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.

该项目的主要目的是开发新的药物来治疗儿童期癌症，重点是基于当前对人类癌症分子发病机理的理解，对药物开发的更为理性，有针对性的方法。基于药物的作用机理和靶标在儿童期癌症中的重要性，将对成年癌症进行临床发育的新分子靶向药物将应用于儿童期癌症。此外，新型的细胞毒性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（P＆ET）部分进行的。正在进行的临床试验和发展中的例子包括：1）为难治性癌症和白血病儿童提供RAF激酶和受体酪氨酸激酶抑制剂索拉非尼的发展。最近完成了由儿童肿瘤学组（COG）I期联盟进行的索拉非尼的I期试验，最近完成了协议主席，目前正在扩展，以确定索拉非尼在具有难治性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，以作为COG广泛的研究进行某些实体瘤地层。同时为1型神经纤维瘤病（NF1）相关肿瘤开发了索拉非尼（请参阅项目1）。 2）MTOR途径参与了人类癌症的进展和相关肿瘤1型（NF1）型神经瘤病的进展，并且正在进行MTOR抑制剂的临床试验，并且将针对两个患者种群进行追求。例如，针对与MTOR抑制剂RAD001结合血管生成抑制剂bevacizumab结合使用MTOR抑制剂RAD001的难治性零星或NF1相关的恶性外周神经鞘肿瘤（MPNST）的多机构临床试验将很快开放。该审判是通过国防部的临床试验奖获得资金，该审判Pi B. Widemann）。 3）此外，我们正在为儿童和年轻人的难治性癌症的新型细胞毒性剂的临床开发。我们目前正在针对具有高级，不可切除，化学疗法中神中神中神经外周神经鞘（MPNST）的患者进行新辅助化学疗法的多机构II期试验。 MPNST是侵略性的软组织肉瘤，与较差的预后有关，尤其是在NF1患者中（请参阅项目1）。我们还评估了抗抑制蛋白剂，抑制微管蛋白去聚合的抗蛋白剂ixabepilone（BMS-247550）（BMS-247550）。 NCI内的I阶段试验完成了，随后进行了COG广泛的II期试验，该试验最近也完成了。 Satraplatin的I期临床试验是一种新型的口服生物利用铂剂，目前正在作为I阶段I阶段试验中开发。 satraplatin在包括抗铂耐药模型在内的临床前模型中表现出抗肿瘤活性，并在成人试验中显示了包括前列腺癌在内的几种固体恶性肿瘤的活性。 Satraplatin的剂量限制毒性是骨髓抑制。在接受Satraplatin的患者中尚未描述与顺铂和卡铂有关的神经毒性和肾毒性。缺乏这些毒性，临床前和临床活动为难治性癌症儿童开发Satraplatin提供了有力的理由。将研究临床发育中药物的药代动力学和药效学，并将其与成人的结果进行比较。另外两个临床试验是在发育的较早阶段：1）我们提出了针对患有难治性实体瘤儿童的口服IGF1受体和胰岛素受体抑制剂的I期试验。在许多小儿恶性肿瘤中隐含IGF途径，这是NCI POB的一个积极研究领域。 2）我们提出了口服RET和VEGFR和MET抑制剂的I期试验。这些靶标在小儿恶性肿瘤和遗传性甲状腺癌（MTC）中很重要，为此，我们与口服RET抑制剂进行了持续的临床试验。该试验的开发将使患有难治性MTC患者可以参加另一项试验，这可能会带来好处。