) Dr. Douglas Hawkins seeks to become a patient-oriented clinical investigator committed to improving the prognosis for pediatric sarcomas by developing a bone-seeking radiopharmaceutical. The prognosis for patients with recurrent or refractory Ewing's sarcoma family of tumors (ESFT) is quite poor, particularly for those with bone metastases. Although ESFT are radiosensitive, effective treatment with radiation therapy is limited by the toxicity of standard external beam radiation therapy to normal tissues, especially when bone metastases are widespread. A strategy that targets radiation to bone while sparing non-osseous tissue could allow the delivery of radiation to bone metastases with acceptable toxicity to normal organs. Holmium-166 (Ho)-DOTMP is a beta-particle emitting radiopharmaceutical that localizes to trabecular bone, with enhanced uptake in areas of active bone turnover. Studies in animals and in patients with multiple myeloma demonstrate that Ho-166-DOTMP delivers high doses of radiation to bone and bone marrow, with minimal non-hematopoietic toxicity. Dr. Hawkins will conduct a Phase I/II study of Ho-166-DOTMP in the treatment of recurrent or refractory ESFT with bone disease. The first specific aim of the project is to define the MTD and the range of toxicity for Ho-166-DOTMP using peripheral blood progenitor calls (PBPC) to support hematopoietic recovery. The second specific aim of the project is to determine the biodistribution and pharmacokinetics of Ho-166-DOTMP in ESFT, including estimation of the radiation dose to bone lesions. Because all patients will be required to have evaluable disease, the third specific aim of this project is to evaluate response to Ho-166-DOTMP. Once the MTD of Ho-166-DOTMP is defined, the fourth specific aim is to initiate a phase II study to estimate the response rate for recurrent or refractory ESFT with bone disease and to initiate a trial incorporating Ho-166-DOTMP into myeloablative therapy for poor risk ESFT. The clinical research environment at Children's Hospital and Regional Medical Center, the University of Washington, and the Fred Hutchinson Cancer Research Center are particularly well suited to the development of his clinical investigation. Dr. Irwin Bernstein, who has extensive clinical research and training experience, will serve as Dr. Hawkins' mentor. Dr. Hawkins also proposes to take courses in radiation biology, radiation pharmacology, biostatistics, and medical ethics at the University of Washington and Children's Hospital and Regional Medical Center. Upon completion of the five-year K23 award, he anticipates having acquired a strong foundation biostatistics and radiation biology, as well as considerable experience planning and conducting clinical trials enabling him to emerge as an independent clinical investigator.
