(P 113) METASTATIC EWING'S TRAIL TESTING SCHEDULE ENHANCEMENT TO IMPROVE OUTCOMES (METTSEO)

Objective: The chemotherapy regimens used to treat the more common pediatric sarcomas are decades old. These same regimens are typically used for both localized disease, where they are moderately effective, and metastatic sarcomas with woefully inferior outcomes. While a few novel agents are in development, their activity in sarcomas preclinically or in early phase trials has been far from overwhelming and our track record of adding single agents, or cassettes of agents, to our standard of care regimens has failed to demonstrate significant improvements for metastatic disease.
Given specific patient populations with survival rates in the single digits using current standards, a paucity of new drugs and what appear to be an insurmountable bar for statistically significant improvement with a single addition to a standard of care backbone, we propose testing extensive changes in treatment schedule and strategy, using known agents, with the intent to prevent the emergence and dominance of resistant sarcoma cell populations.

Methods: The National Pediatric Cancer Foundation’s Sunshine Consortium has developed a trial focused on widely metastatic Ewing sarcoma, that carries a 3-year probability of event-free survival of as low as 8%. The strategy proposed involves only using agents that have already shown activity in Ewing sarcoma but changing the combination every 6-8 weeks (Fig.1), as opposed the standard repetition of 14-cycles of VDC/IE. In so doing, the hope is to prevent resistant populations from emerging and prolong the progression free survival, while at the same time decreasing toxicity and improving quality of life. Cumulative doses of agents are comparable to VDC/IE and administered over a prolonged timespan (Table 1). Most regimens are intended to be administered in an outpatient setting. The sequence of regimens is completely empirical but sought to capitalize on known response to upfront VDC, regimens able to be given with radiation, the more active relapsed regimens demonstrated by the rEEcur trial and very loosely based on the phases that make up Acute Lymphoblastic Leukemia therapy, where combinations of different agents, of varying intensities, are used at different times throughout the treatment course. The collection of serial blood samples to evaluate circulating tumor cells and circulating tumor DNA, imaging and, when appropriate, serial tumor tissue collected will be used to evaluate response and the emergence of resistant cell populations.

Results: The protocol has been written and revised with substantial input from colleagues and collaborators. Scientific and regulatory review is underway with enrollment anticipate to start in late 2024.

Conclusion: The lack of progress in the treatment of metastatic sarcomas calls for substantial changes in how we approach and design clinical trials for these patients. One proposed strategy is the frequent, sequential, changes in chemotherapy combinations, albeit using agents already known to have activity in the specific cancer. Informative correlative studies built into the trial are essential to provide insight into any success or failure of new strategies.