WASHINGTON (EGMN) – The investigational drugs elotuzumab and panobinostat appear to enhance bortezomib’s efficacy in treating multiple myeloma with acceptable toxicity, according to data from early trials presented at the International Myeloma Workshop.
Elotuzumab is a humanized monoclonal antibody that targets CS1, a cell surface glycoprotein. CS1 is highly expressed in myeloma cells during all stages but is not expressed in normal cells or stem cells. The drug, being developed by PDL BioPharma Inc., appears to enhance the anti-tumor activity of bortezomib, based on animal studies.
Dr. Andrzej J. Jakubowiak reported interim results from an ongoing phase I trial of patients with multiple myeloma who had relapsed on anywhere from one to three previous therapies.
The efficacy analysis included 11 patients who had undergone an average of five treatment cycles. The objective response rate (partial response or better) was 55%, and the clinical response rate (minimal response or better) was 82%. Although it is still early, “the combination shows encouraging activity,” said Dr. Jakubowiak, a professor of hematology and oncology at the University of Michigan in Ann Arbor.
No patients had complete response, and six had partial response. Three had minimal response; one had stable disease; and one had progressive disease. Response was assessed using European Group for Blood and Marrow Transplant (EBMT) criteria starting on day 11 of cycle 2 and then once every cycle.
For the study, patients were not allowed to receive any antimyeloma treatment within 2 weeks of the first dose of elotuzumab, and a minimum of 12 weeks had to have passed following transplantation.
The treatment was based on 3-week cycles, with bortezomib given on days 1, 4, 8, and 11, and elotuzumab given on days 1 and 11. The study included four dose-escalating cohorts. All four cohorts received 1.3 mg/m2 bortezomib. Cohorts 1, 2, 3, and 4 received 2.5 mg/kg elotuzumab, 5 mg/kg elotuzumab, 10 mg/kg elotuzumab, and 20 mg/kg elotuzumab, respectively. If disease progression was seen at the end of the second or third cycle, dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) could be added. Patients with stable disease at the end of four cycles were allowed to continue on the treatment.
Dr. Jakubowiak reported demographic and toxicity data for 13 patients (mean age 64 years). Of those, nine had prior autologous stem cell transplantation, three were refractory to their last treatment, and two had high-risk disease. Four patients had previously received bortezomib. Cohorts 1-3 had three patients each, and cohort 4 had four patients. Nine patients are still receiving treatment. Dexamethasone was added for two patients.
There were five serious adverse events: sepsis, vomiting, pneumonia, chest pain, and diarrhea. However, there were no dose-limiting toxicities. The most common adverse events were diarrhea (64%), fatigue (36%), and nausea/vomiting (36%).
Dr. Orhan Sezer reported interim results from an ongoing phase Ib trial of panobinostat in 22 patients with relapsed/refractory multiple myeloma. Patients had to have received at least one prior therapy and relapsed.
Panobinostat is a pan-deacetylase inhibitor that interferes with epigenetic and nonepigenetic pathways implicated in cancer. The drug may affect modulation of cell cycle protein expression, cell cycle arrest, and apoptosis, said Dr. Sezer of the Charité-Universitätsmedizin Berlin. Novartis Oncology is developing the drug and sponsored the trial.
Cohort 1 (seven patients) received 10 mg oral panobinostat three times per week, plus 1 mg/m2 intravenous bortezomib (on days 1, 4, 8, and 11) during a 21-day cycle. Cohort 2 (seven patients) received 20 mg panobinostat and 1 mg/m2 bortezomib. Cohort 3 (eight patients) received 20 mg panobinostat and 1.3 mg/m2 bortezomib. Cohort 4 will receive 30 mg panobinostat and 1.3 mg/m2 bortezomib.
Dr. Sezer reported efficacy data for 11 patients. Three were complete responders, one had very good partial response, and seven had partial response. Of particular note: Five patients were previously refractory to bortezomib, he said.
No dose-limiting toxicities were reported in any of the patients in the first and third cohorts. There was one dose-limiting toxicity in cohort 2: grade 4 neutropenia. The most common adverse events were thrombocytopenia and neutropenia. Nonhematologic adverse events included diarrhea, fatigue, fever, and nausea.
“Preliminary data from this ongoing phase I trial suggest that oral panobinostat can be safely combined with bortezomib,” Dr. Sezer noted.
Dr. Jakubowiak has reported financial relationships with Millenium Pharmaceuticals Inc. and Celgene Corporation. Dr. Sezer has reported receiving honoraria from Novartis.
