FOCUS（PX-171-011）研究的设计和原理：卡非佐米与最佳支持治疗方案治疗复发/难治性多发性骨髓瘤（R/R MM）患者的随机、开放标签、3 期研究。
Design and rationale of FOCUS (PX-171-011): a randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM).
机构信息
University Hospital Brno, Czech Republic.
出版信息
BMC Cancer. 2012 Sep 19;12:415. doi: 10.1186/1471-2407-12-415.
BACKGROUND
Carfilzomib is a next-generation proteasome inhibitor with single-agent activity in patients with relapsed and refractory multiple myeloma (R/R MM). In PX-171-003-A1, a single-arm phase 2 study of carfilzomib monotherapy in heavily pretreated patients, the overall response rate was 23.7%, 37% of patients achieved ≥ minimal response and median overall survival (OS) was 15.6 months. Based on this study, carfilzomib was recently approved by the US Food and Drug Administration for the treatment of R/R MM. Herein we describe the trial design and rationale for a phase 3 randomized study, FOCUS (CarFilzOmib for AdvanCed Refractory MUltiple Myeloma European Study), being conducted to compare OS after treatment with single-agent carfilzomib to best supportive care (BSC) regimen in R/R MM.
METHODS
Patients must have received ≥3 prior regimens, must be responsive to at least 1 line of therapy, and be refractory to their most recent therapy. Eligible patients are randomized 1:1 to receive either carfilzomib (28-day cycles at 20 mg/m(2) IV on Days 1-2 of Cycle 1, escalating to 27 mg/m(2) IV on Days 8, 9, 15, and 16 and continuing at 27 mg/m(2) through Cycle 9 and Days 1, 2, 15, and 16 ≥ Cycle 10) or an active BSC regimen (corticosteroid treatment of prednisolone 30 mg, dexamethasone 6 mg, or equivalent every other day with optional cyclophosphamide 50 mg PO once daily). Patients will continue treatment until disease progression, unacceptable toxicity, or treatment discontinuation and will then enter long-term follow-up for survival. The primary endpoint is OS and secondary endpoints include progression-free survival, overall response rate, and safety. Disease assessments will be determined according to the International Myeloma Working Group Uniform Response Criteria with minimal response per European Blood and Marrow Transplantation Group criteria.
CONCLUSIONS
This phase 3 trial will provide more rigorous data for carfilzomib, as this is the first carfilzomib study with OS as the primary endpoint and will not be confounded by crossover and will provide more robust secondary response and safety results that will add to the data set from prior phase 2 studies. FOCUS will facilitate regulatory approvals around the world and expand treatment options for patients with R/R MM.
TRIAL REGISTRATION
EudraCT No. 2009-016840-38; NCT01302392.
背景
卡非佐米是一种新一代蛋白酶体抑制剂，在复发和难治性多发性骨髓瘤（R/R MM）患者中具有单药活性。在 PX-171-003-A1 中，一项卡非佐米单药治疗既往大量治疗患者的单臂 2 期研究中，总缓解率为 23.7%，37%的患者达到了至少微小缓解，中位总生存期（OS）为 15.6 个月。基于这项研究，卡非佐米最近被美国食品和药物管理局批准用于治疗 R/R MM。在此，我们描述了一项 3 期随机研究的试验设计和原理，该研究称为 FOCUS（用于 ADVANCED 难治性多发性骨髓瘤的欧洲研究），旨在比较单药卡非佐米治疗 R/R MM 后与最佳支持治疗（BSC）方案的 OS。
方法
患者必须接受过≥3 种治疗方案，必须对至少 1 种治疗方案有反应，并且对最近的治疗方案有耐药性。合格的患者以 1:1 的比例随机接受卡非佐米（第 1 天和第 2 天的 28 天周期为 20 mg/m2 IV，第 1 周期的第 8 天、第 9 天、第 15 天和第 16 天逐渐增加至 27 mg/m2 IV，第 9 周期及第 10 天及以上的周期继续为 27 mg/m2，第 1 天、第 2 天、第 15 天和第 16 天≥第 10 周期）或活性 BSC 方案（泼尼松龙 30 mg，地塞米松 6 mg，或每天每两天的等效剂量，同时可选择每天一次口服环磷酰胺 50 mg）。患者将继续接受治疗，直到疾病进展、不可接受的毒性或停止治疗，然后进入长期随访以观察生存情况。主要终点是 OS，次要终点包括无进展生存期、总缓解率和安全性。疾病评估将根据国际骨髓瘤工作组统一缓解标准进行，最小缓解标准为欧洲血液和骨髓移植组标准。
结论
这项 3 期试验将为卡非佐米提供更严格的数据，因为这是第一项以 OS 为主要终点的卡非佐米研究，不会受到交叉的影响，并且将提供更强大的次要缓解和安全性结果，这将增加来自之前 2 期研究的数据。FOCUS 将促进全球监管审批，并为 R/R MM 患者提供更多的治疗选择。
试验注册
EudraCT 编号 2009-016840-38；NCT01302392。
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