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

这种多药耐药（MDR）表型是由于 MDR 1/Pgp是一种有文献记载的耐药机制， 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 已经证明了相当大的毒性和有限的效力。 PSC 833 是环孢菌素D的非免疫抑制、非肾毒性衍生物， 因其调节Pgp和逆转MDR的能力而被特别选择。 31例患者，28例复发性骨髓瘤，3例复发性低- 20例20 - 30级非霍奇金淋巴瘤患者参加了PSC 833的I期试验 与阿曲斯汀、阿霉素和地塞米松（VAD）联合。 PSC 833口服给药，作为软明胶胶囊或 口服溶液，根据5种不同的给药方案。 十三 患者接受PSC 833最终推荐剂量（FRD）治疗 加上心室辅助装置 PSC 833口服液的FRD为4 mg/kg qid。 FRD 4 长春新碱的日剂量从标准剂量0.4 mg/天降至 0.2 mg/天，阿霉素的FRD从标准 9 mg/m2/天至7 mg/m2/天。 观察到显著的骨髓抑制 所有剂量水平（77%的患者），3级或4级 在FRD治疗的38%患者中观察到粒细胞减少症。 31个中的4个 患者出现中性粒细胞减少性发热，但无中毒性死亡。 独特 非血液学毒性，通常与VAD无关， 暂时性静止（48%），其中8%为3级，未观察到4级静止， FRD;和高胆红素血症（35%），其中15%为3级，8%为4级 FRD时胆红素升高。 全血药代动力学分析 PSC 833的浓度显示，28名患者中的13名患者中有12名（92%） 29个周期（97%）接受PSC 833（4 mg/kg/qid）的FRD 已知足够浓度的PSC 833（>1000 ng/ml）逆转MDR， 体外 在26例可评价缓解的骨髓瘤患者中，5例患者 部分缓解，3例轻微缓解。 研究来 确定PSC 833对阿霉素药代动力学的影响， 目前正在分析中。 PSC 833 + VAD的II期和III期研究 在骨髓瘤患者中的应用将很快开始 从这个I期研究中确定。

This multidrug resistant (MDR) phenotype due to the overexpression of MDR1/Pgp is a documentated 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 efficacity. PSC 833 is a non-immunosuppressive, non-nephrotoxic derivative of Cyclosporin D, specifically selected for its ability to modulate Pgp and reverse MDR. Thirty-one patients, 28 with relapsed myeloma and 3 with relapsed, low- grade non-Hodgkin's lymphoma were enrolled in a Phase I trial of PSC 833 in combination with Vincristine, Daxorubicin, and Dexamethasone (VAD). PSC 833 was administered orally, either as a soft-gelatin capsule or an oral solution, according to 5 different dosing schedules. Thirteen patients were treated at the final recommended dose (FRD) of PSC 833 plus VAD. THe FRD of PSC 833 oral solution was 4 mg/kg qid. FRD for 4 days of vincristine was reduced from the standard dose of 0.4 mg/day to 0.2 mg/day, and the FRD of doxorubicin was reduced form the standard of 9 mg/m2/day to 7 mg/m2/day. Significant myelosuppression was observed at all dosing levels (77% of patients), with grades 3 or 4 granulocytopenia observed in 38% of patients treated at FRD. Four of 31 patients had neutropenia fevers, but there were no toxic deaths. Unique non-hematologic toxicities, not usually associated with VAD, were transient staxia (48%) with 8% grade 3 and no grade 4 staxia 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 28 of 29 cycles (97%) receiving the FRD of PSC 833 (4mg/kg/qid) achieved adequate concentrations of PSC 833 (>1000 ng/ml) known to reverse MDR in vitro. Of the 26 myeloma patients evaluable for response, 5 patients had a partial response and 3 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 will soon be underway using the doses determined from this Phase I study.