Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia.
Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia.
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DOI：
10.1111/j.1365-2141.2009.07881.x
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发表时间：
2009-11
影响因子：
6.5
通讯作者：
Byrd JC
中科院分区：
文献类型：
--
作者：
Blum KA;Advani A;Fernandez L;Van Der Jagt R;Brandwein J;Kambhampati S;Kassis J;Davis M;Bonfils C;Dubay M;Dumouchel J;Drouin M;Lucas DM;Martell RE;Byrd JC
MGCD0103是一种口服I类组蛋白去乙酰化酶（HDAC）抑制剂，研究了其在慢性淋巴细胞白血病（CLL）中的临床前活性。进行了II期临床试验，起始剂量为85 mg/天，每周3次。对于2个或更多周期后无反应的患者，允许剂量增加至110 mg或添加利妥昔单抗。MGCD0103对CLL细胞具有临床前活性，LC50（致死浓度为50%）为0.23 μM，并增加HDAC I类特异性靶蛋白H3的乙酰化。21名患者接受了MGCD0103的中位数2个周期（范围0-12）。所有患者先前均接受过氟达拉滨治疗，33%的患者氟达拉滨难治性，71%的患者出现del（11q22.3）或del（17p13.1）。根据国家癌症研究所1996年的标准，没有观察到任何反应。3例患者接受110 mg治疗，4例患者同时接受利妥昔单抗治疗，疗效无改善。3-4级毒性包括感染、血小板减少、贫血、腹泻和疲劳。在第8天，9例患者中有6例出现HDAC抑制。MGCD0103单药治疗CLL高危患者的疗效有限。CLL的未来研究应侧重于广泛的HDAC抑制、联合策略和减少与这类药物相关的体质症状的方法。
MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/day, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after 2 or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC50 (concentration lethal to 50%) of 0.23 μM and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of 2 cycles of MGCD0103 (range, 0–12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22.3) or del(17p13.1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and 4 patients received concomitant rituximab, with no improvement in response. Grade 3–4 toxicity consisted of infections, thrombocytopenia, anemia, diarrhea, and fatigue. HDAC inhibition was observed in 6 out of 9 patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs.
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影响因子：
11.4
作者：
Lucas, DM;Davis, ME;Grever, MR
通讯作者：
Grever, MR
影响因子：
11.5
作者：
Bonfils, Claire;Kalita, Ann;Li, Zuomei
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Li, Zuomei
影响因子：
20.3
作者：
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Grever, Michael R.
影响因子：
11.4
作者：
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通讯作者：
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影响因子：
20.3
作者：
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通讯作者：
Rai, KR