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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 甲磺酸伊马替尼治疗诱导大多数CML患者的完全细胞遗传学缓解CCR，并导致生存率显著提高，目前是CML的一线治疗。()然而，大多数患者仍然有通过PCR分析可检测到的持续残留疾病的证据，并且有几条证据表明，尽管伊马替尼治疗，残留的BCR-ABL+干细胞可能在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，需要采取措施加强残留疾病的消除，以进一步改善白血病的预后和有效治愈。 在临床前研究中，与单独的伊马替尼或LAQ824相比，HDAC抑制剂LAQ824与伊马替尼的组合导致CML原始祖细胞的凋亡显著增强。一种非常相似的HDAC抑制剂LBH 589正处于早期临床试验中，并且耐受性良好。这些结果为检测伊马替尼中添加LBH 589是否能增强CCR中伊马替尼治疗的CML患者中残留BCR-ABL+干/祖细胞的消除提供了强有力的依据。 我们建议进行一项I期研究，以确定LBH 589与伊马替尼联合使用时的安全剂量。由于伊马替尼单药治疗与良好的预后相关，LBH 589剂量递增将限于基于当前LBH 589单药治疗试验已知耐受良好的最大剂量，以降低潜在毒性的风险。将计划进行II期研究。

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.