Efficacy, safety, pharmacokinetics and biomarker findings in patients with HER2-positive advanced or metastatic breast cancer treated with lapatinib in combination with capecitabine: results from 51 Japanese patients treated in a clinical study.

BACKGROUND: The results from a phase III trial conducted outside of Japan demonstrated a significant improvement in time to progression (TTP) when lapatinib was combined with capecitabine compared with capecitabine alone in patients with HER2-positive advanced or metastatic breast cancer. In this clinical study of lapatinib in combination with capecitabine, efficacy, safety, pharmacokinetics (PK) and biomarkers were investigated in Japanese patients with HER2-positive advanced or metastatic breast cancer treated with prior trastuzumab. METHODS: Eligible women received lapatinib 1250 mg once daily and capecitabine 1000 mg/m(2) twice daily on days 1 through 14 of a 21-day cycle. The primary endpoint was the clinical benefit rate (CBR: complete response, partial response or stable disease for at least 24 weeks). RESULTS: Lapatinib in combination with capecitabine was well tolerated in the 51 patients enrolled in this study. CBR was 59 % (95 % CI 44.2, 72.4), and the median TTP in the Kaplan-Meier estimate was 36 weeks (95 % CI 27.1, 48.0). The majority of drug-related adverse events were mild to moderate (grade 1 or 2); the most common adverse events reported were palmar-plantar erythrodysesthesia syndrome (76 %), diarrhea (67 %) and stomatitis (41 %). CONCLUSIONS: Lapatinib in combination with capecitabine in Japanese HER2-positive breast cancer patients was well tolerated. Overall, our findings on the efficacy, safety and PK were similar to those reported from the overseas studies.

A phase I/II study of ofatumumab (GSK1841157) in Japanese and Korean patients with relapsed or refractory B-cell chronic lymphocytic leukemia.

The tolerability, efficacy, safety and pharmacokinetic profile of a human anti-CD20 monoclonal antibody, ofatumumab, was evaluated in this phase I/II study in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). This study consisted of two parts. Tolerability was assessed in phase I (Part A), while the overall response rate (ORR) was assessed in phase II (comprising Parts A and B). Three patients were enrolled in Part A, and another seven patients were enrolled in Part B. Ofatumumab 300 mg was given at the first infusion, followed by seven weekly and four monthly infusions of 2000 mg. No patients experienced dose-limiting toxicity, and tolerability was confirmed. The ORR was 70 %. The most commonly reported adverse events (AEs) were leukopenia, neutropenia, and lymphopenia. No patients discontinued the study due to AEs. Plasma concentrations of ofatumumab prior to the next weekly dose increased steadily over the 8 weeks and did not reach steady state; with monthly dosing, pre-dose ofatumumab concentrations decreased. Inter-patient variability of pharmacokinetic parameters was larger after the first dose than after the later dose. In conclusion, this phase I/II study suggests that ofatumumab provides favorable safety and efficacy in Japanese/Korean patients with relapsed or refractory B-CLL.

Oral eltrombopag for up to three years is safe and well-tolerated in Japanese patients with previously treated chronic immune thrombocytopenia: an open-label, extension study.

Eltrombopag is an oral, nonpeptide, thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (ITP). The safety, tolerability, and efficacy of eltrombopag for up to 3 years were evaluated in 19 Japanese patients with chronic ITP who had completed a prior 6-month study. Patients received eltrombopag once daily at the last dosage received in the prior study (12.5, 25, or 50 mg). Dose adjustments and treatment interruptions were permitted to maintain platelet counts of 50,000-200,000/µL. Primary evaluations were safety and tolerability of long-term eltrombopag treatment. The median duration of exposure was 27.5 months (range, 9.9-32.3). Adverse events were similar to those reported with short-term use of eltrombopag, and none led to treatment discontinuation. Nine serious adverse events were reported. Median platelet counts began to increase after 1 week of treatment and remained above 50,000/µL for most assessments. Bleeding episodes decreased from 63 % at baseline to 21 % after 2 weeks of treatment and remained below baseline for all assessments. Of 15 patients receiving concomitant baseline ITP medications, 10 permanently discontinued or achieved a sustained reduction of at least one treatment without requiring rescue treatment. Long-term treatment with eltrombopag was safe, well tolerated, and effective in Japanese patients with chronic ITP.

Phase I study of ofatumumab, a human anti-CD20 antibody, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.

