to study treatment.

In part A, treatment-related AEs involving liver function, such as AST/ALT and bilirubin increased, occurred in 8 patients (62 %), most of which were grade 2 or lower. Grade 3 or higher AEs involving liver function were reported in 3 patients (23 %). In part B, 11 patients (65 %) had treatment-related AEs involving liver function, most of which were grade 2 or lower. Grade 3 AEs involving liver function occurred in 1 patient.

In part A, 5 patients (38 %) had drug-related hypertension. Treatment was not discontinued or interrupted or the dose reduced in any patient due to hypertension. In part B, drug-related hypertension occurred in 8 patients (47 %), none of whom underwent treatment discontinuation, interruption, or dose reduction due to hypertension.

In part A, there was no clinically important prolongation of QTc interval on electrocardiography. In part B, grade 2 prolongation of QTc interval occurred in 1 patient who had a grade 2 supraventricular arrhythmia 14 days after discontinuation of the study drug. In part B, the LVEF did not decrease by at least 20 % from the baseline value in any patient.

In Part A, 1 patient (8 %) had a grade 3 drug-related increase in serum lipase levels. No patient had increased amylase levels. In part B, 4 patients (24 %) had grade 3 or higher drug-related increases in serum lipase levels, and 1 patient (6 %) had a drug-related grade 3 increase in amylase levels. None of the patients had any signs or symptoms suggesting acute pancreatitis on physical examinations. Treatment discontinuation or interruption or dose reduction was not required.

Pharmacokinetics

In part A, the PK of pazopanib were evaluated in all 13 patients in the original and the additional cohorts after single-dose treatment on day 1 and in 11 patients after repeated treatment on day 22 (Table 3). There were considerable inter-patient variations in the PK parameters of pazopanib. Median tmax was approximately 2.5 and 4.0 h, and the geometric mean of t1/2 was between 28.4 and 42.5 h. The AUC from 0 to 24 h (AUC0–24) and Cmax did not increase in proportion to the doses of pazopanib on day 1 (400, 800, and 1,000 mg). The geometric mean of plasma pazopanib concentration 24 h after treatment (C24) on day 22 was higher than the target trough concentration of pazopanib for the inhibition of VEGFR-2 activity (>20 μg/mL in this study) after repeated doses of pazopanib 800 mg and 1,000 mg.
Table 3

Pharmacokinetic parameters of pazopanib in part A

Parameter

Day

Cohort

P400/800

(n = 3)

P800

(n = 7)

P1000

(n = 3)

Cmax (μg/mL), geometric mean (% CVb)

1

25.1 (34.0)

22.9 (69.5)

21.3 (118.1)

22

55.8a (35.2)

40.6b (47.7)

53.9 (55.4)

tmax (h), median (min–max)

1

4.0 (3.0–23.7)

3.0 (2.0–6.0)

3.0 (3.0–3.0)

22

2.5a (2.0–3.0)

2.5b (1.9–4.0)

4.0 (3.0–4.1)

AUC0–24 (h × μg/mL), geometric mean (% CVb)

1

402.3 (17.7)

324.6 (76.7)

305.0 (128.6)

22

962.4a (46.3)

677.3b (45.5)

759.5 (63.8)

t1/2 (h), geometric mean (% CVb)

1

28.4 (35.9)

42.5 (31.6)

33.0 (23.8)

C24 (μg/mL), geometric mean (% CVb)

1

14.8 (12.7)

9.1 (90.1)

8.5 (139.6)

22

34.6 (47.2)

22.0b (48.4)

21.1 (80.5)

