2579 Background: Glucocorticoids (GC) are a common component of blood cancer regimens, typically at doses 40 mg or lower due to concerns of pancreatitis and hepatotoxicity (Walasik-Szemplińska et al. Thyroid Research. 2019;12:13; Ataallah et al. Cureus. 2020;12[7]) and neuropsychiatric effects. AVM Biotechnology has developed a high concentration, high volume, preservative-free, patent pending formulation of dexamethasone (AVM0703), that allows administration of up to 21 mg/kg (1470 mg for 70 kg) over a one-hour IV infusion. Prophylactic use of circadian physiologic hydrocortisone reduces the risk of GC neuropsychiatric side-effects (Warris LT, et al. J. Clin. Oncol. 2016;34:2287; Meijer & de Kloet Endocrinology. 2017;158:448). Acute supra-pharmacologic doses (>6 mg/kg) AVM0703 mobilizes endogenous bispecific gamma delta invariant TCR+ bi-specific Natural Killer T-like cells (AVM-NKT) (PCT/US21/19773), via a non-GC receptor, that rapidly home to diseased organs in preclinical models and are directly related to tumor killing, including Non-Hodgkin’s Lymphoma, Melanoma, and Multiple Myeloma. Methods: Cancer cell lines and (mouse host) were i) immune-resistant mouse A20 B lymphoma (Balb/c), ii) xenografted human T-ALL CCRF-CEM (NCRnu), iii) mouse B16F10 melanoma (B62DF1), and iv) mouse MOPC315 (Balb/c). Cancer cell lines were inoculated into the flank either as single cell suspensions or encased in Matrigel. When tumor volume reached between 100-500mm3 well-established tumors, mice were orally gavaged with a human equivalent dose (HED) of 15-18 mg/kg AVM0703 as monotherapy, or as a preconditioning prior to adoptive cell transfer (ACT), or in combination with chemotherapy. Responses were determined by tumor volume measurements, tumor immunohistochemistry or flow cytometry detection of residual cancer cells. Results: Immunohistochemistry analysis of tumors from AVM0703 treated mice demonstrated pseudoprogression similar to checkpoint inhibitors: i.e. tumors were measurable however in some cases all cancer cells had been eradicated. Therefore, subsequent tumor monitoring at end point was done by flow cytometry to quantify the total number of live cancer cells more accurately than tumor measurements by calipers or immunohistochemistry, due to pseudoprogression and limitations of examining only a few sections from each tumor. Conclusions: AVM0703 led to: i) complete response (CR) in 27% of immune-resistant mouse A20 tumors as monotherapy and CR in 60% when combined with 2 doses of cyclophosphamide/fludarabine (CyFlu); ii) tumor eradication and long-term memory against xenografted human T-ALL; iii) enhancement of ACT equivalent to CyFlu preconditioning in mouse melanoma; and iv) preliminary 95% CR against mouse multiple myeloma.

Dexamethasone has been widely used since its initial approval by the FDA in 1958, either individually or as part of a therapeutic regimen for a variety of diseases and disorders, including lymphoma and leukemia and most recently, COVID-19 mediated disease. During a preclinical experiment with A20 B-cell lymphoma bearing mice, a suprapharmacologic dose of dexamethasone phosphate, equivalent to a Human (Equivalent) Dose of 17.5 mg/kg, was inadvertently administered. Blood samples were collected and analyzed by flow cytometry, revealing the presence of a new cell 48 hours after dosing. Subsequent experiments confirmed this finding following a single dose of AVM0703. This cell has since been identified as a bi-specific gamma-delta+ NKT cell, or AVM-NKT cell. One of the challenges of being able to deliver suprapharmacologic dexamethasone doses was the drug product itself. These limitations led to the development of a new drug product, AVM0703, which permits the safe administration of the doses necessary to mobilize these cells. AVM0703 is supplied as a sterile, single-use 50 mL, 24 mg/mL solution for infusion, without preservatives. The ability to rapidly mobilize and activate these cells following a single dose of AVM0703 in as little as 6 hours is the subject of an on-going clinical trial, in patients with lymphoid malignancies (NCT04329728), specifically no-option, R/R ALL, MCL, DLBCL, Primary Mediastinal Large B-cell, Burkitt, CLL/SLL and B-or T-ALL. The study consists of 2-parts, dose-escalation to determine the Phase 2 dose, followed by an adaptive-design, expansion cohort study in the same patient population. Concurrently, clinical data has also been obtained from Expanded Access-Single Patient INDs. Based on the murine model, a theoretically effective HED was determined to be at least 18 mg/kg. Because the maximum dose approved for generic injectable dexamethasone is 6 mg/kg, the starting dose for the clinical trial was set at 6 mg/kg. The dose escalation study design is a 3 x 3 design, originally consisting of cohorts escalating by 3 mg/kg to 21 mg/kg (6, 9, 12, 15, 18 and 21 mg/kg). Since that time and based on safety data (see below), the FDA has permitted a revision to the study, in which the 12 and 15 mg/kg cohorts are skipped. Table 1 provides the original and current study design, with the corresponding total dose for a 70 kg patient. For example, 18 mg/kg is 1.26 g for a 70 kg patient. The trial also incorporates a validated Quality of Life questionnaire and a 12-month follow-up period. In Expanded Use, Single-Patient IND setting, 4 patients received at least one AVM0703 dose: glioblastoma: one 6 mg/kg; B-cell ALL: one 18 mg/kg dose; and two prostate cancer patients: one 18 mg/kg dose and patient #2: repeat doses for the past year as depicted in Table 2. Figure 1 depicts the flow cytometry analysis 24 hours following an 18 mg/kg AVM0703 dose. From a safety perspective, there have been no reports of drug-related or treatment emergent SAE's. The murine model safety findings correlate to the human experience. Adverse events reported to date have been self-limiting and mild to moderate. Frequent AEs include slight elevations of blood pressure, glucose and BUN that resolve without treatment in < 1 week post dose. Leukocytosis and lymphocytosis were reported 24 hours post infusion from the B-cell ALL patient but resolved by 7-days without reported intervention. Because a single AVM0703 dose triggers the rapid mobilization and activation of an endogenous bi-specific gamma-delta+ NKT cell with a favorable emerging safety profile, AVM0703 shows promise as a therapeutic agent in treating this serious disease. Figure 1 Figure 1. Disclosures Rea: AVM Biotechnology, LLC: Current Employment. Deisher: AVM Biotechnology, LLC: Current Employment. Jarzyna: AVM Biotechnology, LLC: Current Employment. Zahid: AVM Biotechnology, LLC: Ended employment in the past 24 months. Suwito: AVM Biotechnology, LLC: Current Employment. Poulin: AVM Biotechnology, LLC: Current Employment.