Clinical Development of Novel Drugs for Children with Refractory Cancers

该项目的主要目标是开发治疗儿童癌症的新药物，重点是基于目前对人类癌症分子发病机制的理解，开发更合理、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，正在进行成人癌症临床开发的新型分子靶向药物将应用于儿童癌症。此外，新的细胞毒性药物正在进行临床评估。这项工作通过NCI POB的药理学和实验治疗学（P&ET）部分完成。正在进行和正在开发的临床试验包括：1)开发用于难治性癌症和白血病儿童的raf激酶和受体酪氨酸激酶抑制剂索拉非尼。由儿童肿瘤组（COG） I期联盟进行的索拉非尼I期试验最近完成，我担任协议主席。这项研究扩展到确定索拉非尼在患有难治性AML和FLT3-ITD突变的儿童和年轻人中的活性。已经观察到索拉非尼在该患者队列中的活性，COG正在进行一项将索拉非尼纳入AML和FLT3ITD突变儿童的前期治疗的II期研究。此外，我们针对选定的实体肿瘤分层开展了II期试验，该试验正在COG内进行，招募工作即将完成。同时，我们对患有1型神经纤维瘤病（NF1）相关肿瘤的儿童进行了索拉非尼的I期试验（见项目1）。2)mTOR途径参与人类癌症和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，并将在两种患者群体中进行。例如，一项针对难治性散发或NF1相关恶性周围神经鞘肿瘤（MPNST）患者使用mTOR抑制剂RAD001联合血管生成抑制剂贝伐单抗的多机构临床试验正在开放招募。该试验获得了国防部临床试验奖的资助（试验PI B. Widemann）。基于Dr. Karen Cichowski实验室的临床前工作，我们还开发了mTOR抑制剂西罗莫司与HSP90抑制剂ganetespib联合用于成人难治性肉瘤和MPNST的I/II期临床试验。我们目前正在与几位NCI研究者合作进行临床前研究，目标是开发一项使用ganetespib治疗难治性癌症儿童的I期试验。3)此外，我们正在为患有难治性癌症的儿童和年轻人寻求新型细胞毒性药物的临床开发。我们最近完成了一项多机构的II期临床试验，新辅助化疗治疗高度不可切除的恶性周围神经鞘肿瘤（MPNST）。mpnst是侵袭性软组织肉瘤，预后较差，尤其是NF1患者（见项目1）。萨特铂是一种新型口服生物可利用铂类药物，目前正在进行一项单机构I期临床试验。沙特铂在包括顺铂耐药模型在内的临床前模型中显示出抗肿瘤活性，并在包括前列腺癌在内的几种实体恶性肿瘤的成人试验中显示出活性。沙特铂的剂量限制性毒性是骨髓抑制。神经毒性和肾毒性，与顺铂和卡铂相关，在接受萨特铂的患者中尚未被描述。这些毒性的缺乏以及临床前和临床活性为开发沙铂治疗难治性癌症儿童提供了强有力的理由。将研究临床开发中的药物的药代动力学和药效学，并与成人的结果进行比较。在与博士合作。Helman和Grohar还开发了米霉素的I/II期试验，这是一种抗肿瘤抗生素，可以特异性抑制EWS/FLI1融合转录物，这是尤文氏肉瘤的特征。该试验正在进行中，将确定米霉素在儿童中的安全性和药代动力学，以及米霉素在患有尤文氏肉瘤的儿童和成人中的活性。4)我们正在加大对罕见癌症临床试验的开发力度。我们与COG合作开发了XL184 （cabozantinib）和口服RET、VEGFR和MET抑制剂的I期临床试验。这项试验对登记开放。这些靶点在儿童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。该试验的发展将允许难治性MTC患者参加另一项试验，这可能会带来益处。与Helman博士和Arnaldez博士合作，我们还开发了vandetanib（一种靶向药物）的II期试验，用于儿童和成人儿童野生型SDH缺陷胃肠道间质细胞肿瘤。目前还没有针对这种罕见癌症的有效治疗方案。在Helman博士的领导下，这项工作建立在儿童间质瘤间质瘤临床研究的基础上。5)为患有遗传性甲状腺髓样癌（MTC）的儿童和年轻人开发有效的治疗方法是另一个目标。我们最近公布了RET和RTK抑制剂vandetanib治疗MTC儿童和青少年的I/II期试验结果。大约50%的入组患者出现了部分缓解，大多数患者在多个治疗周期后仍在接受治疗。XL184的I期试验为使用vandetanib治疗疾病进展的患者提供了一种治疗选择。此外，我们还为MTC患者开发了一项自然史试验。该研究纳入了17例患者，目的包括监测肿瘤和非肿瘤表现的自然史，并评估MTC肿瘤样本的基因组变化，这可能预测对治疗的反应或耐药性。

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 the Children's Oncology Group (COG) Phase I Consortium with myself serving as protocol chair was recently completed. This study was expanded to determine the activity of sorafenib in children and young adults with refractory AML and FLT3-ITD mutations. Activity of sorafenib in this patient cohort has been observed, and a phase II study incorporating sorafenib into the upfront treatment for children with AML and FLT3ITD mutations is ongoing within the COG. In addition, we developed a phase II trial for select solid tumor strata, which is ongoing within the COG, and enrollment is nearing completion. Simultaneously we performed a phase I trial of sorafenib for children with 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 is open for enrollment. This trial is receiving funding through a Department of Defense Clinical Trial Award to the Trial PI B. Widemann). Based on preclinical work from Dr. Karen Cichowski's laboratory, we also developed a phase I/II clinical trial of the mTOR inhibitor sirolimus in combination with the HSP90 inhibitor ganetespib for adults with refractory sarcomas and MPNST. We are currently performing preclinical studies in collaboration with several NCI investigators with the goal to develop a phase I trial with ganetespib for children with refractory cancers. 3) In addition, we are pursuing the clinical development of novel cytotoxic agents for children and young adults with refractory cancers. We recently completed 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). 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. In collaboration with Drs. Helman and Grohar we have also developed a phase I/II trial of mithramycin, an anti-tumor antibiotic, which specifically inhibits the EWS/FLI1 fusion transcript, which is characteristic of Ewing sarcoma. This trial is ongoing and will determine the safety and pharmacokinetics of mithramycin in children and the activity of mithramycin in children and adults with Ewing sarcoma. 4) We are expanding our efforts into the development of clinical trials for rare cancers. In collaboration with the COG we have developed a phase I clinical trial of XL184 (cabozantinib) and oral RET and VEGFR and MET inhibitor. This trial is open to enrollment. 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. In collaboration with Dr. Helman and Dr. Arnaldez we have also developed a phase II trial with vandetanib, a targeted agent, for children and adults with pediatric wild-type SDH deficient gastrointestinal stromal cell tumors. No effective medical treatment options for this rare cancer are available currently. This effort builds on findings made in the pediatric GIST clinic under leadership of Dr. Helman. 5) The development of effective therapies for children and young adults with hereditary medullary thyroid carcinoma (MTC) has been another goal. We recently published the results of our phase I/II trial of the RET and RTK inhibitor vandetanib in children and adolescents with MTC. Approximately 50% of the patients enrolled experienced a partial response, and most patients remain on treatment after multiple treatment cycles, Our phase I trial of XL184 provides a treatment option for patients who develop disease progression on vandetanib. In addition, we have developed a natural history trial for patients with MTC. Goals of this study, which ahs enrolled 17 patients, include to monitor the natural history of tumor and non tumor manifestations and to evaluate genomic changes in MTC tumor sampels which may predict for response or resistance to treatment .