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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 抽象的 环磷酰胺具有广泛的抗肿瘤活性，可广泛用于治疗小儿实体瘤。环磷酰胺与拓扑异构酶I抑制剂Hycamtin¿（拓扑替克，GlaxoSmithkline）结合使用，在1阶段和第2阶段的小儿临床试验中均已评估。连续5天以250 mg/m2/剂量固定环磷酰胺剂量；在第1阶段试验中，拓扑替康的剂量在2阶段试验中连续5天的0.6至0.75 mg/m2/剂量。 骨髓抑制是这种组合的主要毒性，在第二阶段试验中使用G-CSF支持进行神经磷回收。在包括横纹肌肉瘤（67％），神经母细胞瘤（46％）和ewings肉瘤（35％）在内的多种儿科实体瘤中观察到反应（完全加上部分）。这些数据证明了这一点，环磷酰胺和拓扑异构酶I抑制剂的组合似乎是活跃的。 卡伦尼丁的安全性概况表明，与拓扑替康相比，严重（NCI-CTCAE级= 3）血液学毒性的发生率降低。这是尤其重要的，因为改善的血液毒性特征可能会减少频繁监测骨髓功能和治疗干预措施的需求（例如，治疗延迟，减少剂量，红细胞[RBC]输血，生长因子支持），从而改善患者的安全性，合规性和临床益处。 3期研究的结果清楚地表明，可以在3周的治疗周期中连续5天以1.0 mg/m2/天IV的剂量安全地将Karenitecin的剂量安全地给予患者。主要和剂量限制毒性是非肿瘤，可逆的骨髓抑制的。胃肠道毒性通常为= 2级，而不是剂量限制。 在4阶段2研究中，卡雷尼甲环蛋白在恶性神经胶质瘤患者中表现出可接受的安全性，适度的临床活性以及在转移性黑色素瘤，卵巢癌和腹膜癌以及非小细胞肺癌的患者中潜在的临床活性。 基于这些因素对两种药物的考虑，在医学上是合理的，可以评估与环磷酰胺共同管理的karenitecin的组合，尤其是考虑到卡雷尼甲环素相对于拓扑素的明显优势。