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
• 负责人: Brigitte Widemann
• 金额: $ 69.25万
• 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/8938411
• 关键词: Address; Adolescent; Adult; Aftercare; Angiogenesis Inhibitors; Antibiotics; Award; BAY 54-9085; Bioavailable; Characteristics; Child; Childhood; Children' s Oncology Group; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Cytotoxic agent; Department of Defense; Development; Disease Progression; Drug Kinetics; Drug effect disorder; Enrollment; Ewings sarcoma; FLI1 gene; FLT3 gene; Funding; Genomics; Goals; Heat-Shock Proteins 90; Human; Image; Individual; Inherited; Laboratories; Leadership; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant Peripheral Nerve Sheath Tumor; Medical; Molecular; Monitor; Multi-Institutional Clinical Trial; Mutation; Natural History; Neoadjuvant Therapy; Neurofibromatosis 1; New Agents; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Phase I/II Trial; Phase II Clinical Trials; Platinum Compounds; Plicamycin; Protocols documentation; Publishing; Refractory; Research Personnel; Resistance; Safety; Sampling; Satraplatin; Sirolimus; Solid Neoplasm; Stromal Cells; Therapeutic; Transcript; Tyrosine Kinase Inhibitor; Unresectable; Vascular Endothelial Growth Factor Receptor; Work; base; bevacizumab; cancer therapy; chemotherapy; cohort; drug development; effective therapy; experience; gastrointestinal; human FRAP1 protein; imaging modality; inhibitor/antagonist; leukemia; mTOR Inhibitor; medullary thyroid carcinoma; novel; partial response; patient population; phase 2 study; pre-clinical; preclinical study; programs; raf Kinases; receptor; research clinical testing; response; sarcoma; soft tissue; tumor; tumor metabolism; young adult

The primary objective of this project is to develop new agents for the treatment of cancers in children and young adults 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 solid tumors. 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. This trial recently opened for enrollment. 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, was recently completed. 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 just completed enrollment, and we are planning to develop a phase II trial collaboratively with the COG. 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 has enrolled 23 patients, include to monitor the natural history of tumor and non tumor manifestations and to evaluate genomic changes in MTC tumor samples which may predict for response or resistance to treatment. 6) Developing trials with agents, which address tumor metabolism is a newer effort of our section. In collaboration with Johns Hopkins we are hoping to develop a clinical trial with agents in combination, which will inhibit tumor metabolism. The planned clinical trial will incorporate novel imaging modalities with the goal to image the effects on tumor metabolism

该项目的主要目标是开发治疗儿童和年轻人癌症的新药，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实体瘤的儿童的 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第一阶段试验最近已完成，我本人担任方案主席。这项研究的范围扩大到确定索拉非尼对患有难治性 AML 和 FLT3-ITD 突变的儿童和年轻人的活性。已观察到索拉非尼在该患者队列中的活性，COG 内正在进行一项将索拉非尼纳入针对 AML 和 FLT3ITD 突变儿童的前期治疗的 II 期研究。此外，我们还针对选定的实体瘤层开展了一项 II 期试验，该试验正在 COG 内进行，入组工作即将完成。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（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，一项针对难治性散发性或 NF1 相关恶性周围神经鞘瘤 (MPNST) 患者的多机构临床试验，使用 mTOR 抑制剂 RAD001 联合血管生成抑制剂贝伐珠单抗进行招募。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。基于 Karen Cichowski 博士实验室的临床前工作，我们还开展了 mTOR 抑制剂西罗莫司与 HSP90 抑制剂 ganetespib 联合治疗成人难治性肉瘤和 MPNST 的 I/II 期临床试验。该试验最近开始接受注册。我们目前正在与几位 NCI 研究人员合作进行临床前研究，目标是针对难治性癌症儿童开展 ganetespib 的 I 期试验。 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。我们最近完成了一项针对高级别、不可切除、未接受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）。 Satraplatin（一种新型口服生物可利用的铂类药物）的 I 期临床试验最近完成。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。与博士合作。 Helman 和 Grohar 还开发了光神霉素（一种抗肿瘤抗生素）的 I/II 期试验，它特异性抑制 EWS/FLI1 融合转录本，这是尤文肉瘤的特征。该试验正在进行中，将确定光神霉素在儿童中的安全性和药代动力学，以及光神霉素在患有尤文肉瘤的儿童和成人中的活性。 4) 我们正在加大力度开展罕见癌症的临床试验。我们与 COG 合作开发了 XL184（卡博替尼）和口服 RET、VEGFR 和 MET 抑制剂的 I 期临床试验。该试验刚刚完成入组，我们计划与 COG 合作开发 II 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。我们还与 Helman 博士和 Arnaldez 博士合作，针对患有野生型 SDH 缺陷型胃肠道间质细胞瘤的儿童和成人，开展了靶向药物 vandetanib 的 II 期试验。目前还没有针对这种罕见癌症的有效治疗方案。这项工作建立在赫尔曼博士领导下的儿科胃肠道间质瘤诊所的研究成果的基础上。 5) 另一个目标是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疗法。我们最近发布了 RET 和 RTK 抑制剂凡德他尼治疗 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继续接受治疗。我们的 XL184 I 期试验为使用凡德他尼出现疾病进展的患者提供了一种治疗选择。此外，我们还针对 MTC 患者开展了自然史试验。这项研究招募了 23 名患者，其目标包括监测肿瘤和非肿瘤表现的自然史，并评估 MTC 肿瘤样本中的基因组变化，这可能预测对治疗的反应或耐药。 6) 开展针对肿瘤代谢的药物试验是我们部门的一项新工作。我们希望与约翰·霍普金斯大学合作开展一项联合用药的临床试验，这将抑制肿瘤代谢。计划中的临床试验将采用新颖的成像方式，旨在成像对肿瘤代谢的影响