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ASH2014:武田ixazomib单药维持疗法有效改善多发性骨髓瘤(MM)缓解深度

  1. ixazomib
  2. 多发性骨髓瘤
  3. 武田

来源:生物谷 2014-12-09 10:02

ixazomib单药维持疗效,有效改善了多发性骨髓瘤(MM)的缓解深度。该药如果上市,将作为一种重要的单药维持疗法。

武田ixazomib单药维持疗法有效改善多发性骨髓瘤(MM)缓解深度 

2014年12月9日讯 /生物谷BIOON/ --2014年第56届美国血液学会年会(ASH)于12月6日-9日在美国旧金山举行。近日,武田在会上公布了口服抗癌药物ixazomib(MLN9708)一项多发性骨髓瘤(MM)II期临床的数据。该研究在已接受12个周期ixazomib+来那度胺+地塞米松诱导治疗的多发性骨髓瘤(MM)患者中开展,评估了ixazomib作为一种单药维持疗法的疗效和安全性。研究结果证明了ixazomib作为单药维持疗法的潜在可行性,扩大了缓解深度并具有可接受的耐受性。

该研究的主要目标是实现极佳部分缓解(VGPR)或更好缓解[定义为完全缓解(CR)+VGPR]的患者比例。有50例患者进入II期研究,并接受了12个疗程(28天为一疗程)ixazomib+来那度胺+地塞米松诱导治疗。经6个疗程后符合移植条件的患者可退出试验进行自体干细胞移植(ASCT),对于那些继续接受ixazomib维持治疗的患者,将继续接受治疗直到病情进展或产生不可接受的毒性。所有接受ixazomib维持疗法的患者均对诱导疗法具有响应。

在诱导期(1-12疗程),29例患者停止治疗,主要是接受自体干细胞移植(ASCT,14/50),其他原因包括不良事件(6/50)、患者停药(4/50)、疾病进展(2/50)、不满意的响应(1/50)及其他因素(2/50)。

21例患者完成诱导治疗并进入到维持治疗阶段,在维持期,患者平均接受了19个疗程的ixazomib单药治疗(范围:3-23疗程),中位治疗持续时间为29.0个月(范围:14.3-33.3个月)。相关数据如下:52%的患者(11/21)实现完全缓解(CR)或更好缓解,71%的患者(15/21)实现极佳部分缓解(VGPR)或更好缓解。48%的患者(10/21)在维持期改善了缓解,包括2例(2/10)由极佳部分缓解(VGPR)达到接近完全缓解(nCR),5例(5/10)由极佳部分缓解(VGPR)达到完全缓解(CR),1例(1/10)由极佳部分缓解(VGPR)达到严格意义的完全缓解(sCR),2例(2/10)由完全缓解(CR)达到严格意义的完全缓解(sCR)。进入维持期的患者中位无进展生存期(PFS)尚未达到。在数据截至后,有52%的患者(11/21)仍保留在ixazomib维持治疗。实现首次缓解(≥部分缓解(PR))的中位时间为0.99个月(范围:0.92-5.78),实现最佳缓解的中位时间为7.46个月(范围:1.02-24.74个月)。诱导期和维持期平均ixazomib相对剂量强度为95%和89.5%。所有接受ixazomib维持疗法的患者从进入研究至随访25.2-33.9个月均还存活。

此次研究结果表明,多方(MM)患者经诱导治疗后,将ixazomib作为一种维持疗法能够扩大缓解的深度。在未来诸如这类药物,将成为多发性骨髓瘤(MM)患者维持治疗的重要补充。目前,武田已启动一项III期Tourmaline-MM3研究,评估ixazomib作为单药疗法,用于经自体干细胞移植治疗的多发性骨髓瘤(MM)患者的治疗,该研究将进一步提供ixazomib作为单药疗法的重要信息。ixazomib是一种实验性口服蛋白酶体抑制剂,正开发用于多发性骨髓瘤(MM)和AL型淀粉样变性的治疗。(生物谷Bioon.com)

英文原文:Takeda Presents Phase 2 Data on Maintenance with Single-Agent Investigational Ixazomib in Patients with Newly Diagnosed Multiple Myeloma

Takeda Pharmaceutical Company Limited (TSE:4502) today announced results from an open-label, Phase 2 study evaluating the safety and efficacy of oral, single-agent ixazomib (MLN9708) as maintenance therapy in patients with multiple myeloma (MM) who had received ixazomib, lenalidomide and dexamethasone as induction therapy. The data from this trial demonstrate the potential feasibility of single-agent ixazomib maintenance therapy following 12 cycles of ixazomib-lenalidomide-dexamethasone, with deepening responses and an acceptable tolerability profile. These data were presented today at the 56th American Society of Hematology (ASH) annual meeting in San Francisco, CA.

