抗骨髓瘤新药前景
2012-06-19 田磊磊 医学论坛网
一项小型Ⅰ期研究的研究者报告，实验性口服蛋白酶体抑制剂MLN9708可能有望用于治疗复发或对治疗耐药的多发性骨髓瘤患者。 58例多发性骨髓瘤患者中有6例至少得到客观缓解，其中1例接近完全缓解，美国埃默里大学Winship肿瘤研究所的Sagar Loniol博士说，这例患者既往未接受蛋白酶体抑制剂治疗，并
一项小型Ⅰ期研究的研究者报告，实验性口服蛋白酶体抑制剂MLN9708可能有望用于治疗复发或对治疗耐药的多发性骨髓瘤患者。
58例多发性骨髓瘤患者中有6例至少得到客观缓解，其中1例接近完全缓解，美国埃默里大学Winship肿瘤研究所的Sagar Loniol博士说，这例患者既往未接受蛋白酶体抑制剂治疗，并且属于该研究扩展队列。
“初步研究数据提示，在曾接受反复治疗的复发和/或耐药的多发性骨髓瘤患者中，MLN9708具有临床治疗活性，Loniol在2012年美国临床肿瘤学会年会（ASCO2012）上说。
他还指出，1例患者接近完全缓解，另外1例得到很好地部分缓解。总体上，32例疾病稳定持续至少17.3个月。
在这项Ⅰ期剂量爬坡（dose escalation）和用药安全性试验中，各组患者实验性地接受多种剂量（0.24 mg/m2 ～2.23 mg/m2）的MLN9708治疗，直至最大耐受剂量。
研究受试者为接受硼替佐米、沙利度胺/来那度胺、或皮质醇类药物治疗后疾病进展的体能状态为0～2分的成人患者。
该研究共纳入了58例患者，26例属于剂量爬坡试验队列，28例属于扩展队列。患者中位年龄为65岁，52%为男性，90%为白人，确诊多发性骨髓瘤的中位时间为4.8年。患者已经接受中位值为4个周期的患者，其中1例患者接受了27个周期的治疗。
截至2012年3月27日，受试者尚存8例。
虽然剂量爬坡队列和扩展队列均发生一些不良事件，但剂量爬坡队列无患者出组，而扩展队列中12%的患者因不良事件终止试验。
Loniol说，51患者可评估缓解情况。研究确定的最大耐受剂量为2.0 mg/kg。“患者对口服MLN9708的总体耐受性良好，”他说，并特别指出，周围神经病变发生率低且病情轻微，未观察到3或4级周围神经病变。
美国Dana Farber研究所/哈佛大学医学助理教授Irene Ghobrial博士说，MLN9708联合其他药物可能对多发性骨髓瘤有治疗效果。
“该药方便给药，毒性反应似乎也轻于现有其他药物，”她说。她预测，该药可能将被用于高危多发性骨髓瘤的维持治疗。“它是口服的，且副作用较小，因此可能有使用空间。”Ghobrial在报告讨论环节说。
Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM)
Abstract
Background: MLN9708 is the first oral proteasome inhibitor to enter clinical investigation in MM. This study (NCT00932698) assessed safety, MTD, and response rate with twice-weekly oral MLN9708 in pts with relapsed and/or refractory MM, and characterized plasma pharmacokinetics (PK) and blood pharmacodynamics.
Methods: Pts aged ≥18 yrs with measurable MM received MLN9708 on d 1, 4, 8, and 11 of 21-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD (2.0 mg/m2), pts were enrolled to relapsed and refractory [RR], bortezomib-relapsed [VR], proteasome-inhibitor [PI] naïve, and carfilzomib [CZ] expansion cohorts.