OBJECTIVES: Ofatumumab is a human IgG1κ monoclonal antibody that targets a membrane proximal epitope encompassing the small and large loops of CD20. This Phase I study evaluated the safety, tolerability, efficacy and pharmacokinetics of ofatumumab monotherapy in Japanese patients with relapsed/refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma. METHODS: Ofatumumab was administered intravenously weekly for a total of eight doses (dose escalation: 500 and 1000 mg). Six patients (two chronic lymphocytic leukemia and four small lymphocytic lymphoma) were enrolled into two dose cohorts (500 mg, three patients; 1000 mg, three patients). All six patients received 300 mg ofatumumab at the first infusion and either 500 or 1000 mg at seven subsequent weekly infusions. RESULTS: No dose-limiting toxicities or serious adverse events were observed. Grade 3-4 adverse events observed were grade 3 lymphocytopenia (n = 1) and neutropenia (n = 1). Grade 1-2 infusion-related adverse events leading to temporary interruption of ofatumumab infusion were observed in all six patients on the first infusion day, and all patients completed the planned eight infusions. The overall response rate was 50% (3/6). CONCLUSIONS: Ofatumumab was well tolerated at doses up to 1000 mg and showed preliminary evidence of activity in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, warranting further investigations.

A phase II study of lapatinib for brain metastases in patients with HER2-overexpressing breast cancer following trastuzumab based systemic therapy and cranial radiotherapy: subset analysis of Japanese patients.

BACKGROUND: It is known that one third of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer (MBC) treated with trastuzumab will develop brain metastases. As the development of brain metastases is fatal, controlling its progression is clinically meaningful. However, effective therapy for MBC patients with brain metastasis after cranial radiation is limited. The international clinical study in which six Japanese patients participated indicated the antitumor activity of lapatinib against brain metastases of HER2-overexpressing breast cancer. METHODS: The efficacy, safety, and pharmacokinetics of lapatinib 750 mg given twice daily to Japanese HER2-overexpressing MBC patients with brain metastases were assessed as part of the international clinical study. RESULTS: Of six Japanese patients treated in this study, two patients had shown volumetric reduction >20 % in their central nervous system (CNS), one of whom had >50 % reduction. Three patients, including two of these patients, had shown >20 % volumetric reduction in non-CNS lesions. Frequently reported adverse events were diarrhea and rash, all of which were controllable. The AUC0-12 of lapatinib on day 28 was 1.74 times higher than that on day 1. CONCLUSION: These results suggest that lapatinib monotherapy 750 mg given twice daily can exert some efficacy and has potential as a clinically meaningful treatment option for Japanese HER2-overexpressing breast cancer patients with brain metastases after cranial radiation.

Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: a randomized, open-label, phase II study.

BACKGROUND: Eltrombopag is an oral thrombopoietin receptor agonist that stimulates thrombopoiesis and shows higher exposure in East Asian patients than in non-Asian patients. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with thrombocytopenia associated with chronic liver disease (CLD). METHODS: Thirty-eight patients with CLD and thrombocytopenia (platelets <50,000/µL) were enrolled in this phase II, open-label, dose-ranging study that consisted of 2 parts. In the first part, 12 patients received 12.5 mg of eltrombopag once daily for 2 weeks. After the evaluation of safety, 26 patients were randomly assigned to receive either 25 or 37.5 mg of eltrombopag once daily for 2 weeks in the second part. RESULTS: Pharmacokinetics showed that the geometric means of the maximum plasma concentration (C(max)) and the area under the curve (AUC) in the 12.5 mg group were 3,413 ng/mL and 65,236 ng h/mL, respectively. At week 2, the mean increases from baseline in platelet counts were 24,800, 54,000, and 60,000/µL in the 12.5, 25, and 37.5 mg groups, respectively. The median platelet counts increased within 2 weeks of the beginning of administration in all groups, and remained at the same level throughout the 2-week post-treatment period in the 12.5 mg group, whereas the platelet counts peaked a week after the last treatment in both the 25 and 37.5 mg groups. Most adverse events reported were grade 1 or 2; 2 patients in the 37.5 mg group had drug-related serious adverse events. CONCLUSIONS: Eltrombopag ameliorated thrombocytopenia in Japanese patients with CLD and thrombocytopenia. The recommended dose for these patients is 25 mg daily for 2 weeks.

[Phase I study of nelarabine in patients with relapsed or refractory T-ALL/T-LBL].

The safety, tolerability, pharmacokinetics and efficacy of nelarabine were evaluated in adult and pediatric patients with relapsed or refractory T-ALL/T-LBL. Adult patients received nelarabine i.v. over 2 hours on days 1, 3 and 5 in every 21 days, and pediatric patients received this regimen over 1 hour for 5 consecutive days in every 21 days. Safety was evaluated in 7 adult and 6 pediatric patients. Adverse events (AEs) were reported in all patients. Most frequently reported AEs included somnolence and nausea in adult patients and leukopenia and lymphocytopenia in pediatric patients. Five grade 3/4 AEs were reported in both adult and pediatric patients, most of which were hematologic events. There were no dose-limiting toxicities. Efficacy was evaluated in 7 adult and 4 pediatric patients. Complete response was noted in 1 adult and 2 pediatric patients. Higher intracellular ara-GTP concentrations were suggested to be associated with efficacy. Japanese adult and pediatric patients with T-ALL/T-LBL well tolerated nelarabine treatment, warranting further investigation.