一项新的临床研究的中期报告显示，一种实验性的抗癌药物Carfilzomib在复发或者难治性的多发性骨髓瘤患者中表现出了可喜得效果。这一研究结论在美国血液学会(ASH)第51届年会上予以发布。78例没有接受过硼替佐米治疗的和33例曾经接受过硼替佐米治疗的患者进行了28天一次静脉注射Carfilzomib治疗。

   研究人员之一，Dr David Siegel在发言中说到，Carfilzomib可以给那些对目前化疗方案不再起作用的患者带来好处。

   对于那些没有接受过硼替佐米治疗的（难治或复发）患者，54例应用了Carfilzomib 20mg/次治疗，总体有效率(ORR)为46%，19例患者接受的剂量是27mg，总体有效率(ORR) 为53%。疾病进展时间为7.6月，持续缓解时间为8.4月。

    对于那些曾经接受过硼替佐米治疗的难治或复发患者，总体有效率(ORR)为18%。疾病进展时间为5.3月，持续缓解时间为9月。

    这一研究结果对于多发性骨髓瘤患者来说是一个很大的进步，休斯顿市安德森癌症中心的Dr. Michael Wang和其中一位研究人员说到。

    其他一些延长寿命的药物都有较多的副作用，包括神经疼痛。Michael Wang说Carfilzomib具有较高的有效率和性较少的副作用。

    Carfilzomib治疗耐受性很好，20%以上的患者完成了12周期（48周）的治疗，没有发生蓄积的副作用，神经病变发生率也很低，研究人员说。

    Michael Kauffman, Onyx Pharmaceuticals Inc制药公司的过渡首席官员说，公司将力争使美国在2010年底前批准该药的临床应用。

Carfilzomib Is Effective For Multiple Myeloma – Part 1: As A Single Agent Or In A Combination Therapy (ASH 2009)

Preliminary results from several clinical trials testing carfilzomib for the treatment of multiple myeloma will be presented at the 51st American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans December 5 through 8.

Carfilzomib, a proteasome inhibitor, is under development as a treatment for relapsed or refractory multiple myeloma. It is currently in Phase 2 of clinical testing, which means that its safety and efficacy are being studied.

The ASH presenters will examine the effects of carfilzomib in patients who have previously been treated with Velcade (bortezomib); in patients who are receiving carfilzomib in combination with Revlimid (lenalidomide) and dexamethasone (Decadron); and in patients with kidney failure, chromosomal abnormalities, or peripheral neuropathy. Carfilzomib for the treatment of patients with specific conditions will be presented in Part 2 of this series.

Carfilzomib As A Single Agent

One of the studies that will be presented at the ASH meeting is a Phase 2 study examining the effectiveness of carfilzomib in the treatment of relapsed or refractory myeloma patients. The participants were split into two groups: those who had previously been treated with Velcade and those who had not.

Participants received 20 mg/m² of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle for up to 12 cycles.

Prior Treatment With Velcade

Thirty-three participants who had previously been treated with Velcade were evaluated for their response to carfilzomib treatment. It was determined that 18 percent experienced a complete or partial response, meaning they experienced either remission or a significant decrease in clinical indicators of cancer.

The side effects observed most frequently in this study were fatigue (57 percent of participants) and nausea (54 percent). More severe side effects such as low red blood cell counts (14 percent), low white blood cell counts (11 percent), and peripheral neuropathy (11 percent) were observed. Peripheral neuropathy is nerve damage that can result in numbness and pain in the hands and feet. Among patients with kidney failure, none had to discontinue carfilzomib treatment.

The results of this group indicate that carfilzomib could potentially be a safe and effective treatment for patients who do not respond to Velcade.

No Prior Treatment With Velcade

The second group of 57 study participants all had relapsed or refractory multiple myeloma but had not been previously treated with Velcade. Of the 51 patients evaluated, 45 percent experienced complete response, very good partial response, or partial response.

Like the Velcade group, the most common side effects were fatigue (59 percent) and nausea (41 percent), and a similar percentage of patients experienced peripheral neuropathy (12 percent). The 12 patients who had poor kidney function coming into the study tolerated carfilzomib well.

The study authors highlighted that a response rate of 45 percent is noteworthy for a single-agent treatment for patients who have not have success with other therapies.

This study is still underway and is currently recruiting new participants. Based on the demonstrated safety of carfilzomib, participants may now receive 27 mg/m², an increase from the original dose of 20 mg/m².

For more information, see the ASH abstracts 303 (Velcade refractory) and 302 (Velcade-naïve). To enroll in this study, see the United States Clinical Trials Web site.

Carfilzomib In Combination With Revlimid And Dexamethasone

A Phase 1B study was conducted to assess the safety of carfilzomib in combination with Revlimid and low dose dexamethasone in relapsed or refractory myeloma patients.

The participants, split into groups, received a combination regimen of 15 to 27 mg/m² intravenous carfilzomib, 10 to 25 mg Revlimid, and 40 mg low dose dexamethasone. The six different dose combinations of carfilzomib and Revlimid will help determine the maximum dosages that should be administered to maintain effectiveness as well as a low rate of serious side effects.

It was determined that relapsed myeloma patients can tolerate a combination of 20 mg/m² carfilzomib, 25 mg Revlimid, and low dose dexamethasone. Several participants are currently receiving 27 mg carfilzomib, 25 mg Revlimid, and low dose dexamethasone to determine the safety of that combination. Because carfilzomib and Revlimid do not have overlapping toxicities, full doses of these regimens over long periods of time (greater than 10 months) are possible.

Based on the results of this trial, a Phase 3 trial is being planned for early 2010 that will test carfilzomib, Revlimid, and dexamethasone compared to Revlimid and dexamethasone without carfilzomib.

For more information, see abstract 304 on the ASH Meeting Web site and Part 2 of this series
    Carfilzomib一种新的治疗多发性骨髓瘤的蛋白酶体抑制剂

    蛋白酶体已经成为肿瘤治疗的重要靶点，这一点已经被硼替佐米(bortezomib)所证实。硼替佐米是第一代的可逆的蛋白酶体抑制剂，用于治疗复发难治的多发性骨髓瘤(MM)。然而，因为产生耐药性，所以许多患者对硼替佐米没有反应，这就表明需要更具活性的抑制剂来治疗这些患者。美国和荷兰的研究人员评价了一种新的，不可逆的蛋白酶体抑制剂carfilzomib对骨髓瘤的疗效。在MM的模型中，carfilzomib能够特异地和强有力地抑制胰凝乳蛋白酶样蛋白酶体和免疫蛋白酶体的活性。Carfilzomib诱导剂量依赖性和时间依赖性的增殖抑制，最终导致调亡。这种细胞程序性死亡与c-Jun-N末端激酶的活性，线粒体膜的去极化，细胞色素c的释放，活化直接的和间接的caspase途径等有关。Carfilzomib同样能够抑制从骨髓瘤患者体内分离出来的肿瘤细胞和其他恶性血液病患者的肿瘤细胞的增殖，以及促进调亡。重要的是carfilzomib比硼替佐米更具活性，能够抑制硼替佐米耐药的骨髓瘤细胞系和从硼替佐米耐药的骨髓瘤患者体内分离的肿瘤细胞。Carfilzomib同样能够克服细胞对其他传统药物耐药性，并且与地塞米松具有协同作用。总之，这些数据为进一步的carfilzomib临床试验提供了依据。[Blood, 1 November 2007, Vol. 110, No. 9, pp. 3281-3290.]