(P 237) EVOLUTIONARILY INSPIRED THERAPY FOR NEWLY DIAGNOSED, METASTATIC, FUSION POSITIVE RHABDOMYOSARCOMA, TRIAL IN PROGRES, NCT04388839, A REPORT FROM THE NATIONAL PEDIATRIC CANCER FOUNDATION

Objective: Patients with newly diagnosed, metastatic, fusion-positive rhabdomyosarcoma (mFPRMS) typically respond well to initial therapy with regimens such as vincristine, actinomycin D, and cyclophosphamide (VAC). However, nearly all patients subsequently relapse, with 3-year event-free survival of < 10%. This pattern of early response followed by inevitable, later relapse suggests that a majority of cells are sensitive to VAC, but a smaller population of resistant cells, either present at diagnosis or arising during therapy, lead to recurrence. Vinorelbine is the most active agent for recurrent MFPRMS arising after standard treatment, and we hypothesize that incorporating vinorelbine into initial therapy prior to recurrence may improve outcomes.

Methods: Evolutionary concepts suggested three novel therapy regimens: 1) augmenting the first strike drugs with vinorelbine, 2) applying vinorelbine as a second strike agent once the disease is in clinical remission due to the first strike drugs, or 3) using an adaptive therapy protocol to manage the competitive release of resistant tumor cells. We hypothesize that any (or all) of these evolutionary therapies could improve progression-free survival.

Results: Based on our hypotheses outlined above, we have developed a clinical trial by which enrolling patients have 4 options (arms) of therapy to choose from with their treating oncologist. In Arm A, vinorelbine is combined with actinomycin D and cyclophosphamide as the initial therapy. In Arm B, patients are treated with VAC therapy until remission is achieved, and then transitioned to a second strike of vinorelbine maintenance therapy. Patients enrolled on Arm C receive adaptive therapy in which conventional agents are given at intervals designed to contain but not eliminate the tumors, thereby restraining the competitive release of resistant cells that typically follows from the eradication of all chemosensitive tumor cells. For Arm C, imaging serves to monitor tumor volume and guide decisions regarding when to stop and restart treatment. Arm D serves as a control, and patients will receive VAC or any other conventional chemotherapy (exs: VAC/VI, ARST0431, VAC with higher dose cyclophosphamide, etc). Serial measures of circulating tumor cells and cell free DNA will evaluate disease status over time. A novel mathematical model has been created to evaluate overall tumor burden and the frequency of resistant cells across arms. The model is iteratively updated as patient data is collected over time resulting in the creation of a patient-personalized model.

Conclusion: Evolutionary concepts can be translated into clinical trials in an effort to improve event-free survival for pediatric patients with mFPRMS. This trial is a first step towards more response-based and dynamic treatment plans for heterogeneous and evolving sarcomas.