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是白血病患者耐药的一种已知机制 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 已经显示出巨大的毒性和有限的疗效。PSC 833 是环孢菌素D的一种非免疫抑制、无肾毒性的衍生物， 因其调制PGP和逆转MDR的能力而特别被选中。 31例患者中，28例为复发性骨髓瘤，3例为复发性低度恶性骨髓瘤。 恶性非霍奇金淋巴瘤参加PSC 833的I期试验 联合长春新碱、阿霉素和地塞米松(VAD)。 PSC 833口服，以软胶囊剂或 口服液，根据5种不同的给药方案。十三 患者接受PSC 833的最终推荐剂量(FRD)治疗 外加VAD。PSC-833口服液的FRD为4 mg/kg，qid。FRD，4个 长春新碱的天数从每天0.4毫克的标准剂量减少到 0.2 mg/d，阿霉素的FRD从标准的 9 mg/m2/天至7 mg/m2/天。观察到明显的骨髓抑制。 所有剂量水平(77%的患者)，3级或4级 在FRD接受治疗的患者中，有38%观察到粒细胞减少。31次中的4次 患者有中性粒细胞减少症发烧，但没有中毒性死亡。独一无二 非血液学毒性，通常与VAD无关， 暂时性静止(48%)，其中8%为3级静止，无4级静止 FRD；高胆红素血症(35%)，3级15%，4级8% 法兰克福机场的胆红素浓度。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28名 29个周期(97%)获得PSC 833(4 mg/kg/qid)的FRD 已知的足够浓度的PSC 833(&gt；1000 ng/ml)可以逆转人的MDR 体外培养。在26名可评价疗效的骨髓瘤患者中，有5名患者 部分缓解，3例轻微缓解。研究到 测定PSC 833对阿霉素药代动力学的影响 目前正在分析中。PSC 833加VAD的第二阶段和第三阶段研究 在骨髓瘤患者中使用的剂量将很快进行 从这项第一阶段研究中确定。

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.