Results: 57 pts (53% M) were enrolled, 37 to the expansion cohorts (16 RR, 14 VR, 6 PI naïve, 1 CZ). Median age was 65 yrs (range 50-86). Median number of prior lines of therapy was 4 (range 1-28); 88%, 84%, 61%, and 5% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 3 cycles (range 1-24) to date (data cut-off Dec 1, 2011); 7 (12%) have received ≥13 cycles. Drug-related AEs were seen in 89% of pts, including fatigue (46%), thrombocytopenia (40%), and nausea (30%); 63% had drug-related grade ≥3 AEs, including thrombocytopenia (33%), neutropenia (14%), fatigue (9%), and rash (7%). Only 6 (11%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 7 pts discontinued due to AEs. 2 pts died on study, due to PD and an unrelated cardiac disorder. Of 46 response-evaluable pts, 6 have achieved ≥PR, with 1 sCR (PI naïve cohort) and 5 PRs (2 in dose-escalation, 1 in RR, 2 in VR cohorts), and 1 VR pt has achieved MR, with duration of disease control of up to 18.6 mo. PK analyses showed MLN2238 (biologically active hydrolysis product) has linear plasma PK (0.8-2.23 mg/m2), Tmax of 0.5-1.25 hr, and terminal half-life of 4-6 d. A dose-dependent increase in whole blood 20S proteasome inhibition was observed.
Conclusions: Current data suggest MLN9708 has clinical activity in heavily pretreated MM pts, with durable responses/disease control, and is generally well tolerated with infrequent low-grade PN.
Methods: Pts aged ≥18 yrs with measurable MM received MLN9708 on d 1, 4, 8, and 11 of 21-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD (2.0 mg/m2), pts were enrolled to relapsed and refractory [RR], bortezomib-relapsed [VR], proteasome-inhibitor [PI] naïve, and carfilzomib [CZ] expansion cohorts.
Results: 57 pts (53% M) were enrolled, 37 to the expansion cohorts (16 RR, 14 VR, 6 PI naïve, 1 CZ). Median age was 65 yrs (range 50-86). Median number of prior lines of therapy was 4 (range 1-28); 88%, 84%, 61%, and 5% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 3 cycles (range 1-24) to date (data cut-off Dec 1, 2011); 7 (12%) have received ≥13 cycles. Drug-related AEs were seen in 89% of pts, including fatigue (46%), thrombocytopenia (40%), and nausea (30%); 63% had drug-related grade ≥3 AEs, including thrombocytopenia (33%), neutropenia (14%), fatigue (9%), and rash (7%). Only 6 (11%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 7 pts discontinued due to AEs. 2 pts died on study, due to PD and an unrelated cardiac disorder. Of 46 response-evaluable pts, 6 have achieved ≥PR, with 1 sCR (PI naïve cohort) and 5 PRs (2 in dose-escalation, 1 in RR, 2 in VR cohorts), and 1 VR pt has achieved MR, with duration of disease control of up to 18.6 mo. PK analyses showed MLN2238 (biologically active hydrolysis product) has linear plasma PK (0.8-2.23 mg/m2), Tmax of 0.5-1.25 hr, and terminal half-life of 4-6 d. A dose-dependent increase in whole blood 20S proteasome inhibition was observed.
Conclusions: Current data suggest MLN9708 has clinical activity in heavily pretreated MM pts, with durable responses/disease control, and is generally well tolerated with infrequent low-grade PN.
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本网站所有内容来源注明为“梅斯医学”或“MedSci原创”的文字、图片和音视频资料，版权均属于梅斯医学所有。非经授权，任何媒体、网站或个人不得转载，授权转载时须注明来源为“梅斯医学”。其它来源的文章系转载文章，或“梅斯号”自媒体发布的文章，仅系出于传递更多信息之目的，本站仅负责审核内容合规，其内容不代表本站立场，本站不负责内容的准确性和版权。如果存在侵权、或不希望被转载的媒体或个人可与我们联系，我们将立即进行删除处理。
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如果有静脉用蛋白酶体抑制剂将是个好事情
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