Phase I study of BCX1777 (forodesine) in patients with relapsed or refractory peripheral T/natural killer-cell malignancies
Phase I study of BCX1777 (forodesine) in patients with relapsed or refractory peripheral T/natural killer-cell malignancies
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DOI：
10.1111/j.1349-7006.2012.02287.x
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发表时间：
2012-07-01
期刊：
影响因子：
5.7
通讯作者：
Tobinai, Kensei
中科院分区：
文献类型：
--
作者：
Ogura, Michinori;Tsukasaki, Kunihiro;Tobinai, Kensei
BCX 1777（forodesine）是一种新型嘌呤核苷磷酸化酶抑制剂，主要在T细胞中诱导凋亡。为了评估BCX 1777的安全性、耐受性和药代动力学，我们在复发性或难治性外周T/天然巨噬细胞恶性肿瘤患者中进行了一项I期研究。符合条件的患者患有复发性或难治性外周T/天然巨噬细胞恶性肿瘤，无任何主要器官功能障碍。BCX 1777口服给药，每日一次（剂量递增：100、200和300，类似于mg），直至疾病进展需要新的治疗或发生不可接受的不良事件。共有13例患者入组并接受了3个剂量队列的治疗（100例与mg/天相似，5例患者; 200例与mg/天相似，3例患者; 300例与mg/天相似，5例患者）。虽然没有患者发生剂量限制性毒性，但基于海外数据，未进行进一步剂量递增。因此，未确定最大耐受剂量。3级或以上（≥ 2例患者）的不良事件包括淋巴细胞减少症（62%）、贫血（15%）、白细胞减少症（8%）和发热（8%）。每个队列第1天的BCX 1777血浆药代动力学参数（血浆浓度-时间曲线下面积）分别为1948 +/- 884、4608 +/- 1030和4596 +/- 939 ng/mL。在大约一半的患者中实现了疾病控制。1例间变性大细胞淋巴瘤患者（间变性淋巴瘤激酶阴性）获得完全缓解，2例皮肤T细胞淋巴瘤患者获得部分缓解。BCX 1777在高达300 mg每日一次的剂量下耐受性良好，并且在复发性或难治性外周T/天然巨噬细胞恶性肿瘤中显示出活性的初步证据，从而避免了进一步的研究。（Cancer Sci 2012; 103：12901295）
BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 similar to mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 similar to mg/day, five patients; 200 similar to mg/day, three patients; 300 similar to mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (=2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 +/- 884, 4608 +/- 1030, and 4596 +/- 939 ngh/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation. (Cancer Sci 2012; 103: 12901295)