ZIA SC 010354 (ZIA) | |||
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Title | Clinical Development of Novel Drugs for Children with Refractory Cancers | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Widemann, Brigitte | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $483,032 | Project Dates | 10/01/1999 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Childhood Cancers (100.0%) Digestive Diseases (10.0%) |
Central Nervous System - Not Including Brain (5.0%) Childhood Leukemia (10.0%) Leukemia (10.0%) Nervous System (10.0%) Neuroblastoma (5.0%) Sarcoma (60.0%) Thyroid (10.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
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Abstract | |||
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 ph" |