AUC0–24 the area under the plasma drug concentration–time curve from 0 to 24 h, Cmax maximum plasma concentration, C24, plasma concentration 24 h after treatment (trough), t1/2 elimination half-life, tmax, time to maximum plasma concentration, % CVb, between-subject coefficient of variation

an = 2

bn = 6

In part B, the PK of pazopanib and lapatinib were evaluated in all 10 patients on days 1 and 22 in the dose-escalation cohort, and in all 6 patients on days 15 and 37 in the PK cohort (Tables 4, 5). There were considerable inter-patient variations in the PK parameters of pazopanib and lapatinib in both the dose escalation and the PK cohorts. The PK parameters of AUC0–24 or Cmax in the dose-escalation cohort apparently did not depend on the doses of pazopanib or lapatinib. The geometric mean of C24 of pazopanib after multiple doses of pazopanib plus lapatinib was higher than the target trough concentration of pazopanib for inhibition of VEGFR-2 activity (>20 μg/mL in this study) in all dose groups (P400/L1000, P800/L1000, P400/L1500, and P600/L1250) in part B. There were large variations in the ratio of combination therapy to monotherapy for Cmax and AUC0–24 of pazopanib and lapatinib, with the 90 % confidence intervals including 1 (Table 5).
Table 4

Pharmacokinetic parameters of pazopanib and lapatinib in the dose-escalation cohort of Part B

Pazopanib parameter

Cohort

Day

P400/L1000

(n = 4)

P800/L1000

(n = 3)

P400/L1500

(n = 3)

Cmax (μg/mL), geometric mean (% CVb)

1

46.4 (10.1)

48.9 (51.1)

31.7 (68.6)

22

57.9 (18.6)

55.6 (7.3)

51.7 (69.8)

tmax (h), median (min–max)

1

5.0 (3.0–8.0)

6.0 (4.0–8.0)

4.0 (3.0–4.0)

22

4.1 (4.0–8.0)

3.0 (0.5–6.2)

4.0 (3.0–8.0)

AUC0–24 (h × μg/mL), geometric mean (% CVb)

1

755.0 (15.0)

853.4 (53.8)

523.7 (66.6)

22

988.1 (33.2)

1,140.6 (18.4)

1,003.8 (65.6)

t1/2 (h), geometric mean (% CVb)

1

30.1 (21.5)

33.7 (48.3)

29.3 (24.8)

C24 (μg/mL), geometric mean (% CVb)

1

26.8 (17.9)

31.0 (37.5)

17.6 (61.2)

22

34.8 (27.6)

41.9 (28.5)

35.2 (65.2)

Lapatinib parameter

Cohort

Day

P400/L1000

(n = 4)

P800/L1000

(n = 3)

P400/L1500

(n = 3)

Cmax (μg/mL), geometric mean (% CVb)

1

2.4 (21.4)

1.5 (50.5)

2.8 (36.9)

22

1.6 (39.1)

1.6 (77.3)

2.0 (107.1)

tmax (h), median (min–max)

1

6.0 (3.0–8.0)

6.0 (6.0–8.0)

6.0 (4.1–6.1)

22

4.1 (3.0–6.0)

4.0 (4.0–6.0)

6.0 (4.0–8.0)

AUC0–24 (h × μg/mL), geometric mean (% CVb)

1

33.8 (25.9)

18.0 (61.5)

32.6 (52.3)

22

22.8 (44.2)

23.6 (36.1)

32.0 (92.1)

t1/2 (h), geometric mean (% CVb)

1

11.6 (30.8)

7.8 (21.5)

9.8 (19.0)

AUC0–24 the area under the plasma drug concentration–time curve from 0 to 24 h, Cmax maximum plasma concentration, C24 plasma concentration 24 h after treatment (trough), L lapatinib, P pazopanib, t1/2 elimination half-life, tmax time to maximum plasma concentration, % CVb between-subject coefficient of variation

Table 5

Pharmacokinetic parameters of pazopanib and lapatinib in the PK cohort of part B

Pazopanib parameter

P600 → P600/L1250

 

Day 15

Pazopanib monotherapy

(n = 3)

Day 37

Combination therapy

(n = 6)

Ratioa (90 % CI)

(n = 3)

Cmax (μg/mL), geometric mean (% CVb)

79.6 (10.3)

63.5 (40.6)

0.68 (0.27, 1.73)

tmax (h), median (min–max)

3.0 (3.0–4.0)

3.0 (3.0–5.9)

 

AUC0–24 (h × μg/mL), geometric mean (% CVb)

1,331.4 (13.8)

1,188.8 (37.1)

