Clinical Development of Novel Drugs for Children with Refractory Cancers

儿童难治性癌症新药的临床开发

基本信息

项目摘要

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,目前正在扩大以确定索拉非尼在难治性AML和FKT3-ITD突变的儿童和年轻人中的活性。此外,我们正在开发一项II期试验,选择实体瘤层,作为COG范围的研究。同时,索拉非尼被开发用于1型神经纤维瘤病(NF1)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(NF1)相关肿瘤的进展,mTOR抑制剂的临床试验正在进行中,并将在这两种患者群体中进行。例如,一项针对难治性散发性或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将很快开放招募。该试验获得了国防部临床试验奖的资助(试验PI B. Widemann)。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。目前,我们正在领导一项多机构的二期临床试验,对高级别、不可切除的化疗恶性周围神经鞘肿瘤(MPNST)患者进行新辅助化疗。mpnst是侵袭性软组织肉瘤,预后较差,尤其是NF1患者(见项目1)。我们还评估了艾替隆B类似物ixabepilone (BMS-247550),一种抗微管蛋白药物,可抑制微管蛋白解聚。NCI内的单一机构一期试验已经完成,随后是COG范围内的二期试验,该试验最近也完成了。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。另外两项临床试验处于早期发展阶段:1)我们正在提议一项口服IGF1受体和胰岛素受体抑制剂治疗难治性实体瘤儿童的I期试验。IGF通路在许多儿科恶性肿瘤中都存在,这是NCI POB的一个活跃研究领域。2)我们正在提议一项口服RET、VEGFR和MET抑制剂的I期试验。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。

项目成果

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Brigitte Widemann其他文献

Brigitte Widemann的其他文献

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{{ truncateString('Brigitte Widemann', 18)}}的其他基金

2012 Neurofibromatosis (NF) Conference
2012年神经纤维瘤病(NF)会议
  • 批准号:
    8400330
  • 财政年份:
    2012
  • 资助金额:
    $ 88.04万
  • 项目类别:
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:
    8938411
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:
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:
    8763704
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:
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:
    7735408
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:
Clinical Development of Therapies for Neurofibromatosis Type 1-Related Tumors
1 型神经纤维瘤病相关肿瘤治疗的临床开发
  • 批准号:
    7592948
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:
Therapy for NF1-Related Tumors and other Genetic Tumor Predisposition Syndromes
NF1相关肿瘤和其他遗传性肿瘤易感综合征的治疗
  • 批准号:
    9556368
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:
Therapies for patients with rare tumors and genetic tumor predisposition
罕见肿瘤和遗传肿瘤易感性患者的治疗
  • 批准号:
    10487193
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:
Clinical Development of Novel Drugs for Children with Ca
儿童钙化新药的临床开发
  • 批准号:
    7292086
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:
Novel Drugs for Children With Cancer /Neurofibromatosis
治疗儿童癌症/神经纤维瘤病的新药
  • 批准号:
    6558756
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:
Therapy for NF1-Related Tumors and other Genetic Tumor Predisposition Syndromes
NF1相关肿瘤和其他遗传性肿瘤易感综合征的治疗
  • 批准号:
    9153674
  • 财政年份:
  • 资助金额:
    $ 88.04万
  • 项目类别:

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使用肿瘤特异性血管生成抑制剂和药物重新定位开发新型肺癌疗法
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脑血管生成抑制剂 (BAIs/ADGRB) 的结构和功能研究
  • 批准号:
    9813883
  • 财政年份:
    2019
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血管生成抑制剂蛋白尿表达机制的阐明及不良反应避免的研究
  • 批准号:
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接受血管生成抑制剂的癌症患者的心脏毒性评估和心脏毒性分子机制的阐明
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血管生成抑制剂双重治疗的体内微创疗效评价
  • 批准号:
    23591763
  • 财政年份:
    2011
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    $ 88.04万
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ANGIOGENESIS INHIBITORS IN THE MULTIMODAL TREATMENT OF PEDIATRIC SOLID TUMORS
血管生成抑制剂在小儿实体瘤多模式治疗中的应用
  • 批准号:
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    7351352
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    8002099
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