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是一种有记录的耐药机制， 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 已经显示出相当大的毒性和有限的功效。PSC 833 是环孢菌素的非免疫抑制、非肾毒性衍生物 D，特别选择其调节Pgp和逆转 MDR。48例复发性骨髓瘤患者入组研究， PSC 833与阿托斯汀，阿霉素， 和地塞米松（VAD）。PSC 833口服给药，无论是作为 软胶囊或口服溶液，根据五种不同 给药方案。最后有33名患者接受了治疗， PSC 833加VAD的推荐剂量（FRD）。PSC 833口服液的FRD 溶液为0.4 mg/kg qid。长春新碱4天的FRD为 从标准剂量0.4 mg/天降至0.2 mg/天，FRD 阿霉素的标准从9毫克/平方米/天降至7毫克/平方米/天， mg/m2/天。在所有给药时均观察到显著的骨髓抑制 水平（77%的患者），伴有3级或4级粒细胞减少症 观察到35%的患者在FRD接受治疗。的百分之十五 患者出现贫血性发热。虽然没有中毒死亡， 研究中有三例死亡被认为与 PSC。独特的非血液学毒性，通常与 VAD为一过性共济失调（40%），其中8%为3级，无4级共济失调 在FRD时观察到;以及高胆红素血症（35%），其中15%为3级，8%为8级 FRD时4例胆红素升高。全血药代动力学分析 PSC 833的浓度显示，13名患者中的12名（92%）在2%的 29个周期（97%）接受PSC 833（4 mg/kg/qid）的FRD 已知逆转MDR的足够浓度的PSC 833（>1000 ng/ml） 体外在最初的26例可评价或缓解的骨髓瘤患者中， 患者有部分反应，3名患者有轻微反应。 确定PSC 833对多柔比星影响的研究 目前正在分析药物代谢动力学。II期和III期 正在骨髓瘤患者中进行PSC 833加VAD的研究， I期研究确定的剂量。

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.