Osteosarcoma: Our study with newly diagnosed localized and metastatic osteosarcoma (OS), in collaboration with several other centers was concluded almost 3 years ago, and patients are continued to be followed. We will likely report the findings within the next 2 years with sufficient follow-up. The companion study evaluating the value of dynamic MRI imaging (DEMRI) is predicting response to neoadjuvant chemotherapy evaluated approximately 22 patients studied at the NCI and was insufficient to reach any conclusions unfortunately based on the small sample size. The high-dose chemotherapy with autologous stem cell rescue arm of this study did not improve DFS by greater than 50% in poor risk patients. A multi-institutional study to evaluate an Astra-Zeneca src-kinase inhibitor in pulmonary metastatic osteosarcoma is now open and we have just entered out first 2 patients at the NCI. We performed preclinical testing in our osteosarcoma models and demonstrated that the drug inhibits targets of src and also showed that human osteosarcoma tumors express high levels of activated src. The study is a randomized double blind placebo controlled study. Patients who present with pulmonary metastases will receive either complete resection of pulmonary nodules plus treatment with the kinase inhibitor (orally daily) vs. placebo to determine whether DFS can be prolonged with treatment of the src kinase inhibitor. The study will be performed through a new sarcoma treatment consortium called SARC and all agreements between SARC and AstraZeneca are now in place. We also completed accrual to the osteosarcoma cohort in a SARC Phase II study using a human monoclonal antibody to the IGFIR in recurrent osteosarcoma. Thirty-five patients from around the U.S. were entered, and data are currently being analyzed. Finally, we are about to open a study in collaboration with St. Jude and Johns Hopkins to study potential role of bevacizumab in combination with standard cytotoxic chemotherapy in newly diagnosed osteosarcoma patients. St. Jude has recently opened this study and we are in the process of getting IRB approval and will have this study open within the next 2 months. Ewings Sarcoma: A combination of sequential gemcitabine/docetaxel based on preliminary in vitro synergy and previous activity of the single agents was also tested through the SARC consortium). Like the osteosarcoma cohort, this cohort was terminated and no significant activity was observed. A manuscript is being prepared to report this negative study. We recently opened an international study using a human monoclonal antibody directed against the IGFI receptor in Ewings, rhabdomyosarcoma, osteosarcoma, synovial sarcoma and several other rare adult type sarcomas through the SARC clinical trials consortium. I serve as the chairman of the study committee and played a major role writing the protocol. The study opened in December 2007 and now has completed accrual in all cohorts including rhabdomyosarcoma, osteosarcoma and Ewings sarcoma. Clear objective responses have been seen in both the Ewings cohort and the rhabdomyosarcoma cohort. We have now locked the data and are currently completing initial analysis to determine overall response rates, toxicity, and pharmacokinetic data. We have recently completed an amendment to open a new cohort of Ewings sarcoma patients under the age of 18 since the median age of patient entered on this SARC study was above 30. This study will be done in collaboration with the Childrens Oncology Group (COG). We have also amended the cohort to evaluate an every 3 week schedule of antibody. We also have now begun to receive data on the companion biology study to try to identify biomarkers that might predict response to this targeted therapy. There has been some delay in opening a follow-up randomized study comparing standard salvage therapy for Ewings sarcoma, cytoxan plus topotecan, to the same chemotherapy regimen plus the IGFIR Ab. The study will also be done in collaboration with the COG and we are awaiting initial analysis of the Phase II study prior to beginning what is hope to serve as a registration study if the results show an improvement of progression-free survival in the arm that includes the IGFIR Ab. I will again serve as the protocol study chairman for this study that we hope to have open by late spring 2009. We continue to accrue patients to a study evaluating treatment of MPNST patients, in both the sporadic and NF-1 associated setting. This study under the leadership of Dr. Brigitte Widemann. We will evaluate the objective response rate of alternating Ifos/etoposide with Adria/Ifos in these patients, followed by surgical resection after 4 cycles of therapy. We have now entered 8 patients to date, and this study is now accruing patients across the SARC Consortium. Finally, in collaboration with Dr. Su Young Kim, we have developed a program to study pediatric GIST patients, a very rare disease that is biologically distinct from adult GIST patients. We have held several clinics where we bring in patients from across the country as well as physicians with interest/expertise in this rare disease from several centers across the country including surgeons, pediatric and medical oncologists as well as pediatric endocrinologists. We have already identified specific novel germline mutations in patients with non-syndromic, apparently sporadic GIST tumors, and have written a pilot protocol to test the IGFIR Ab in refractory patients since others have already published that these pediatric GIST tumors express high levels of IGFIR. Several abstract have been presented describing this novel NIH clinic, and we are currently working to complete identification of the germline mutations for publication.
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