FDA drug approval summary:: Pegaspargase (Oncaspar ®) for the first-line treatment of children with acute lymphoblastic leukemia (ALL)
FDA drug approval summary:: Pegaspargase (Oncaspar ®) for the first-line treatment of children with acute lymphoblastic leukemia (ALL)
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DOI：
10.1634/theoncologist.12-8-991
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发表时间：
2007-01-01
期刊：
影响因子：
5.8
通讯作者：
Pazdur, Richard
中科院分区：
文献类型：
--
作者：
Dinndorf, Patricia Anne;Gootenberg, Joseph;Pazdur, Richard
2006 年 7 月 24 日，美国食品和药物管理局批准 Pegaspargase（Oncaspar (R)；Enzon Pharmaceuticals, Inc.，Bridgewater，NJ；以下简称 O）作为多药化疗方案的组成部分用于急性淋巴细胞白血病 (ALL) 患者的一线治疗。 O 此前于 1994 年 2 月被批准用于治疗对天然形式的门冬酰胺酶过敏的 ALL 患者。支持这一新适应症的试验是一项开放标签、随机、多中心临床试验，入组了 118 名患有先前未经治疗的标准风险 ALL 的儿童（年龄为 1-9 岁）。患者在缓解诱导和延迟强化 (DI) 治疗阶段接受天然大肠杆菌天冬酰胺酶（Elspar (R)；默克，新泽西州怀特豪斯站；以下简称 E）或 O 以及多药化疗。 O，剂量为 2,500 IU/m(2)，肌内施用。 4 周诱导阶段的第 3 天以及两个 8 周 DI 阶段各阶段的第 3 天。 E，剂量为 6,000 IU/m(2)，肌内施用。每周 3 次，诱导期间 9 剂，每个 DI 阶段 6 剂。这项研究可以直接比较 O 和 E 的天冬酰胺消耗、天冬酰胺酶活性和天冬酰胺酶抗体的形成。对无事件生存期 (EFS) 进行计划外的比较，以排除有害的 O 疗效影响。诱导和 DI 治疗后完成（O 治疗受试者中的 0.03 IU/ml 大于 E 治疗受试者在诱导和 DI 治疗阶段的天数。然而，天冬酰胺酶活性和血清天冬酰胺水平之间不存在相关性，使得 使用方案预先指定的阳性结果阈值>2.5倍对照，在研究期间任何时间测试的56名受试者中，有7名（12％）显示出抗天冬酰胺酶抗体，在研究期间任何时间测试的57名E受试者中，有16名（28％）具有抗天冬酰胺酶抗体。在两个研究组中，3 年时的 EFS 都在 80% 范围内。最严重的是，有时 致命的O毒性包括过敏反应、其他严重过敏反应、血栓形成（包括矢状窦血栓形成）、胰腺炎、葡萄糖不耐受和凝血病。最常见的不良事件是过敏反应（包括过敏反应）、高血糖、胰腺炎、中枢神经系统血栓形成、凝血障碍、高胆红素血症和 转氨酶升高。
July 24, 2006, the U. S. Food and Drug Administration granted approval to pegaspargase (Oncaspar (R); Enzon Pharmaceuticals, Inc., Bridgewater, NJ; hereafter, O) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. O was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of Lasparaginase.The trial supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (age, 1-9 years) with previously untreated, standard risk ALL. Patients received either native Escherichia coli asparaginase (Elspar (R); Merck, Whitehouse Station, NJ; hereafter, E) or O along with multiagent chemotherapy during remission induction and delayed intensification (DI) phases of treatment. O, at a dose of 2,500 IU/m(2), was administered i.m. on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. E, at a dose of 6,000 IU/m(2), was administered i.m. three times weekly for nine doses during induction and for six doses during each DI phase. This study allowed direct comparison of O and E for asparagine depletion, asparaginase activity, and development of asparaginase antibodies. An unplanned comparison of event-free survival (EFS) was conducted to rule out a deleterious O efficacy effect.Following induction and DI treatment there was complete (0.03 IU/ml in O-treated subjects was greater than the number of days in E-treated subjects during both the induction and DI phases of treatment. There was no correlation, however, between asparaginase activity and serum asparagine levels, making the former determination less clinically relevant.Using the protocol-prespecified threshold for a positive result of >2.5 times the control, 7 of 56 (12%) subjects tested at any time during the study demonstrated antiasparaginase antibodies and 16 of 57 (28%) E subjects tested at any time during the study had antiasparaginase antibodies. In both study arms EFS was in the range of 80% at 3 years.The most serious, sometimes fatal, O toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy. The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases.