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和年轻人癌症的新药物，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。临床试验分为单点试验和多点试验。此外，我们正在与儿童肿瘤小组（COG）、肉瘤合作小组SARC和NF临床试验联盟合作开展试验。临床试验的目标是顽固性实体肿瘤，如尤文氏肉瘤或横纹肌肉瘤，以及没有已知有效药物治疗的肿瘤，如肺泡软组织肉瘤或恶性周围神经鞘肿瘤（MPNST）。这项工作通过NCI POB的药理学和实验治疗学（PET）部分进行。正在进行和正在开发的临床试验的例子包括：1)与儿童肿瘤组（COG）合作的例子：cabozantinib （XL184）治疗难治性实体肿瘤的I期试验：cabozantinib是一种多受体酪氨酸激酶（RTK）的小分子抑制剂，主要包括MET、VEGFR2和RET，以及较小程度的KIT和TIE-2。RET抑制为我们开发卡博赞替尼治疗小儿甲状腺髓样癌（MTC）提供了基本原理。然而，cabozantinib也靶向多种儿科癌症中过表达的rtk，包括儿童肉瘤中的VEGFR2，骨肉瘤、胶质瘤和甲状腺乳头状癌中的MET。因此，我们与COG I期/试点联盟合作，在针对MTC和包括脑肿瘤在内的难治性实体肿瘤的I期试验中开发cabozantinib。本试验已完成入组，达到主要目的。基于一些客观反应和长期疾病稳定的有希望的结果，我们与COG（主席：Srivandana Akshintala， NYU，副主席：Brigitte Widemann）合作，开发了cabozantinib用于几种实体肿瘤层的II期试验。2)与SARC肉瘤合作小组和国防部赞助的NF临床试验联盟合作的例子：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。我指导了一项SARC协调的多机构临床试验，针对难治性散发或NF1相关的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。该试验获得了国防部临床试验奖的资助。基于Karen Cichowski博士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联合用于难治性肉瘤和MPNST成人的I/II期临床试验（PI: AeRang Kim, Co-PI: Brigitte Widemann）。这个试验也完成了。基于有希望的临床前结果，一项联合mTOR抑制剂（双重TORC激酶抑制剂）和MEK抑制剂的II期试验将很快开放入组（PI: AeRang Kim, Co-PI: Brigitte Widemann）。SARC、国防部赞助的NF联盟和研究人员在开发MPNST有效疗法方面的密切合作表明，及时进行组织学特异性试验是可行的。3)将CCR实验室结果转化为临床试验发展的例子：横纹肌肉瘤（Rhabdomyosarcoma， RMS）是儿童最常见的软组织肉瘤，在美国，15岁以下儿童的年发病率为每百万4-7例。转移性和复发性疾病的患者基本上是无法治愈的，5年总生存率低于20%，并且在过去的几十年里，预后只有很小的改善。靶向1型胰岛素样生长因子受体（IGF-1R）在儿童肉瘤的治疗中显示出希望，在早期试验中约10%的患者有临床意义的反应。在RMS模型中，CCR的临床前工作（Helman博士）已经证明，阻断IGF-1R导致YES激活，并且YES激活与对IGF-1R阻断的抗性有关。此外，同时阻断IGF-1R和YES的联合治疗可增强体外和体内对RMS的生长抑制。在与博士合作。Helman和Heske，我们为RMS患者开发了针对IGF-1R的单克隆抗体联合靶向YES的药物的I/II期临床试验。这项试验是开放登记的。在另一个例子中，基于有希望的临床前研究，我们目前也在开发一项早期临床试验，将一种bomodomain抑制剂与一种拓扑异构酶II抑制剂结合起来，针对儿童和年轻人的难治性实体瘤。该试验将由Jack Shern博士（POB助理临床研究员）指导。4)与NCI CCR发育治疗诊所合作的例子：我们正在与Alice Chen博士合作，招募患有难治性癌症（如肺泡软组织肉瘤）的儿童，主要是由她指导的成人临床试验。同样，陈医生将在儿科肿瘤科的试验中评估成人患者。这确保患有罕见肿瘤的儿童和成人获得最佳的靶向治疗。我们目前正在制定一项儿科-成人罕见肿瘤方案，目标是在选定的罕见肿瘤中进行深入的自然史研究。NCI POB和我的部门在两个NCI CCR计划中发挥领导作用：NCI CCR罕见肿瘤计划（RTI）促进NCI （CCR和DCEG）的基础和临床研究人员以及校外研究人员之间的重点合作。罕见肿瘤患者参与网络（RTPEN）由癌症登月计划（Cancer Moonshot）支持，旨在通过共享的基础设施和网络连接患者和研究人员，加速对罕见肿瘤的了解，并通过患者、倡导者、临床医生、临床和基础研究人员以及其他利益相关者的这些国家和国际合作，开发罕见肿瘤的临床试验。RTPEN的长期目标是有效地研究罕见肿瘤的生物学和临床病程，将这些发现转化为改善护理和治疗，并确保所有患者都能获得可能有益于他们的临床试验。

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. Clinical trials are conducted as single site and multi-site trials. In addition, we are collaborating with the Children's Oncology Group (COG), the sarcoma cooperative group SARC, and the NF Clinical Trials Consortium in the development and conduct of trials. Clinical trials target refractory solid tumors such as Ewing sarcoma or rhabdomyosarcoma, and tumors with no known effective medical therapy such as alveolar soft part sarcoma or malignant peripheral nerve sheath tumors (MPNST). This work is performed through the Pharmacology and Experimental Therapeutics (PET) Section of the NCI POB. Examples of clinical trials ongoing and in development include: 1) Example of collaboration with the Children's Oncology Group (COG): Phase I trial of cabozantinib (XL184) for refractory solid tumors: Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases (RTK) including primarily MET, VEGFR2 and RET and to a lesser extent KIT and TIE-2. RET inhibition provided the rationale for our development of cabozantinib for pediatric medullary thyroid carcinoma (MTC). However, cabozantinib also targets RTKs that are overexpressed in a variety of pediatric cancers including, VEGFR2 in pediatric sarcomas, MET in osteosarcoma, glioma, and papillary thyroid carcinoma. We thus collaborated with the COG Phase I/Pilot Consortium in the development of cabozantinib in a phase I trial with an arm specifically for MTC and an arm for refractory solid tumors including brain tumors. This trial has completed enrollment and has achieved the primary objectives. Based on promising results with several objective responses and prolonged disease stabilization we developed a phase II trial of cabozantinib for several solid tumor strata in collaboration with the COG (Chair: Srivandana Akshintala, NYU, Vice Chair: Brigitte Widemann). 