Jackson D V, Cruz J M, Zekan P J, Caponera M E, Spurr C L, White D R, Richards F, Muss H B
Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27103.
Invest New Drugs. 1989 Jul;7(2-3):203-7. doi: 10.1007/BF00170858.
A phase I trial of vincristine and etoposide was designed following the identification of a potentially synergistic antitumor effect in a murine model. The dose of vincristine was fixed (0.5 mg daily for 3 days). Etoposide was given at 1 of 3 total dose levels (250, 500, or 750 mg/m2) per treatment. Each dose was given in 3 equal fractions and each fraction was given daily for 3 days, i.e., 83.3 mg/m2/d x 3d, 166.7 mg/m2/d x 3d, or 250 mg/m2/d x 3d. A total of 31 patients were entered into study including 10, 18, and 3 patients treated at the 250, 500, and 750 mg/m2 dose levels, respectively. Dose-limiting toxicity occurred at the 750 mg/m2 level, in which Grade 4 myelosuppression developed in all of the patients. Life-threatening gram negative sepsis occurred in two of these patients and both required platelet transfusions. Grade 3-4 WBC toxicity was observed in 9 of 16 (56%) evaluable patients treated at the 500 mg/m2 level, but reversal of toxicity was generally rapid with repeat courses given at 3 week intervals in most patients. Non-hematologic toxicity was negligible. Objective responses were observed in 2 of 4 patients with Hodgkin's disease. The starting dose of etoposide recommended for phase II trials of this agent in combination with vincristine is 500 mg/m2; dose escalation may be possible in some patients.
在小鼠模型中发现长春新碱和依托泊苷具有潜在的协同抗肿瘤作用后，设计了一项长春新碱和依托泊苷的I期试验。长春新碱的剂量固定（每日0.5mg，共3天）。依托泊苷在每次治疗时给予3个总剂量水平（250、500或750mg/m²）中的1个。每个剂量分为3个相等的部分，每个部分每日给药3天，即83.3mg/m²/d×3d、166.7mg/m²/d×3d或250mg/m²/d×3d。共有31名患者进入研究，分别有10、18和3名患者接受250、500和750mg/m²剂量水平的治疗。剂量限制性毒性出现在750mg/m²水平，所有患者均出现4级骨髓抑制。其中两名患者发生危及生命的革兰氏阴性菌败血症，两人均需要输注血小板。在接受500mg/m²剂量水平治疗的16名可评估患者中，有9名（56%）观察到3 - 4级白细胞毒性，但大多数患者在3周间隔重复疗程后毒性通常迅速逆转。非血液学毒性可忽略不计。4例霍奇金病患者中有2例观察到客观缓解。该药物与长春新碱联合进行II期试验推荐的依托泊苷起始剂量为500mg/m²；部分患者可能可以增加剂量。
