Approval summary for bortezomib for injection in the treatment of multiple myeloma
Approval summary for bortezomib for injection in the treatment of multiple myeloma
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DOI：
10.1158/1078-0432.ccr-03-0781
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发表时间：
2004-06-15
影响因子：
11.5
通讯作者：
Pazdur, R
中科院分区：
文献类型：
--
作者：
Bross, PF;Kane, R;Pazdur, R
目的：多发性骨髓瘤是一种恶性浆细胞疾病，约占血液系统恶性肿瘤的10%。尽管治疗进展，包括造血干细胞移植，以促进高剂量细胞毒性化疗的管理，中位生存期保持约3年，长期缓解是罕见的。硼替佐米（Velcade，以前称为PS-341; Millennium Pharmaceuticals，剑桥MA）是一种二肽硼酸，可抑制参与细胞内蛋白降解的20 S蛋白酶体，包括影响哺乳动物细胞细胞周期调节的蛋白。本文描述了美国食品药品监督管理局（FDA）对新药申请中提交的临床和非临床数据的分析。化学生产和控制，动物毒理学，和生物制药数据进行了描述。总结了多发性骨髓瘤患者的I期和II期临床研究结果。的上市批准和上市后的承诺进行了讨论。结果：毒理学研究在大鼠和猴子的血液，淋巴，心脏，肾脏，胃肠道和神经毒性硼替佐米。当剂量大于或等于0.9 mg/m2时，观察到急剧的剂量毒性效应。给药剂量大于或等于3.0 mg/m2时，猴在给药后12-14 h出现心血管性虚脱和死亡。在猴和啮齿类动物中观察到背根神经节、周围神经和脊髓轴突和髓鞘变性的组织学证据;在晚期恶性肿瘤患者中进行的药代动力学研究表明，在1.45 - 2.00 mg/m2的剂量范围内，硼替佐米首次给药后的平均消除半衰期为9 - 15 h（2）.药物通过细胞色素P450- 3A 4、-2D6、-2C19、-2C9和-1A2代谢。在总共123例晚期恶性肿瘤患者中进行了3项I期研究。剂量限制性毒性包括腹泻和感觉神经毒性。在一项开放标签的II期研究中评估了202例多发性骨髓瘤患者的安全性和有效性，这些患者既往接受过至少两种治疗，并且在最近的治疗中表现出疾病进展。一项54例患者的较小剂量探索研究提供了额外的支持性信息。硼替佐米在21天周期中的第1、4、8和11天通过静脉推注给药，最多持续8个周期。初始剂量为1.3 mg/m（2），剂量探索研究中的28名患者除外，他们接受了1.0 mg/m（2）剂量。这项单组试验的主要研究终点是缓解率，很容易测量，并被认为与骨髓瘤患者的临床获益相关。188例符合入选标准的患者被纳入FDA疗效分析人群。5例患者观察到完全缓解（CR），47例患者观察到部分缓解（PR），总缓解（OR）率（OR = CR + PR）为28%。对54名患者进行的剂量探索研究显示，在3周方案中，每周两次给予1.3 mg/m2的患者的反应率高于每周两次给予1.0 mg/m2的患者，但该研究规模太小，无法进行统计学剂量反应比较。最常报告的不良事件是虚弱状况（包括疲劳、不适和虚弱）65%，恶心（64%），腹泻（51%），食欲下降（包括厌食症; 43%）、便秘（43%）、血小板减少症（43%）、周围神经病变（37%，包括周围感觉神经病变和周围神经病变加重）、发热（36%）、呕吐（36%）和贫血（32%）。FDA于2003年5月13日批准Millennium Pharmaceuticals上市，将硼替佐米作为单一药物用于治疗至少接受过两次既往治疗并在最后一次治疗中表现出疾病进展的多发性骨髓瘤患者。加速批准是基于反应率的替代终点，而不是临床获益，如生存率的改善。硼替佐米的推荐剂量为1.3 mg/m2，每周给药两次，持续2周（第1、4、8和11天），然后休息10天（第12-21天）。加速批准是基于两项II期研究的结果，共256例患者和额外的I期安全性信息。强制性IV期研究承诺，以更准确地描述临床疗效和安全性进行了讨论。
Purpose: Multiple myeloma is a malignant plasma cell disorder accounting for about 10% of hematological malignancies. Despite treatment advances, including hematopoietic stem-cell transplantation to facilitate administration of high-dose cytotoxic chemotherapy, the median survival remains approximately 3 years and long-term remissions are rare. Bortezomib (Velcade, formerly known as PS-341; Millennium Pharmaceuticals, Cambridge MA) is a dipeptide boronic acid that inhibits the 20S proteasome involved in the degradation of intracellular proteins, including those affecting cell cycle regulation in mammalian cells. Described herein are the analyses by the United States Food and Drug Administration (FDA) of clinical and nonclinical data submitted in the New Drug Application. Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. The results of Phase I and Phase II clinical studies in patients with multiple myeloma are summarized. The marketing approval and postmarketing commitments are discussed.Results: Toxicology studies in the rat and monkey identified hematological, lymphoid, cardiac, renal, gastrointestinal, and neurological toxicities of bortezomib. A steep dose-toxicity effect was noted at doses greater than or equal to0.9 mg/m(2). Administration