PROJECT SUMMARY Non-Hodgkin’s Lymphoma (NHL) represents 4% of all cancer diagnosed in the U.S., and as many as 50% of patients will relapse within 2 years of diagnosis and treatment. The current standard of care is chemotherapy. For Diffuse Large B cell Lymphoma subtype (DLBCL) CHOP (cyclophosphamide- doxorubicin-vincristine-prednisone) is given in combination with an anti-CD20 monoclonal antibody, such as rituximab (R-CHOP). Unfortunately, chemotherapy requires numerous treatment cycles with challenging side effects and does not completely remove the cancerous lymphocytes, as indicated by the frequency of relapse. A drug that could reduce the lymphoma population and essentially increase the potency of the chemotherapy regimen (fewer lymphoma cells to the chemotherapy concentration) would have the potential to be synergistic as a treatment strategy. AVM0703, a proprietary formulation of high concentration dexamethasone developed by AVM Biotechnology, has been shown to control NHL growth in murine models. It also safely reduces lymphocytes following a single very high dose via one-hour infusion, in both pre-clinical and clinical settings. AVM0703 is currently the subject of a US-based clinical study in no-option, relapsed/refractory NHL patients and is distinguished from other investigative drugs in this ‘terminal no-option’ patient population by its absence of safety concerns with patients reporting feeling great, regaining appetite and energy, and durable response recorded. The goal of this project is to validate the combination of AVM0703 and standard DLBCL chemotherapy R-CHOP. This approach is expected to increase complete response rates and potentially reduce the required number of chemotherapy cycles, providing a more tolerable therapeutic option for newly diagnosed NHL patients. The feasibility of this approach will be validated in Phase I with the following aims: Aim 1) Evaluate the ability of AVM0703 in combination with R-CHOP to reduce R-CHOP cycles in an aggressive, immune-resistant murine B cell NHL model. Aim 2) Assessment of AVM0703 combination therapy with reduced dose R-CHOP to enhance outcomes in elderly patients. The Phase II project will further focus on efficacy studies, and a small clinical trial with newly diagnosed NHL patients to evaluate the effects of this novel therapeutic treatment approach.