0.77 (0.33, 1.79)

C24 (μg/mL), geometric mean (% CVb)

45.1 (4.2)

43.0 (38.4)

 

Lapatinib parameter

L1250 → P600/L1250

 

Day 15

Lapatinib monotherapy

(n = 3)

Day 37

Combination therapy

(n = 6)

Ratioa (90 % CI)

(n = 3)

Cmax (μg/mL), geometric mean (% CVb)

2.09 (49.2)

2.07 (37.0)

0.89 (0.49, 1.62)

tmax (h), median (min–max)

4.0 (3.0–4.0)

4.0 (3.0–6.0)

 

AUC0–24 (h × μg/mL), geometric mean (% CVb)

28.4 (45.4)

29.5 (41.6)

0.97 (0.45, 2.09)

AUC0–24 the area under the plasma drug concentration–time curve from 0 to 24 h, CI confidence interval, Cmax maximum plasma concentration, C24 plasma concentration 24 h after treatment (trough), L lapatinib, P pazopanib, tmax time to maximum plasma concentration, % CVb between-subject coefficient of variation

aRatio of combination therapy/monotherapy

Clinical activity

In part A, none of the 13 patients had a complete response (CR) or partial response (PR). Three patients (2 patients who received P800; 1 patient who received P400/800) had stable disease (SD). In 2 of these patients (1 patient with gastrointestinal stromal tumor [GIST]; 1 patient with head and neck cancer), SD lasted for more than 6 months. The other 9 patients had progressive disease (PD). In 1 patient with colorectal cancer, clinical response was undetermined because the target lesion could not be evaluated because of cystic changes occurring during treatment.

In part B, clinical response was assessable in all 17 patients. None of the patients had a CR, and 3 patients had PR (1 patient with renal cell cancer; 1 patient with a mediastinal carcinoid tumor who received P400/L1000; 1 patient with HER2-positive breast cancer who received P400/L1500). Nine patients had SD, 5 of whom had prolonged SD lasting for more than 6 months (2 patients with head and neck cancer; 1 patient each with abdominal carcinoid tumor, central nervous system neoplasm, and thyroid cancer). The remaining 5 patients had PD.

Discussion

This phase 1 study of Japanese patients with solid tumors showed that pazopanib monotherapy was well tolerated and had a manageable toxicity profile up to a dose of 1,000 mg once daily and that combination therapy with pazopanib and lapatinib was well tolerated and had a manageable toxicity profile at all dose levels studied (P400/L1000, P800/L1000, P400/L1500, and P600/L1250). Because no patient had DLT, the MTD for monotherapy and combination therapy was not determined. The safety profiles and the PK of pazopanib and lapatinib in Japanese patients were similar to those reported in non-Japanese patients [5, 13]. There were no consistent trends in PK interactions between pazopanib and lapatinib.

Drug-related liver toxicity is one of the most clinically important AEs in pazopanib-treated patients. Adverse events of grade 3 or higher involving liver function developed in 4 patients in this study: 3 of 13 patients in part A (23 %; P400/800, P1000) and 1 of 17 patients in part B (6 %; P600/L1250). The frequencies and grades of AEs involving liver function in Japanese patients were similar to those in non-Japanese patients [2, 4, 18].

Two of the 17 patients in part B received the study treatment for more than 3 years with no evidence of PD. The first patient was a 56-year-old man with renal cell carcinoma in whom a PR was maintained while receiving P400/L1000. Urinary protein became positive approximately 2 years after starting the study treatment, and proteinuria gradually progressed without serious clinical symptoms. Eventually, treatment was stopped because proteinuria exceeded 3 g/g creatinine per day 54 months after study entry. The results of liver function tests remained normal throughout the study. The other patient was a 56-year-old woman with thyroid medullary carcinoma who received P600/L1250. She has been receiving the study treatment for more than 40 months, with a best response of SD (as of June 2013). The patient has had several AEs, including liver toxicity, most of which were grade 1. Although the number of patients is small, these findings provide important information on the safety and efficacy of prolonged treatment with pazopanib and lapatinib.