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华盛顿(EGMN)——来自国际骨髓瘤研讨会的一项前期临床试验的数据显示，在研药物埃罗妥珠单抗(elotuzumab)和帕比司他(panobinostat)可提高硼替佐米(bortezomib)治疗多发性骨髓瘤的疗效，且毒性反应轻微。
埃罗妥珠单抗是一种靶向细胞表面糖蛋白CS1的人源化单克隆抗体。CS1在各个阶段骨髓瘤细胞均高水平表达，但并不表达于正常细胞或干细胞。由PDL BioPharma公司在研的该药物在动物实验中似乎可以提高硼替佐米(商品名：万珂)的抗肿瘤活性。
Andrzej J. Jakubowiak博士报道了一项正在进行的I期临床试验的中期结果，入选对象为经历1到3次治疗后复发的多发性骨髓瘤患者。
对平均经历了5个周期治疗的11例患者的疗效分析显示，客观缓解率(部分缓解PR或更好)达到55%，临床缓解率(轻微缓解MR或更好)则达到82%。虽然目前尚处于初期试验阶段，“联合用药的疗效令人鼓舞。”密歇根大学安娜堡分校血液学和肿瘤学教授Jakubowiak博士说道。
无患者出现完全缓解， 部分缓解6例。有反应3例，病情稳定1例，疾病进展1例。参照欧洲血液和骨髓移植组(EBMT)标准在第2周期治疗的第11天进行第一次疗效评价，然后每周期进行一次。
此项研究中，患者首次接受埃罗妥珠单抗治疗2周内及移植后至少12周内不能接受其他抗骨髓瘤治疗。
治疗每3周为一个周期，d1、d4、d8和d11给予硼替佐米，d1和d11给予埃罗妥珠单抗。这项研究包括4个剂量递增队列。所有4个队列均给予硼替佐米1.3mg/m2，并分别给予埃罗妥珠单抗2.5mg/kg、5mg/kg、10mg/kg和20mg/kg。如果在第二、三周期治疗中发现疾病进展，则可给予地塞米松(20mg，d1、d2、d4、d5、d8、d9、d11、d12)。4个周期结束后，如患者病情稳定则可继续治疗。
Jakubowiak博士报道了13例平均年龄为64岁的患者的个人信息和毒性反应数据。其中，自体造血干细胞移植者9例，对治疗耐受者 3例，患高危疾病者2例。 4例患者曾接受过硼替佐米治疗。共分为4个队列，队列1、2、3各有3例患者，队列4有4例。 9例患者仍在接受治疗，2例给予了地塞米松。
治疗过程中发生了5个严重不良反应事件，包括脓毒症、呕吐、肺炎、胸痛和腹泻，但未出现剂量限制性毒性反应。最常见的不良反应有腹泻(64%)、疲劳(36%)及恶心呕吐(36%)。
Orhan Sezer博士报道了一项正在进行的帕比司他Ib期临床试验的中期结果。共有22例至少经历过一次治疗并复发的难治性/复发性多发性骨髓瘤患者入选。
“帕比司他是一个泛去乙酰化酶抑制剂，可能通过干扰表观遗传学和非表观遗传学途径致癌。该药物可能会影响细胞周期调控蛋白的表达，从而导致细胞周期阻滞，诱发细胞凋亡。”柏林夏里特大学医学院Sezer博士说。该临床试验由开发该药物的诺华制药有限公司肿瘤药品事业部赞助。
队列1共 7例，在为期21天的治疗周期内每周口服3次帕比司他，每次10mg，并静注1mg/m2硼替佐米(d1、d4、d8、d11)。队列2共 7例，给予20mg帕比司他和1mg/m2硼替佐米。队列3共78例，给予20mg帕比司他和1.3mg/m2硼替佐米。队列4给予30mg帕比司他和1.3mg/m2硼替佐米。
Sezer博士报告11例患者疗效的数据。完全缓解3例，很好的部分缓解1例， 部分缓解7例。“特别值得注意的是，这其中有5例是对硼替佐米耐药的。” Sezer博士说。
队列1和队列3患者中未出现剂量限制性毒性反应。队列2出现1例4级中性粒细胞减少症的剂量限制性毒性反应。最常见的不良事件是血小板和中性粒细胞减少症。 非造血系统方面的副作用包括腹泻、疲劳、发热及恶心。
“该I期临床试验初步数据表明口服帕比司他联合硼替佐米是安全的。”Sezer博士指出。
Jakubowiak博士报告了与Millenium制药有限公司和Celgene公司有财务往来。Sezer博士的报告接受过诺华公司提供的酬金。
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