CLINICAL TRIAL: A PHASE I TRIAL OF ESCALATING DOSES OF KARENITECIN PLUS CYCLOPHO

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。 环磷酰胺具有广谱的抗肿瘤活性，广泛应用于儿童实体瘤的治疗。环磷酰胺与拓扑异构酶I抑制剂Hycamtin(拓扑替康，GlaxoSmithKline)联合使用已在1期和2期儿科临床试验中进行了评估。环磷酰胺剂量固定在250 mg/m2/剂，连续5天；拓扑替康剂量在0.6~0.75 mg/m2/剂，2期试验固定在0.75 mg/m2/剂，连续5天。 骨髓抑制是这种组合的主要毒性，在第二阶段试验中，G-CSF支持用于中性粒细胞的恢复。在各种儿童实体瘤中观察到(完全+部分)反应，包括横纹肌肉瘤(67%)、神经母细胞瘤(46%)和尤文氏S肉瘤(35%)。因此，正如这些数据所证明的，环磷酰胺和拓扑异构酶I抑制剂的组合似乎是有效的。 与Topotecan相比，Karenitecin的安全性说明严重血液毒性(NCI-CTCAE分级=3)的发生率降低。这一点特别重要，因为改善的血液毒性特征可以减少对骨髓功能和治疗干预(例如，治疗延迟、剂量减少、红细胞[RBC]输注、生长因子支持)的频繁监测的需要，从而提高患者的安全性、依从性和临床效益。 3个第1阶段研究的结果清楚地表明，在为期3周的治疗周期中，患者可以安全地服用Karenitecin，剂量水平为1.0 mg/m2/day IV，持续1小时，连续5天。主要的和剂量限制的毒性是非累积的、可逆的骨髓抑制。胃肠道毒性一般为2级，不受剂量限制。 在4期2期试验中，Karenitecin显示出可接受的安全性，在恶性胶质瘤患者中具有中等的临床活性，在转移性黑色素瘤、卵巢和腹膜癌以及非小细胞肺癌患者中具有潜在的显著临床活性。 基于这两种药物的这些考虑，医学上有理由评估Karenitecin与环磷酰胺联合使用的情况，特别是考虑到Karenitecin相对于Topotecan的明显优势。 我们的目标是确定这项研究的最大耐受剂量(MTD)水平和推荐的第二阶段剂量水平，并获得关于Karenitecin在两组患有难治性或复发性儿童实体瘤的儿科受试者中抗肿瘤活性的初步信息。每一阶层将招收约25名科目，总数为50人。 主要目标： 目的：根据儿童难治性或复发性实体瘤患者有无骨髓转移或既往接受强化骨髓抑制治疗，确定连续5天静脉注射固定剂量环磷酰胺的最大耐受剂量(MTD)水平和推荐的第二阶段剂量水平。 次要目标： 次要目标包括评估与环磷酰胺联合使用的卡列奈特素的毒性；以及评估卡列奈特素与环磷酰胺联合使用的抗肿瘤活性。

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. Cyclophosphamide has a broad spectrum of antitumor activity and is extensively used in the treatment of pediatric solid tumors. Cyclophosphamide in combination with the topoisomerase I inhibitor, Hycamtin¿¿ (topotecan, GlaxoSmithKline), has been evaluated in both Phase 1 and Phase 2 pediatric clinical trials. Cyclophosphamide doses were fixed at 250 mg/m2/dose for 5 consecutive days; while topotecan doses in the Phase 1 trial ranged from 0.6 to 0.75 mg/m2/dose; and were fixed at 0.75 mg/m2/dose for 5 consecutive days in the phase 2 trial. Myelosuppression was the predominant toxicity of this combination, and G-CSF support was used for neutrophil recovery in the Phase 2 trial. Responses (complete plus partial) were observed in a variety of pediatric solid tumors including rhabdomyosarcoma (67%), neuroblastoma (46%), and Ewing¿??s sarcoma (35%). Thus, as evidenced by these data, the combination of cyclophosphamide plus a topoisomerase I inhibitor appears to be active. The safety profile of Karenitecin suggests a reduced incidence of severe (NCI-CTCAE grade = 3) hematologic toxicity when compared with that of topotecan. This is of particular importance since an improved hematologic toxicity profile may reduce the need for frequent monitoring of bone marrow function and treatment interventions (for example, treatment delays, dose reductions, red blood cell [RBC] transfusions, growth factor support), thus improving patient safety, compliance, and clinical benefit. Results from 3 Phase 1 studies clearly indicate that Karenitecin can be safely administered to patients at the dose level of 1.0 mg/m2/day IV over one hour for 5 consecutive days in a 3-week treatment cycle. The principal and dose-limiting toxicity is non-cumulative, reversible myelosuppression. Gastrointestinal toxicity is generally = grade 2 and is not dose-limiting. In 4 Phase 2 studies, Karenitecin demonstrated an acceptable safety profile, moderate clinical activity in patients with malignant gliomas, and potentially significant clinical activity in patients with metastatic melanoma, ovarian and peritoneal cancer, and non-small cell lung cancer. Based on these considerations for both agents, it is medically justified to evaluate the combination of Karenitecin co-administered with cyclophosphamide, particularly given the apparent advantages of Karenitecin relative to topotecan. We aim to determine a maximum tolerated dose (MTD) level and determine the recommended Phase 2 dose level for this study, and obtain preliminary information on the antitumor activity of karenitecin in two groups of pediatric subjects with refractory or recurrent pediatric solid tumors. Approximately 25 subjects will be enrolled in each stratum for a total of fifty. Primary Objective: To determine the maximum tolerated dose (MTD) levels and recommended Phase 2 dose levels of Karenitecin when administered intravenously for 5 consecutive days with a fixed dose of cyclophosphamide to children with refractory or recurrent solid tumors stratified according to the presence or absence of bone marrow metastases or treatment with previous intensive myelosuppressive therapy. Secondary Objectives: Secondary objectives include the assessment of toxicity associated with Karenitecin administered in combination with cyclophosphamide; and the assessment of antitumor activity of Karenitecin administered in combination with cyclophosphamide.