There were no apparent differences in PK parameters of pazopanib and lapatinib between Japanese and non-Japanese patients. The plasma concentrations of pazopanib did not increase in proportion to doses exceeding 800 mg in a previous study of non-Japanese patients (VEG10003) [5] or exceeding 400 mg at single dosing and 800 mg at multiple dosing in our study. These findings suggested that the absorption of pazopanib is saturated at least after doses of 800 mg or higher, and this partially accounts for why the MTD of this oral drug could not be determined despite dose escalation. However, the trough concentrations of pazopanib were consistently above the threshold of >20 μg/mL after monotherapy at doses of 800 mg and 1,000 mg and combination therapy at doses of 400 mg, 600 mg, and 800 mg together with lapatinib. These doses were therefore considered adequate for antitumor efficacy. The large variations in the ratios of combination therapy to monotherapy for the concentrations of pazopanib and lapatinib indicated no consistent trends in drug interactions between pazopanib and lapatinib. However, because a phase 1 study of non-Japanese patients (VEG10006) reported that the AUC and Cmax of pazopanib increased by approximately 50–60 % when pazopanib 800 mg was combined with lapatinib 1,500 mg [13], potential PK interactions between these drugs cannot be excluded.

In part B, 1 patient each with renal cell cancer, carcinoid tumor, and HER2-positive breast cancer achieved PR. Substantial antitumor activity with prolonged SD was obtained in 1 patient each with GIST and head and neck cancer in part A, and in 2 patients with head and neck cancer and 1 patient each with carcinoid tumor, thyroid cancer, and central nervous system neoplasm in part B. The response of thyroid cancer in part B is consistent with the results of a previous phase 2 study in which pazopanib monotherapy was effective against advanced differentiated thyroid cancer [19]. On the other hand, although 1 patient with GIST achieved long-term SD in part A, suggesting the potential activity of pazopanib against this disease, the efficacy of pazopanib against GIST remains uncertain because a pivotal study of pazopanib in advanced soft tissue sarcoma (PALETTE study) excluded patients with GIST [4]. Furthermore, long-term SD was obtained in 3 of 6 patients with head and neck cancer (1 of 2 patients in part A; 2 of 4 patients in part B), and 2 of 2 patients with carcinoid tumor (both in part B) had PR and long-term SD, respectively. However, the effectiveness of pazopanib alone and in combination with lapatinib against these diseases remains unconfirmed because the evaluation of efficacy for specific types of cancer was beyond the scope of the present study.

Our findings confirmed that pazopanib monotherapy at a dose of 800 or 1,000 mg once daily and pazopanib plus lapatinib at any of the doses investigated in this study are well tolerated in Japanese patients with solid tumors. No patient had DLT, and the MTD for monotherapy and combination therapy was not determined. The PK profiles of pazopanib and lapatinib in Japanese patients were similar to those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib.

We concluded that pazopanib monotherapy at a dose of 800 mg once daily (the recommended dose for non-Japanese patients) and pazopanib plus lapatinib at any of the doses investigated in this study were appropriate for Japanese patients.

Acknowledgments

Appreciation is expressed to the patients and their families, as well as the many investigators who participated in the study.

Ethical standards

This study was approved by the appropriate ethics committee(s), was performed in accordance with the Declaration of Helsinki, and complied with the current laws of the country (Japan) in which it was conducted. All patients provided informed consent before inclusion in the study.

Conflict of interest

This study (VEG109693; NCT00516672) was supported by research funding from GlaxoSmithKline Pharmaceuticals. Editorial assistance was provided by ProEd Communications, Inc., Beachwood, Ohio, USA, and was supported by GlaxoSmithKline. Akiko Takekura is employee but not stockholder of GSK. Kazuo is employee and stockholder of GSK. Yasutsuna Sasaki served as a consultant/advisor for Takeda-Bio, Kowa, and GlaxoSmithKline. Yuichi Ando served as a consultant/advisor for GlaxoSmithKline. The other authors have no conflicts of interest to disclose concerning this study.

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© Springer-Verlag Berlin Heidelberg 2014