Armstrong Deborah K, Fleming Gini F, Markman Maurie, Bailey Howard H
John Hopkins Kimmel Cancer Center, Bunting Blaustein Cancer Research Building, Baltimore, MD 21231-1000, USA.
Gynecol Oncol. 2006 Nov;103(2):391-6. doi: 10.1016/j.ygyno.2006.02.029. Epub 2006 Apr 19.
Paclimer is a biodegradable polymer microsphere formulation containing 10% (w/w) paclitaxel that is designed to provide a sustained-release form of paclitaxel after intraperitoneal (IP) administration. The goals of this phase I study were to determine the maximum tolerated dose (MTD) of IP paclitaxel microspheres and the pharmacology of paclitaxel after IP paclitaxel microsphere administration.
Twelve patients with recurrent or persistent ovarian or primary peritoneal carcinoma were treated. After placement of an IP catheter, patients were treated with escalating doses of IP paclitaxel microspheres administered with 2 l of normal saline following premedication. Treatment could be repeated once, 8 weeks after initial treatment. The starting dose was 60 mg/m2 and no intrapatient dose escalation was used.
One dose-limiting toxicity consisting of abdominal pain, ileus and bowel obstruction was seen with the second cycle of therapy in one patient who received 900 mg/m2. Patients received up to 1200 mg/m2 without further evidence of dose-limiting toxicities (DLT). The study was discontinued before MTD was defined due to the manufacturer's decision to suspend further clinical development of paclitaxel microspheres. Pharmacokinetic analysis showed a trend toward a dose-dependent effect of IP paclitaxel microspheres on measured plasma paclitaxel levels. Sustained paclitaxel levels were maintained throughout all 8 weeks of therapy; however, paclitaxel concentrations were well below the plasma concentrations associated with toxicity. In one patient, laparoscopy revealed extensive adhesions, fat necrosis, foreign body giant cell reaction and detectable residual polymer filaments 7 months after completion of treatment with paclitaxel microspheres.
IP administration of paclitaxel microspheres is well tolerated up to 1200 mg/m2 without defining MTD. The low but persistent detection of plasma paclitaxel indicates that paclitaxel continues to be released for at least 8 weeks after IP paclitaxel microsphere treatment. The finding of significant peritoneal abnormalities, including the presence of residual polymer filaments, months after IP Paclimer treatment suggests that the polymer preparation used in Paclimer degrades slowly.
Paclimer是一种可生物降解的聚合物微球制剂，含有10%（重量/重量）的紫杉醇，旨在腹腔内（IP）给药后提供紫杉醇的缓释形式。本I期研究的目的是确定腹腔内紫杉醇微球的最大耐受剂量（MTD）以及腹腔内给予紫杉醇微球后紫杉醇的药理学特性。
对12例复发性或持续性卵巢癌或原发性腹膜癌患者进行治疗。放置腹腔内导管后，患者在预处理后接受递增剂量的腹腔内紫杉醇微球治疗，并注入2升生理盐水。初始治疗8周后可重复治疗一次。起始剂量为60mg/m²，未在患者内进行剂量递增。
在接受900mg/m²的一名患者的第二个治疗周期中出现了一例剂量限制性毒性，表现为腹痛、肠梗阻和肠阻塞。患者接受高达1200mg/m²的剂量，未出现进一步的剂量限制性毒性（DLT）证据。由于制造商决定暂停紫杉醇微球的进一步临床开发，在确定MTD之前该研究终止。药代动力学分析显示腹腔内紫杉醇微球对测得的血浆紫杉醇水平有剂量依赖性效应趋势。在整个8周的治疗过程中紫杉醇水平持续维持；然而，紫杉醇浓度远低于与毒性相关的血浆浓度。在一名患者中，腹腔镜检查显示在完成紫杉醇微球治疗7个月后出现广泛粘连、脂肪坏死、异物巨细胞反应和可检测到的残留聚合物细丝。
腹腔内给予紫杉醇微球，在未确定MTD的情况下，高达1200mg/m²的剂量耐受性良好。血浆紫杉醇水平虽低但持续可检测到，表明腹腔内给予紫杉醇微球治疗后紫杉醇至少持续释放8周。腹腔内给予Paclimer治疗数月后发现明显的腹膜异常，包括残留聚合物细丝的存在，提示Paclimer中使用的聚合物制剂降解缓慢。
