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Thiết kế thử nghiệm giai đoạn I thích ứng dựa trên mô hình cho điều trị bảo trì decitabine sau cấy ghép ở hội chứng myelodysplastic
Tóm tắt
Báo cáo này tập trung vào thiết kế thử nghiệm giai đoạn I thích ứng nhằm tìm liều lượng có thể áp dụng lâm sàng cho điều trị bảo trì decitabine sau cấy ghép tế bào gốc huyết học đồng loại ở những bệnh nhân bị hội chứng myelodysplastic nguy cơ cao và bệnh bạch cầu cấp dòng tủy thứ phát. Tổ hợp đầu tiên (ba bệnh nhân) được cho sử dụng liều khởi đầu hàng ngày giống nhau của decitabine (5 mg/m2/ngày, năm ngày liên tiếp với các khoảng thời gian 4 tuần). Trong tất cả các tổ hợp, liều dùng cho các Chu kỳ 2 đến 4 được cá nhân hóa bằng cách sử dụng mô hình dược động học-dược lực học và mô phỏng. Mục tiêu của việc cá nhân hóa liều dùng là xác định liều tối đa cho từng bệnh nhân mà không để xảy ra độc tính cấp độ 4 (CTC-AE) đối với cả số lượng tiểu cầu và bạch cầu trung tính. Liều khởi đầu cho các tổ hợp tiếp theo cũng được ước tính từ dữ liệu của các tổ hợp trước đó theo cách tương tự. Trong tất cả trừ một bệnh nhân (14 trong số 15), số lượng bạch cầu trung tính là yếu tố giới hạn liều trong suốt các chu kỳ. Trong các chu kỳ mà liều dùng được cá nhân hóa, mức nadir bạch cầu trung tính trung vị quan sát được là 1100/mm3 (cấp độ 2) và độc tính cấp độ 4 xảy ra trong 5,1% số chu kỳ (trong khi nó xảy ra trong 36,8% những trường hợp mà liều không được cá nhân hóa). Các liều khởi đầu ước tính cho các tổ hợp 2 đến 5 lần lượt là 4, 5, 5.5, và 5 mg/m2/ngày. Liều duy trì trung vị là 7 mg/m2/ngày. Chúng tôi xác định liều khởi đầu chấp nhận được và cá nhân hóa liều duy trì cho từng bệnh nhân, đồng thời giảm thiểu độc tính bằng cách sử dụng phương pháp thích ứng. Hiện tại, 5 mg/m2/ngày được coi là liều khởi đầu phù hợp nhất cho phác đồ đã nghiên cứu. Clinicaltrials.gov NCT01277484
Từ khóa
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