Ramnath Nithya, Schwartz Gary N, Smith Patrick, Bong Daniel, Kanter Peter, Berdzik Joanne, Creaven Patrick J
Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cancer Chemother Pharmacol. 2003 Mar;51(3):227-30. doi: 10.1007/s00280-002-0566-8. Epub 2003 Feb 25.
Anhydrovinblastine (AVLB) is a novel semisynthetic vinca alkaloid. We conducted a phase I trial to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacokinetics of AVLB given as a 1-h intravenous infusion once every 3 weeks in patients with advanced refractory solid tumors.
Entered into the study were 24 patients with normal bone marrow, hepatic and renal function, and of these 21 were evaluable. There were 12 males and 12 females with a median age of 60 years (range 27-75 years). Diagnoses were non-small-cell lung cancer (NSCLC) (11), colorectal cancer (5), soft tissue sarcoma (4), and miscellaneous (4). Patients had had a median of three prior chemotherapy regimens (range one to six). A total of 51 courses were administered at doses of 2.5, 5, 10, 16.5, 21, 25 and 30 mg/m(2) in one, three, one, three, six, six and one patient respectively.
Grade 2 infusional hypertension, anemia, and dizziness were noted at 16.5 mg/m(2). At 25 mg/m(2), two of six evaluable patients had DLT. DLT was grade 4 constipation, neutropenia and grade 3 nausea/vomiting. At 21 mg/m(2) one of six evaluable patients had DLT (grade 3 nausea/vomiting). This dose was the MTD. Stable disease was noted in one patient with metastatic sarcoma to the lungs and in three patients with metastatic NSCLC. The pharmacokinetics of AVLB were linear, and well characterized by a two-compartment model, with a mean clearance of 26.4 l/h per m(2) and median terminal half-life of 18 h.
The recommended phase II dose is 21 mg/m(2). A phase II study in NSCLC is being initiated.
脱水长春碱（AVLB）是一种新型半合成长春花生物碱。我们进行了一项I期试验，以确定晚期难治性实体瘤患者每3周静脉输注1小时AVLB的最大耐受剂量（MTD）、剂量限制性毒性（DLT）和药代动力学。
24例骨髓、肝肾功能正常的患者进入本研究，其中21例可评估。男性12例，女性12例，中位年龄60岁（范围27 - 75岁）。诊断包括非小细胞肺癌（NSCLC）（11例）、结直肠癌（5例）、软组织肉瘤（4例）和其他（4例）。患者既往接受化疗方案的中位数为3个（范围1至6个）。分别以2.5、5、10、16.5、21、25和30 mg/m²的剂量对1、3、1、3、6、6和1例患者共给予51个疗程。
在16.5 mg/m²时观察到2级输注性高血压、贫血和头晕。在25 mg/m²时，6例可评估患者中有2例出现DLT。DLT为4级便秘、中性粒细胞减少和3级恶心/呕吐。在21 mg/m²时，6例可评估患者中有1例出现DLT（3级恶心/呕吐）。该剂量为MTD。1例肺转移肉瘤患者和3例NSCLC转移患者病情稳定。AVLB的药代动力学呈线性，可用二室模型很好地描述，平均清除率为每平方米26.4 l/h，中位终末半衰期为18小时。
推荐的II期剂量为21 mg/m²。正在启动NSCLC的II期研究。
