Clinical Development of Novel Drugs for Children with Refractory Cancers

儿童难治性癌症新药的临床开发

• 批准号: 8350077
• 负责人: Brigitte Widemann
• 金额: $ 88.04万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8350077
• 关键词: Adult; Angiogenesis Inhibitors; Area; Award; BAY 54-9085; Bioavailable; Carboplatin; Child; Childhood; Cisplatin; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cytotoxic agent; Department of Defense; Development; Dose-Limiting; Drug Kinetics; Drug effect disorder; Enrollment; Epothilone B Analogue; Funding; Human; IGF1 gene; Individual; Inherited; Institution; Insulin Receptor; Ixabepilone; Kidney; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant Peripheral Nerve Sheath Tumor; Malignant neoplasm of prostate; Modeling; Molecular; Multi-Institutional Clinical Trial; Mutation; Myelosuppression; Neoadjuvant Therapy; Neurofibromatosis 1; New Agents; Oncology Group; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Platinum Compounds; Pre-Clinical Model; Protocols documentation; Refractory; Research; Resistance; Satraplatin; Solid; Solid Neoplasm; Staging; Therapeutic; Toxic effect; Tubulin; Tyrosine Kinase Inhibitor; Unresectable; Vascular Endothelial Growth Factor Receptor; Work; base; bevacizumab; chemotherapy; depolymerization; drug development; effective therapy; human FRAP1 protein; inhibitor/antagonist; leukemia; mTOR Inhibitor; medullary thyroid carcinoma; neurotoxicity; novel; patient population; preclinical toxicity; programs; raf Kinases; receptor; research clinical testing; sarcoma; soft tissue; tumor; young adult

The primary objective of this project is to develop new agents for the treatment of childhood cancers with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. In addition, novel cytotoxic agents are undergoing clinical evaluation. This work is performed through the Pharmacology and Experimental Therapeutics (P&ET) Section of the NCI POB. Examples of clinical trials ongoing and in development include: 1) The development of the raf kinase and receptor tyrosine kinase inhibitor sorafenib for children with refractory cancers and leukemias. A phase I trial of sorafenib conducted by Childrens Oncology Group (COG) Phase I Consortium with myself serving as protocol chair was recently completed, and is currently being expanded to determine the activity of sorafenib in children and young adults with refractory AML and FKT3-ITD mutations. In addition, we are developing a phase II trial for select solid tumor strata to be performed as a COG wide study. Simultaneously sorafenib is developed for neurofibromatosis type 1 (NF1) related tumors (see project 1). 2) The mTOR pathway is involved in the progression of human cancers and neurofibromatosis type 1 (NF1) related tumors, and clinical trials with mTOR inhibitors are ongoing, and will be pursued for both patient populations. For example, a multi-institutional clinical trial for patients with refractory sporadic or NF1 related malignant peripheral nerve sheath tumors (MPNST) with the mTOR inhibitor RAD001 in combination with the angiogenesis inhibitor bevacizumab will soon open for enrollment. This trial is receiving funding through a Department of Defense Clinical Trial Award to the Trial PI B. Widemann). 3) In addition, we are pursuing the clinical development of novel cytotoxic agents for children and young adults with refractory cancers. We are currently leading a multi-institutional phase II trial of neoadjuvant chemotherapy for patients with high-grade, unresectable, chemotherapy nave malignant peripheral nerve sheath tumors (MPNST). MPNSTs are aggressive soft tissue sarcomas and are associated with poor outcome, particularly in individuals with NF1 (see project 1). We also evaluated the epothilone B analog ixabepilone (BMS-247550), an antitubulin agent, which inhibits tubulin depolymerization. A single institution phase I trial within the NCI was completed, and followed by a COG wide phase II trial, which was also recently completed. A phase I clinical trial of satraplatin, a novel orally bioavailable platinum agent, is currently in development as a single institution phase I trial. Satraplatin demonstrates antitumor activity in preclinical models including cisplatin resistant models, and has shown activity in adult trials for several solid malignancies including prostate cancer. The dose-limiting toxicity of satraplatin is myelosuppression. Neurotoxicity and renal toxicity, which are associated with cisplatin and carboplatin, have not been described in patients receiving satraplatin. The lack of these toxicities and the preclinical and clinical activity provide a strong rationale for the development of satraplatin for children with refractory cancers. The pharmacokinetics and pharmacodynamics of drugs in clinical development will be studied and compared to results in adults. Two other clinical trials are at earlier stages of development: 1) We are proposing a phase I trial of an oral IGF1 receptor and insulin receptor inhibitor for children with refractory solid tumors. The IGF pathway is implied in a number of pediatric malignancies and this is an active area of research at the NCI POB. 2) We are proposing a phase I trial of an oral RET and VEGFR and MET inhibitor. These targets are important in pediatric malignancies and hereditary medullary thyroid carcinoma (MTC), for which we have an ongoing clinical trial with an oral RET inhibitor. Development of this trial will allow for patients with refractory MTC to enroll on another trial, which may provide benefit.