2) Example of collaboration with the sarcoma cooperative group SARC and with the DoD sponsored NF Clinical trials Consortium: 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 for both patient populations. I directed a SARC coordinated 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. This trial received funding through a Department of Defense Clinical Trial Award. 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 (PI: AeRang Kim, Co-PI: Brigitte Widemann). This trial is also complete. Based on promising preclinical results, a phase II trial combining an mTOR inhibitor (dual TORC kinase inhibitor) with a MEK inhibitor will soon open for enrollment (PI: AeRang Kim, Co-PI: Brigitte Widemann). Close collaboration of SARC, the DOD sponsored NF Consortium, and investigators invested in developing effective therapies for MPNST has demonstrated that the timely conduct of histology specific trials is feasible. 3) Example of a clinical trial development translating CCR laboratory findings to the clinic: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, with an annual incidence of 4-7 cases per million children under 15 years in the US. Patients with metastatic and recurrent disease are essentially incurable with a 5-year overall survival of less than 20%, and outcomes have only minimally improved over the past several decades. Targeting of the type-1 insulin-like growth factor receptor (IGF-1R) has shown promise in the treatment of pediatric sarcomas, with clinically meaningful responses in about 10% of patients in early phase trials. In RMS models, preclinical work at the CCR (Dr. Helman) has demonstrated that blockade of IGF-1R results in YES activation and that YES activation is associated with resistance to IGF-1R blockade. In addition, combination treatment blocking both IGF-1R and YES results in enhanced growth inhibition of RMS in vitro and in vivo. In collaboration with Drs. Helman and Heske, we developed a phase I/II clinical trial of a monoclonal antibody against IGF-1R combined with an agent targeting YES for patients with RMS. This trial is open for enrollment. In another example, based on promising preclinical studies, we are also currently developing an early clinical trial combining a bomodomain inhibitor with a topoisomerase II inhibitor directed at refractory solid tumors in children and young adults. This trial will be directed by Dr. Jack Shern (Assistant Clinical Investigator in the POB). 4) Example for collaboration with the NCI CCR Developmental Therapeutics Clinic: We are collaborating with Dr. Alice Chen by enrolling children with refractory cancers such as alveolar soft part sarcoma, on primarily adult clinical trials directed by her. Similarly, Dr. Chen will evaluate adult patients on Pediatric Oncology Branch trials. This ensures that children and adults with rare tumors get optimal access to targeted therapies. We are currently developing a pediatric-adult rare tumor protocol with the goal to perform in depth natural history studies in select rare tumors. The NCI POB and my Section have a leadership role in 2 NCI CCR Initiatives: The NCI CCR Rare Tumors Initiative (RTI) fosters focused collaborations between basic and clinical researchers at NCI (CCR and DCEG), as well as extramural investigators. The Rare Tumor Patient Engagement Network (RTPEN), supported by the Cancer Moonshot, aims to connect patients and investigators through shared infrastructure and networks, accelerate the understanding of rare tumors and develop clinical trials for rare tumors through these national and international collaborations of patients, advocates, clinicians, clinical and basic researchers, and other stakeholders. The long-term goal of the RTPEN is to effectively study the biology and clinical course of rare tumors, translate these findings to improve care and treatment and to ensure that all patients have access to clinical trials which may benefit them.