Clinical Development of Novel Drugs for Children with Refractory Cancers

该项目的主要目标是开发用于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理解，采用更合理、更有针对性的药物开发方法。正在进行成人癌症临床开发的新型分子靶向药物将根据药物的作用机制和靶点在儿童癌症中的重要性应用于儿童癌症。此外，新型细胞毒性药物正在进行临床评价。这项工作通过NCI POB的药理学和实验治疗学（P和ET）部分进行。正在进行和正在开发的临床试验的例子包括：1）开发raf激酶和受体酪氨酸激酶抑制剂索拉非尼用于治疗儿童难治性癌症和白血病。由儿童肿瘤组（COG）第一阶段联盟进行的索拉非尼第一阶段试验，我本人担任方案主席，最近完成，目前正在扩大，以确定索拉非尼在难治性AML和FKT 3-ITD突变的儿童和年轻人中的活性。此外，我们正在为选定的实体瘤分层开发一项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1型神经纤维瘤病（NF 1）相关肿瘤（见项目1）。2)mTOR通路参与人类癌症和1型神经纤维瘤病（NF 1）相关肿瘤的进展，mTOR抑制剂的临床试验正在进行中，并将在两个患者人群中进行。例如，一项针对难治性散发性或NF 1相关恶性外周神经鞘瘤（MPNST）患者的多机构临床试验将很快开放招募，该试验使用mTOR抑制剂RAD 001联合血管生成抑制剂贝伐单抗。本试验通过国防部临床试验奖获得试验PI B的资助。Widemann）。3)此外，我们还在为患有难治性癌症的儿童和年轻人进行新型细胞毒性药物的临床开发。我们目前正在领导一项多机构II期临床试验，对高级别、不可切除、化疗初治的恶性外周神经鞘瘤（MPNST）患者进行新辅助化疗。MPNST是侵袭性软组织肉瘤，预后差，尤其是NF 1患者（见项目1）。我们还评估了埃博霉素B类似物伊沙匹隆（BMS-247550），一种抗微管蛋白剂，可抑制微管蛋白解聚。NCI内的一个单一机构I期试验已经完成，随后是COG范围的II期试验，该试验最近也完成了。沙铂是一种新型口服生物可利用的铂类药物，其I期临床试验目前正在开发中，作为单机构I期试验。沙铂在临床前模型（包括顺铂耐药模型）中显示出抗肿瘤活性，并在成人试验中显示出对几种实体恶性肿瘤（包括前列腺癌）的活性。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。这些毒性的缺乏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）我们正在计划一项针对难治性实体瘤儿童的口服IGF 1受体和胰岛素受体抑制剂的I期试验。IGF途径在许多儿科恶性肿瘤中有意义，这是NCI POB的一个活跃研究领域。2)我们正在计划一项口服RET、VEGFR和MET抑制剂的I期试验。这些靶点在儿科恶性肿瘤和遗传性甲状腺髓样癌（MTC）中很重要，我们正在进行口服RET抑制剂的临床试验。这项试验的开展将允许难治性MTC患者参加另一项试验，这可能会带来益处。

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 and 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 additon, 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.