该项目的主要目标是开发治疗儿童癌症的新药，重点是基于目前对人类癌症分子发病机制的了解，采用更合理、更有针对性的药物开发方法。基于药物的作用机制和靶点在儿童癌症中的重要性，正在针对成人癌症进行临床开发的新型分子靶向药物将应用于儿童癌症。此外，新型细胞毒剂正在接受临床评估。这项工作是通过 NCI POB 的药理学和实验治疗学 (P&ET) 部门进行的。正在进行和正在开发的临床试验的例子包括： 1) 开发用于患有难治性癌症和白血病的儿童的 raf 激酶和受体酪氨酸激酶抑制剂索拉非尼。由儿童肿瘤学组 (COG) 第一阶段联盟进行的索拉非尼 I 期试验最近已完成，我本人担任方案主席，目前正在扩大索拉非尼在患有难治性 AML 和 FKT3-ITD 的儿童和年轻人中的活性突变。此外，我们正在针对选定的实体瘤层开展一项 II 期试验，作为 COG 范围的研究进行。同时索拉非尼被开发用于治疗 1 型神经纤维瘤病 (NF1) 相关肿瘤（参见项目 1）。 2) mTOR 通路参与人类癌症和 1 型神经纤维瘤病 (NF1) 相关肿瘤的进展，mTOR 抑制剂的临床试验正在进行中，并将针对这两种患者群体进行。例如，针对难治性散发性或 NF1 相关恶性周围神经鞘瘤 (MPNST) 患者的一项多机构临床试验，使用 mTOR 抑制剂 RAD001 联合血管生成抑制剂贝伐珠单抗，即将开始招募。该试验通过授予试验 PI B. Widemann 的国防部临床试验奖获得资助。 3) 此外，我们正在致力于针对患有难治性癌症的儿童和年轻人的新型细胞毒性药物的临床开发。我们目前正在领导一项针对高级别、不可切除、未经化疗的恶性周围神经鞘瘤 (MPNST) 患者进行新辅助化疗的多机构 II 期试验。 MPNST 是侵袭性软组织肉瘤，与不良预后相关，特别是对于患有 NF1 的个体（参见项目 1）。我们还评估了埃坡霉素 B 类似物伊沙匹隆 (BMS-247550)，这是一种抗微管蛋白药物，可抑制微管蛋白解聚。 NCI 内的单一机构 I 期试验已完成，随后 COG 范围内的 II 期试验也在最近完成。 Satraplatin（一种新型口服生物可利用的铂类药物）的 I 期临床试验目前正在作为单一机构 I 期试验进行开发。 Satraplatin 在临床前模型（包括顺铂耐药模型）中显示出抗肿瘤活性，并在包括前列腺癌在内的多种实体恶性肿瘤的成人试验中显示出活性。沙铂的剂量限制性毒性是骨髓抑制。尚未在接受沙铂的患者中描述与顺铂和卡铂相关的神经毒性和肾毒性。缺乏这些毒性以及临床前和临床活性为开发沙铂治疗儿童难治性癌症提供了强有力的理由。将研究临床开发中药物的药代动力学和药效学，并与成人的结果进行比较。另外两项临床试验正处于早期开发阶段：1) 我们提议对患有难治性实体瘤的儿童进行口服 IGF1 受体和胰岛素受体抑制剂的 I 期试验。 IGF 通路存在于许多儿科恶性肿瘤中，这是 NCI POB 的一个活跃研究领域。 2) 我们提议进行口服 RET、VEGFR 和 MET 抑制剂的 I 期试验。这些靶点对于儿科恶性肿瘤和遗传性甲状腺髓样癌 (MTC) 非常重要，为此我们正在进行口服 RET 抑制剂的临床试验。该试验的开展将使难治性 MTC 患者能够参加另一项试验，这可能会带来益处。