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

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

• 批准号: 8166696
• 负责人: SUSAN M. BLANEY
• 金额: $ 0.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166696
• 关键词: Bone Marrow; CSF3 gene; Child; Childhood; Childhood Solid Neoplasm; Clinical; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Cyclophosphamide; Data; Dose; Dose-Limiting; Enrollment; Erythrocytes; Funding; Grant; Growth Factor; Hour; In complete remission; Incidence; Institution; Intervention; Karenitecin; Malignant Glioma; Maximum Tolerated Dose; Metastatic Melanoma; Monitor; Myelosuppression; Myelosuppressive Therapy; Neoplasm Metastasis; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Ovarian; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Recovery; Recurrence; Refractory; Relative (related person); Research; Research Personnel; Resources; Rhabdomyosarcoma; Safety; Solid Neoplasm; Source; Topoisomerase-I Inhibitor; Topotecan; Toxic effect; Transfusion; United States National Institutes of Health; base; gastrointestinal; improved; neutrophil; patient safety; peritoneal cancer; phase 1 study; phase 2 study; sarcoma

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 环磷酰胺具有广谱抗肿瘤活性，广泛用于治疗儿童实体瘤。 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估。 环磷酰胺剂量固定为250 mg/m2/剂，连续5天；而一期试验中拓扑替康的剂量范围为0.6至0.75 mg/m2/剂；在 2 期试验中连续 5 天固定为 0.75 mg/m2/剂。 骨髓抑制是该组合的主要毒性，在 2 期试验中，G-CSF 支持用于中性粒细胞恢复。 在多种儿童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效的。 卡伦尼星的安全性表明，与拓扑替康相比，严重（NCI-CTCAE 等级 = 3）血液毒性的发生率降低。 这是特别重要的，因为改善的血液学毒性特征可以减少频繁监测骨髓功能和治疗干预的需要（例如，治疗延迟、剂量减少、红细胞[RBC]输注、生长因子支持），从而提高患者的安全性、依从性和临床效益。 3 项 1 期研究的结果清楚地表明，Karenitecin 可以在 3 周的治疗周期中，以 1.0 mg/m2/天的剂量水平，在 1 小时内连续 5 天静脉注射安全地给予患者。 主要的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，并且没有剂量限制。 在 4 项 2 期研究中，Karenitecin 表现出可接受的安全性、对恶性神经胶质瘤患者的中等临床活性，以及​​对转移性黑色素瘤、卵巢癌和腹膜癌以及非小细胞肺癌患者的潜在显着临床活性。 基于对两种药物的这些考虑，评估卡伦尼汀与环磷酰胺联合给药的组合在医学上是合理的，特别是考虑到卡伦尼汀相对于托泊替康具有明显的优势。 我们的目的是确定本研究的最大耐受剂量（MTD）水平并确定推荐的2期剂量水平，并获得卡伦尼辛在两组患有难治性或复发性儿科实体瘤的儿科受试者中的抗肿瘤活性的初步信息。每个层将招募大约 25 名受试者，总共 50 名受试者。 主要目标： 目的 确定患有难治性或复发性实体瘤的儿童连续 5 天静脉注射固定剂量的环磷酰胺时卡伦尼汀的最大耐受剂量 (MTD) 水平和推荐的 2 期剂量水平，根据是否存在骨髓转移或既往接受过强化骨髓抑制治疗进行分层。 次要目标： 次要目标包括评估卡伦尼星与环磷酰胺联合用药的毒性；以及Karenitecin与环磷酰胺联合施用的抗肿瘤活性的评估。