注射用藤黄酸Ⅰ期临床耐受性研究

PhaseⅠhuman tolerability trial of gambogic acid

目的：观察藤黄酸在人体的安全性，确定藤黄酸静脉给药对肿瘤患者的最大耐受剂量（MTD）及剂量限制性毒性（DLT），为Ⅱ期临床研究提供安全有效的给药剂量及方案。方法：本试验分为单次和连续给药的耐受性试验两部分。单次给药试验采用改良的Fibonacci方法，起始剂量为10mg·m^-2，每剂量组3例，如无明显毒副反应则进入下一剂量组，直到达到剂量限制性毒性。连续给药试验递增剂量分别为10，25，35，45，60mg·m^-2；给药方法有：qd×6d（10mg·m^-2组），每周2次，连用2周（25，35，45mg·m^-2组），qd×7d（45mg·m^-2组调整方案一），qod×7d（45mg·m^-2组调整方案二），qd×5d（60mg·m^-2组）；1月后评价安全性和疗效。结果：单次给药试验共有15例患者入组，在第5剂量组（70mg·m^-2）出现剂量限制性毒性（肝功能损害、疼痛），其他毒性反应有恶心／呕吐、血管刺激等，最大耐受剂量为55mg·m^-2。连续给药试验共有16例患者入组，不良反应有疼痛、恶心／呕吐、转氨酶升高，均为Ⅰ～Ⅱ度．但在60mg·m^-2剂量组（5d）时转氨酶升高持续时间较长；疗效评价结果为稳定（SD）和进展（PD）各8例。结论：藤黄酸的剂量限制性毒性为肝功能损害、疼痛，推荐Ⅱ期临床给药方案为45mg·m^-2，qd×5d或qod×5d，每3～4周重复。

Objective： To assess the safety, maximal tolerated dose （MTD）and dose-limiting toxicity（DLT） of intravenously injected gambogic acid in cancer patient. Methods： Fifteen subjects with cancers were intravenously injected with a single-dose of gambogic acid. By a modified Fibonacci series, the subjects were injected to have an initial dose of 10 mg·m^-2. A cohort of three patients was treated at each dose level, 10, 20, 35, 55 and 70 mg·m^-2 each. The dose escalation to the next level was continuous until DLT reached. Additional 16 subjects with cancer were intravenously injected with successive dose of gambogic acid（10, 25, 35, 45 and 60 mg·m^-2） , respectively. The subjects＇ regimen included qd × 6, 2/W × 2 weeks, qd × 7, qod×7 and qd×5. Safety and efficacy were evaluated in one month after the injection. Results： The subjects injected at 70 mg·m^-2 experienced the incidence rate of the DLT （33%） , manifesting grade 4 increase of ALT and pain, nausea/vomiting and vein irritation. The MTD the subjects had was 55 mg·m^-2 The subjects with the successive dose escalation showed incidence of adverse events including pain, nausea/vomiting, and an escalation of transaminase （all grade Ⅰ-Ⅱ ）. At the dose of 60 mg·m^- 2 （ qd × 5 ） , the subjects remained abnormally higher level of ALT for a long run. Efficacy evaluations disclosed 8 subjects with stable status of cancers and 8 subjects with progressive cancer. Conclusion： The DLT of gambogic acid is involved with liver dysfunction and pain. The recommended regimen of gambogic acid is 45 mg·m^- 2, qd ×5 or 45 mg·m^- 2 , qod× 5 with repeated cycle every 3 -4 weeks in Phase Ⅱ clinical trial.