“These findings suggest that treatment with single-agent ixazomib, an investigational oral proteasome inhibitor, in the maintenance setting has the potential to extend depth of response for patients following induction therapy,” said Shaji K. Kumar, MD, Mayo Clinic, Rochester, NY. “The future availability of such an agent in the maintenance setting could represent an important addition to the treatment of patients with multiple myeloma.”

“These data suggest that as an oral proteasome inhibitor, ixazomib may be an important new agent for further clinical investigation in the maintenance therapy of multiple myeloma," said Michael Vasconcelles, M.D., Head, Oncology Therapeutic Area Unit, Takeda. “Indeed, we have recently initiated enrollment into our Phase 3 TOURMALINE-MM3 study to assess the potential benefit of single-agent ixazomib following autologous stem cell transplant. We look forward to this study completing enrollment and follow up, so that important new information about the use of ixazomib in the maintenance setting may be learned.”

The primary objective of the Phase 2 component of the study was the percent of patients achieving a very good partial response [VGPR] or better (defined as complete response [CR] + VGPR). Fifty patients were enrolled in the Phase 2 cohort and received ixazomib, lenalidomide and dexamethasone as induction therapy for up to twelve 28-day cycles. Transplant-eligible patients could discontinue from the study for autologous stem cell transplant (ASCT) after six cycles. For those patients continuing on to receive ixazomib maintenance, treatment could continue until disease progression or unacceptable toxicity. All patients who received ixazomib maintenance therapy had responded to induction therapy. During induction (cycles 1–12), 29 patients discontinued study treatment, primarily to undergo autologous stem cell transplant (ASCT) (14/50). Other reasons included AEs (6/50), patient withdrawal (4/50), disease progression (2/50), and unsatisfactory response (1/50), among other factors (2/50). Twenty-one patients completed induction and progressed to the maintenance phase of the study, during which they received single-agent ixazomib for a median of 19 treatment cycles (range 3-23), with a median treatment duration of 29.0 months (range 14.3-33.3). Best overall confirmed/unconfirmed study response rates and additional results for patients who underwent any maintenance therapy were reported as follows:

CR or better was reached in 52 percent of patients (11/21) and VGPR or better was reached in 71 percent of patients (15/21).
Forty-eight percent of patients improved their response during maintenance (10/21), including two VGPR to near-CR (2/10), five VGPR to CR (5/10), one VGPR to sCR (1/10), and two CR to sCR (2/10).
Median PFS of patients entering maintenance has not been reached.
Fifty-two percent of patients (11/21) remained on ixazomib maintenance after data cut-off.
Median time to first response (≥PR) was 0.99 months (range 0.92–5.78) and median time to best response was 7.46 months (range 1.02–24.74). Mean ixazomib relative dose intensity was 95 percent and 89.5 percent in the induction and maintenance phases, respectively.
All patients who received ixazomib maintenance were alive after follow-up of 25.1–33.9 months from study entry.

During the maintenance phase of the study with single-agent ixazomib, there were no discontinuations due to AEs and no on-study deaths. Drug-related grade 3 adverse events (AEs) were reported in 14 percent of patients during ixazomib maintenance therapy (3/21), and included one each hypokalemia, thrombocytopenia, and cataract as reported by the investigator. No grade 4 drug-related AEs were reported during maintenance.

Serious AEs were reported in 19 percent of patients during maintenance (4/21), including grade 3 acute myocardial infarction, grade 3 pneumonia, grade 3 orthostatic hypotension, and grade 2 ventricular extrasystoles; all were considered not related to treatment. Only two patients required an ixazomib dose reduction due to AEs (neuralgia, peripheral neuropathy).
All grade drug-related adverse events during maintenance included diarrhea (43 percent; 9/21), nausea (19 percent; 4/21), pain in extremity (14 percent; 3/21), anemia (10 percent; 2/21), skin and SC tissue disorders (10 percent; 2/21), headache (10 percent; 2/21), hypokalemia (10 percent; 2/21), and thrombocytopenia (10 percent; 2/21).
The abstract, titled “Long-Term ixazomib maintenance is tolerable and improves depth of response following ixazomib-lenalidomide-dexamethasone induction in patients (pts) with previously untreated multiple myeloma (MM): Phase 2 study results [Abstract #82]” was delivered as an oral presentation by Shaji K. Kumar, MD, Mayo Clinic, Rochester, MN.

About Ixazomib

Ixazomib (MLN9708) is an investigational oral proteasome inhibitor, which is being studied in multiple myeloma (MM), systemic light-chain (AL) amyloidosis and other malignancies. Ixazomib was granted orphan drug designation in MM in both the U.S. and Europe in 2011, and for AL amyloidosis in both the U.S. and Europe in 2012. It is the first oral proteasome inhibitor to enter Phase 3 clinical trials. Four global Phase 3 trials are ongoing: TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM; TOURMALINE-AL1, investigating ixazomib plus dexamethasone in patients with relapsed or refractory AL amyloidosis; TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant. For additional information on the ongoing Phase 3 studies please visit www.tourmalinetrials.com or www.clinicaltrials.gov.

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