Beer Tomasz M, Javle Milind M, Ryan Christopher W, Garzotto Mark, Lam Gilbert N, Wong Alvin, Henner W David, Johnson Candace S, Trump Donald L
Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health and Science University, Mail Code CR-145, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Cancer Chemother Pharmacol. 2007 Apr;59(5):581-7. doi: 10.1007/s00280-006-0299-1. Epub 2006 Oct 26.
DN-101 is a new, high-dose, oral formulation of calcitriol under investigation for the treatment of cancer. We sought to evaluate the tolerability and pharmacokinetics (PK) of weekly doses of DN-101 in patients with advanced cancer.
Patients who completed a previously reported single dose escalation study of DN-101 [Beer et al. (2005) Clin Cancer Res 11:7794-7799] were eligible for this continuation weekly dosing study. Cohorts of 3-10 patients were treated at doses of 15, 30, 45, 60, and 75 microg calcitriol. Once 45 microg was established as the maximum tolerated dose (MTD), this cohort was expanded to include 18 patients. Dose limiting toxicity (DLT) was defined as > or =grade 2 hypercalcemia or > or =grade 3 persistent treatment-related toxicities.
Thirty-seven patients were recruited. DLT of transient reversible grade 2 hypercalcemia (serum calcium of 11.6-12.5 mg/dL) occurred in two of six patients treated with 60 microg of DN-101. No DLT was observed in the 18 patients who received DN-101 weekly at 45 microg. Overall, DN-101 was well tolerated. The most frequent adverse events were fatigue (27%), hypercalcemia (19%, including five grade 1, two grade 2, and no grade 3 or 4 events), and grade 1 nausea (16%). PK parameters following repeat dosing were comparable to those for the initial dose (n = 4).
The MTD for weekly DN-101 was established as 45 mug. The DLTs observed were two episodes of rapidly reversible grade 2 hypercalcemia in two of the six patients treated at 60 microg weekly. Repeat doses of DN-101 at 45 microg weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients.
DN - 101是一种新型高剂量口服骨化三醇制剂，正用于癌症治疗的研究。我们旨在评估晚期癌症患者每周服用DN - 101的耐受性和药代动力学（PK）。
完成先前报道的DN - 101单剂量递增研究[Beer等人（2005年）《临床癌症研究》11：7794 - 7799]的患者有资格参加这项持续的每周给药研究。3 - 10名患者为一组，分别接受15、30、45、60和75微克骨化三醇的治疗。一旦确定45微克为最大耐受剂量（MTD），该组扩大至包括18名患者。剂量限制毒性（DLT）定义为≥2级高钙血症或≥3级持续的与治疗相关的毒性。
招募了37名患者。6名接受60微克DN - 101治疗的患者中有2名出现了短暂可逆的2级高钙血症（血清钙为11.6 - 12.5毫克/分升）的DLT。在18名每周接受45微克DN - 101治疗的患者中未观察到DLT。总体而言，DN - 101耐受性良好。最常见的不良事件是疲劳（27%）、高钙血症（19%，包括5例1级、2例2级，无3级或4级事件）和1级恶心（16%）。重复给药后的PK参数与初始剂量时相当（n = 4）。
每周DN - 101的MTD确定为45微克。观察到的DLT是在6名每周接受60微克治疗的患者中有2名出现了两例快速可逆的2级高钙血症。每周重复给予45微克的DN - 101耐受性良好，该剂量适用于在癌症患者中进行每周DN - 101的研究。
