Nghiên cứu giai đoạn I về liều dùng liên tục olaparib dạng viên nang kết hợp với carboplatin và/hoặc paclitaxel (Phần 1)

Investigational New Drugs - Tập 38 - Trang 1117-1128 - 2019
Ruud van der Noll1, Agnes Jager2, Joo Ern Ang3, Serena Marchetti1, Marja W. J. Mergui-Roelvink1, Martijn P. Lolkema2,3, Maja J. A. de Jonge2, Diane A. van der Biessen2, Andre T. Brunetto3, Hendrik-Tobias Arkenau3, Ilian Tchakov4,5, Jos H. Beijnen6,7, Johann S. de Bono3, Jan H. M. Schellens1,7
1Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
2Department of Medical Oncology, Erasmus University MC Cancer Institute, Rotterdam, The Netherlands
3The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Surrey, UK
4AstraZeneca, Macclesfield, UK
5Eisai, Hatfield, UK
6Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
7Utrecht Institute of Pharmaceutical Science s (UIPS), Utrecht University, Utrecht, The Netherlands

Tóm tắt

Nền tảng: Chất ức chế PARP olaparib đã cho thấy độc tính chấp nhận được ở liều lên đến 400 mg hai lần mỗi ngày (bid; dạng viên nang) với những dấu hiệu khích lệ về hoạt động chống khối u. Dựa trên cơ chế tác động của nó, olaparib có thể nhạy cảm hóa các tế bào khối u với các tác nhân gây tổn thương DNA. Thử nghiệm giai đoạn I này (NCT00516724) đã đánh giá tính an toàn, dược động học (PK) và hiệu quả sơ bộ của olaparib kết hợp với carboplatin và/hoặc paclitaxel. Phương pháp: Các bệnh nhân mắc khối u đặc biệt ở giai đoạn tiến triển đã nhận olaparib (viên nang bid) cộng với carboplatin (Phần A), carboplatin và paclitaxel (Phần B), hoặc paclitaxel (Phần C). Trong mỗi phần của nghiên cứu, các liều thuốc khác nhau đã được đưa ra để xác định sự kết hợp liều/thuốc thích hợp nhất để sử dụng trong các nghiên cứu tiếp theo. Đánh giá an toàn bao gồm việc đánh giá các độc tính giới hạn liều (DLTs; chỉ chu kỳ 1), các tác dụng phụ (AEs) và các khám sức khỏe. Các đánh giá PK của olaparib, carboplatin và paclitaxel đã được thực hiện. Phản ứng khối u (RECIST) được đánh giá mỗi hai chu kỳ. Kết quả: Năm mươi bảy bệnh nhân đã nhận điều trị. DLTs đã được báo cáo ở hai bệnh nhân (cả hai đều nhận olaparib 100 mg bid và carboplatin AUC 4; Phần A, nhóm 2): giảm tiểu cầu độ 1 kèm với giảm bạch cầu trung tính độ 2 kéo dài 16 ngày, và giảm bạch cầu trung tính độ 2 kéo dài 7 ngày. Các AEs không huyết học chủ yếu là độ 1-2 và bao gồm mệt mỏi (70%) và buồn nôn (40%). Suy tủy xương, chủ yếu là giảm bạch cầu trung tính (51%) và giảm tiểu cầu (25%), thường dẫn đến việc điều chỉnh liều. Kết luận: Olaparib kết hợp với carboplatin và/hoặc paclitaxel đã dẫn đến tăng cường độc tính huyết học, khiến việc thiết lập một chế độ liều có thể được dung nạp trong nhiều chu kỳ mà không cần điều chỉnh liều trở nên khó khăn.

Từ khóa

#olaparib #carboplatin #paclitaxel #độc tính #khối u #dược động học.

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