of doses greater than or equal to3.0 mg/m(2) to monkeys resulted in cardiovascular collapse and death 12-14 h postdose. Histopathological evidence of axonal and myelin degeneration of dorsal root ganglia, peripheral nerves, and spinal cord were observed in monkeys and rodents; concurrent clinical observations included tremors and decreased activity.Pharmacokinetic studies in patients with advanced malignancies demonstrated that the mean elimination half-life after the first bortezomib dose varied from 9 to 15 h at doses ranging from 1.45 to 2.00 mg/m(2). The drug is metabolized by cytochrome P450-3A4, -2D6, -2C19, -2C9, and -1A2. Three Phase I studies were performed in a total of 123 patients with advanced malignancies. Dose-limiting toxicity included diarrhea and sensory neurotoxicity. No dose-limiting hematological toxicity was reported.Safety and efficacy were evaluated in an open-label, Phase II study of 202 patients with multiple myeloma who had received at least two prior therapies and had demonstrated disease progression on their most recent therapy. A smaller dose finding study of 54 patients provided additional supportive information. Bortezomib was administered by i.v. bolus on days 1, 4, 8, and 11 in a 21-day cycle for up to eight cycles. The initial dose was 1.3 mg/m(2) except for 28 patients in the dose-finding study who received a 1.0 mg/m(2) dose. The primary study end point in this single-arm trial was response rate, easily measured and thought to correlate with clinical benefit in patients with myeloma. One hundred eighty-eight patients who met the inclusion criteria were included in the FDA efficacy analysis population. Complete responses (CRs) were observed in 5 patients and partial responses (PRs) in 47 patients for an overall response (OR) rate (OR = CR + PR) of 28%. The dose finding study of 54 patients showed a higher response rate for patients given 1.3 mg/m(2) compared with 1.0 mg/m(2) twice weekly for two of the 3-week schedule, but the study was too small for statistical dose-response comparisons. The most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) in 65%, nausea (64%), diarrhea (51%), appetite decreased (including anorexia; 43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%, including peripheral sensory neuropathy and peripheral neuropathy aggravated), pyrexia (36%), vomiting (36%), and anemia (32%).Conclusions: The FDA granted marketing approval to Millennium Pharmaceuticals on May 13, 2003 for bortezomib for use as a single agent for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. Accelerated approval was based on a surrogate end point of response rate rather than clinical benefit, such as an improvement in survival. The recommended dose of bortezomib is 1.3 mg/m(2) administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). Accelerated approval was based on the results of two Phase II studies in a total of 256 patients and additional Phase I safety information. Mandated Phase IV study commitments to characterize clinical efficacy and safety more precisely are discussed.