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

临床试验：Karenitecin 加 CYCLOPH 剂量递增的 I 期试验

• 批准号: 8356684
• 负责人: SUSAN M. BLANEY
• 金额: $ 4.27万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356684
• 关键词: Bone Marrow; CSF3 gene; Childhood; Childhood Solid Neoplasm; Clinical; Clinical Research; Clinical Trials; Common Terminology Criteria for Adverse Events; Cyclophosphamide; Data; Dose; Dose-Limiting; Erythrocyte Transfusion; Ewings sarcoma; Funding; Grant; Growth Factor; Hour; In complete remission; Incidence; Intervention; Karenitecin; Malignant Glioma; Malignant neoplasm of ovary; Metastatic Melanoma; Monitor; Myelosuppression; National Center for Research Resources; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Principal Investigator; Recovery; Relative (related person); Research; Research Infrastructure; Resources; Rhabdomyosarcoma; Safety; Source; Topoisomerase-I Inhibitor; Topotecan; Toxic effect; United States National Institutes of Health; base; cost; gastrointestinal; improved; neutrophil; patient safety; peritoneal cancer; phase 1 study; phase 2 study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT 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 Ewings 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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 环磷酰胺具有广谱抗肿瘤活性，广泛用于治疗儿科实体瘤。 环磷酰胺与拓扑异构酶I抑制剂Hycamtin？（托泊替康，葛兰素史克）联合使用已在1期和2期儿科临床试验中进行了评价。 环磷酰胺剂量固定为250 mg/m2/剂，连续5天;而1期试验中的托泊替康剂量范围为0.6 - 0.75 mg/m2/剂; 2期试验中的托泊替康剂量固定为0.75 mg/m2/剂，连续5天。 骨髓抑制是该联合治疗的主要毒性，在II期试验中，使用G-CSF支持来恢复中性粒细胞。 在各种儿科实体瘤中观察到缓解（完全加部分），包括横纹肌肉瘤（67%）、神经母细胞瘤（46%）和尤文氏肉瘤（35%）。 因此，如这些数据所证明的，环磷酰胺加拓扑异构酶I抑制剂的组合似乎是有活性的。 Karenitecin的安全性特征表明，与托泊替康相比，重度（NCI-CTCAE = 3级）血液学毒性的发生率降低。 这一点特别重要，因为改善的血液学毒性特征可能减少对频繁监测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）的需求，从而改善患者安全性、依从性和临床获益。 3项I期研究的结果清楚地表明，Karenitecin可以安全地以1.0 mg/m2/天的剂量水平IV给药，持续1小时，连续5天，治疗周期为3周。 主要和剂量限制性毒性是非累积性、可逆性骨髓抑制。 胃肠道毒性通常为≥ 2级，且无剂量限制性。 在4项II期研究中，Karenitecin显示出可接受的安全性特征，在恶性胶质瘤患者中具有中度临床活性，在转移性黑色素瘤、卵巢癌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。 基于两种药物的这些考虑，在医学上有理由评价Karenitecin与环磷酰胺联合给药，特别是考虑到Karenitecin相对于托泊替康的明显优势。