PHASE I CLINICAL TRIAL OF VINCRISTINE, ADRIAMYCIN AND OTHERS IN RELAPSE MYELOMA

这种多药耐药(MDR)表型是由于过度表达 MDR1/Pgp是一种已知的白血病患者耐药机制 多发性骨髓瘤。几种目前可用的化合物，如 维拉帕米和环孢菌素A可调节MDR：然而，临床研究 已经表现出巨大的毒性和有限的疗效。PSC 833 是一种非免疫抑制、无肾毒性的环孢素衍生物 D，因其调制PGP和反向的能力而被特别选择 MDR。48名复发性骨髓瘤患者参加了一项 PSC 833联合长春新碱、阿霉素、 地塞米松(VAD)。PSC 833口服给药，或作为 软胶胶囊或口服液，按五种不同 给药计划。33名患者在决赛中接受了治疗 PSC 833加VAD的推荐剂量(FRD)。PSC 833口试的FRD 口服液为0.4 mg/kg，qid。长春新碱四天的FRD是 从每天0.4毫克的标准剂量减少到0.2毫克/天，FRD 阿霉素的用量从每天9毫克/平方米降至7毫克/天 Mg/m2/天。在所有剂量下都观察到明显的骨髓抑制。 水平(77%的患者)，伴有三级或四级粒细胞减少 观察到35%的患者在FRD接受治疗。15%的人 患者出现中性粒细胞减少性发热。没有中毒死亡，尽管 这项研究中有三人死亡，据信与 PSC。独特的非血液毒性，通常与 VaD为暂时性共济失调(40%)，其中8%为3级共济失调，无4级共济失调 高胆红素血症(35%)，其中15%为3级，8%为级 FRD的4个胆红素升高。全血药代动力学分析 PSC 833浓度显示13名患者中有12名(92%)在2%的 29个周期(97%)获得PSC 833(4 mg/kg/qid)的FRD 已知足够浓度的PSC 833(&gt；1000 ng/ml)可逆转MDR 在试管中。在初诊的26例可评价或有反应的骨髓瘤患者中，有5例 患者有部分反应，3名患者有轻微反应。 PSC-833对阿霉素作用的研究 目前正在对药物动力学进行分析。第二阶段和第三阶段 PSC 833联合VAD治疗骨髓瘤患者的研究正在进行中 根据这项第一阶段研究确定的剂量。

This multidrug resistant (MDR) phenotype due to the overexpression of MDR1/Pgp is a documented mechanism of drug resistance in patients with multiple myeloma. Several currently available compounds such as verapamil and Cyclosporin A can modulate MDR: however, clinical studies have demonstrated substantial toxicity and limited efficacy. PSC 833 is a non-immunosuppressive, non-nephrotoxic derivative of Cyclosporin D, specifically selected for its ability to modulate Pgp and reverse MDR. Forty-eight patients with relapsed myeloma were enrolled in a Phase I trial of PSC 833 in combination with Vincristine, Adriamycin, and Dexamethasone (VAD). PSC 833 was administered orally, either as a soft-gelatin capsule or an oral solution, according to five different dosing schedules. Thrity-three patients were treated at the final recommended dose (FRD) of PSC 833 plus VAD. The FRD of PSC 833 oral solution was 0.4 mg/kg qid. FRD for four days of vincristine was reduced from the standard does of 0.4 mg/day to 0.2 mg/day, and the FRD of doxorubicin was reduced from the standard of nine mg/m2/day to seven mg/m2/day. Signficant myelosuppression was observed at all dosing levels (77% of patients), with grades three or four granulocytopenia observed 35% of patients treated at FRD . Fifteen percent of the patients had neutropenic fevers. There were no toxic deaths, although there were three deaths on the study believed to be unrelated to the PSC. Unique non-hematologic toxicities, not usually associated with VAD, were transient ataxia (40%) with 8% grade 3 and no grade 4 ataxia noted at FRD; and hyperbilirubinemia (35%) with 15% grade 3 and 8% grade 4 bilirubin elevations at FRD. Pharmacokinetic analysis of whole blood concentrations of PSC 833 showed that 12 of 13 patients (92%) in 2% of 29 cycles (97%) receiving the FRD of PSC 833 (4 mg/kg/qid) achieved adequate concentrations of PSC 833 (>1000 ng/ml) known to reverse MDR in vitro. Of the inital 26 myeloma patients evaluable or response, five patients had a partial response and three patients had a minor response. Studies to determine the effects of PSC 833 on doxorubicin pharmacokinetics are currently being analyzed. Phase II and III studies of PSC 833 plus VAD in patients with myeloma are underway using the doses determined from this Phase I study.