Expedited Expansion Cohort Clinical Trial for Relapsed/Refractory 'no-option' Non-Hodgkin's Lymphoma/Leukemia Patients

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ABSTRACT Non-Hodgkin’s Lymphoma (NHL) is the 7th most common cancer in the U.S., with over half of the 77,240 people diagnosed annually over age 65. In about 50% of cases, disease recurs or relapses, typically within two years of initial treatment, and in some patients disease is refractory to additional treatment (Refractory/Relapsed, R/R). Salvage therapy in these patients consists of stronger chemotherapy cocktails or more recently, cell therapy or hematopoietic cell transplantation. Four-year survival rates are about 40% with salvage chemotherapy and 60% for ASCT. Autologous Chimeric Antigen Receptor T (CarT) cell products have triggered great response rates in clinical trials and real-world use for some types of R/R NHL. However, the therapies are not curative with up to 46% relapsing within 2 weeks to 8.5 months even with negative minimal residual disease (MRD); they are associated with significant toxicities and are restricted to administration at accredited treatment centers. AVM Biotechnology’s FDA-approved trial, NCT04329728, is currently ongoing. This clinical trial includes a dose- escalation study of AVM0703 and a pivotal adaptive-design expansion cohort study in no-option patients with lymphoid malignancies who failed at least 1 prior regimen, who do not qualify for any other approved therapy, and who need treatment due to progressive disease. Currently City of Hope, UCLA, Norton Cancer Institute, Levine Cancer Institute, and University of Texas Southwestern are actively enrolling patients. Illinois Cancer Care University of Illinois and Holden Comprehensive Cancer Center at University of Iowa are being activated. Indiana University Melvin and Bren Simon Comprehensive Cancer Center, University of New Mexico Comprehensive Cancer Center, CHI Health St. Francis Hospital, Advent Health Hendersonville, Moffitt Cancer Center and MD Anderson Cancer Center will participate in the expansion cohort phase. Patients dosed to date, in compassionate use and in enrolled dose-escalation cohorts, demonstrate that AVM0703 is distinguished from other investigative drugs in this ‘terminal no-option’ patient population by its absence of safety concerns, and the sites report that their patients feel great, regain appetite and energy, and durable response has been recorded. This proposal requests funding for the adaptive design expansion cohort study. Once the expansion phase dose has been determined (projected for Nov 2021 based on enrollment, safety and response to date) patients will be enrolled in 5 NHL sub-indication specific cohorts, requiring about 18 patients per arm to be able to see significant overall response rates. Adaptive design expansion studies offer a faster way to bring drugs to no-option patients and this expansion study has been specifically designed to meet FDA guidance for a marketing application. In the future AVM0703 will be studied in clinical trials in combination with earlier lines of therapy to determine the potential synergy of AVM0703 with standard of care to enhance complete response rate, reduce relapse rates, and potentially reduce the total number of therapeutic cycles patients require. This could significantly improve acute quality of life by reducing side-effects, reduce medical expenses and reduce long term toxicities.