CLINICAL TRIAL: A PHASE I DOSE ESCALATION STUDY OF LBH589 IN COMBINATION WITH IM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 甲磺酸伊马替尼治疗在大多数CML患者中诱导细胞遗传学完全缓解，并显著提高存活率，目前是CML的一线治疗方法。然而，大多数患者仍然有证据表明，通过PCR分析可以检测到持续的残留病，并且有几条证据表明，尽管接受伊马替尼治疗，BCR-ABL+干细胞残留物仍可能在CML患者中持续存在。因此，患者可能需要无限期地接受伊马替尼治疗，并可能仍有复发的风险，需要采取措施加强消除残留疾病，以进一步改善预后和有效治愈白血病。 在临床前研究中，HDAC抑制剂LAQ824与伊马替尼联合使用与单独使用伊马替尼或LAQ824相比，可显著增强CML原始祖细胞的凋亡。一种非常类似的HDAC抑制剂LBH589正在进行早期临床试验，并已被良好耐受。这些结果为测试将LBH589添加到伊马替尼是否能促进在CCR中接受伊马替尼治疗的CML患者残留的bcr-abl+干/祖细胞的消除提供了强有力的理论依据。 我们建议进行1期研究，以确定LBH589剂量，该剂量可以安全地与伊马替尼联合使用。由于伊马替尼单一疗法与良好的预后相关，根据目前的LBH589单一疗法试验，LBH589剂量的增加将被限制在已知可以很好耐受的最大剂量，以降低潜在毒性的风险。随后将计划进行第二阶段研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Imatinib mesylate treatment induces complete cytogenetic remissions (CCR) in the majority of CML patients and results in significantly improved survival and is currently the front-line treatment for CML. However, most patients continue to have evidence of persistent residual disease detectable by PCR analysis, and there are several lines of evidence that residual BCR-ABL+ stem cells may persist in CML patients despite imatinib treatment. Therefore patients may require to be treated with imatinib indefinitely and may remain at risk of relapse, and measures to enhance elimination of residual disease are needed to further improve outcomes and effect cure of leukemia. In preclinical studies the combination of the HDAC inhibitor LAQ824 with imatinib results in significantly enhanced apoptosis of CML primitive progenitors compared to imatinib or LAQ824 alone. A very similar HDAC inhibitor LBH589 is in early clinical trials and has been well tolerated. These results provide a strong rationale for testing whether addition of LBH589 to imatinib can enhance elimination of residual BCR-ABL+ stem/progenitor cells in imatinib-treated CML patients in CCR. We propose to perform a phase 1 study to determine the LBH589 dose which can be safely used in combination with imatinib. Since imatinib monotherapy is associated with an excellent prognosis, LBH589 dose escalation will be limited to a maximal dose that is known to be well tolerated based on current LBH589 monotherapy trials to reduce risk of potential toxicity. A Phase 2 study will be planned to follow.