Clinical-Biomarker Correlations in Adult AML Patients in a Phase I Trial of AVN944 Support Observations of Clinical Effect and Provide Hypotheses for Patient Selection Criteria for Further Clinical Trials.
Authors: Klisovic Rebecca B. , Coutre Steven , Kovacsovics Tibor J. , Kantarjiam Hagop M. , Tricot Guido J. , Strovel Jeffrey W. , Genna Thomas , Bol David K. , Hamilton Michael , Mitchell Beverly S. 
Published: October 2019

Abstract
Background: AVN944 is an uncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) that catalyzes the rate limiting step in the synthesis of guanine nucleotides. In vitro studies have demonstrated its efficacy in inducing apoptosis in leukemic cell lines. Between 01/06 and 7/07 a total of 117 cycles of AVN944 were administered to 50 patients (pts) with advanced hematologic malignancies (AML = 26, multiple myeloma = 15, CLL = 6, ALL = 2, and NHL = 1) at dose levels of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, and 250 mg bid po x 21d every 28 d. The study employed open label dose escalation with safety, pK, IMPDH activity, gene expression biomarkers, & efficacy endpoints. Biomarker evaluations in AML pts were most useful since AML blasts could be obtained from the peripheral blood in most subjects.
Results: Pharmacokinetics corresponded to dose levels over the dose range tested with a Tmax = 1 hour, T1/2 of 1.5 hours, a mean Cmax=4060 ng/ml and AUC=12146hr*ng/ml at the 200 mg bid dose. Toxicities were generally mild-moderate and/or attributable to the underlying disease. Twenty-four SAEs were observed in 16 pts (10 w/AML; 4 w/CLL, 1w/MM, 1w/ALL). Twenty-two of the SAEs were felt to be unrelated to AVN944; 1 AVN944-related SAE/DLT was observed at both the 150 mg bid (dizziness and fever) and at the 200 mg bid (UGI mucositis w/bleeding) levels, prompting expansion of the accrual to those dose levels. Additional DLTs were not seen. Among AML pts, no protocol-defined responses were seen, but 9 of 26 pts had stable disease of 2 to 9 months’ duration. Peripheral blood mononuclear cell (mean blast percentage 78%) were obtained from all pts before and after receiving AVN944 to determine drug effects on IMPDH enzyme activity (GTP pools) and modulation of 34-gene expression biomarkers that reflect cellular and metabolic effects of AVN944, including inhibition of IMPDH activity, depletion of GTP pools, G1/S phase cell-cycle block, and apoptosis. At the highest doses tested, Western blots show IMPDH-drug binding for at least 4 hours and depletion of GTP pools relative to baseline for at least 8 hours (last time point tested). Gene expression-based biomarkers show a dynamic response in patient samples with a strong correlation of changes in gene expression with GTP pool depletion and clinically stable disease. Specifically, genes involved in cell cycle and cell division (RRM2 & ZWINT), GTP function (GNAQ & PDE7A), and apoptotic signaling (PIM1) change 2–4 fold after drug exposure compared to baseline measurements. Further, in pts naïve to AVN944 therapy, expression of genes related to drug metabolism, drug resistance and apoptosis predict for biochemical activity of AVN944. Based on these data, algorithms were applied retrospectively to define a set of gene expression biomarkers for enrichment for patients more likely to benefit from drug. This set of biomarkers will be validated for their sensitivity and specificity in identifying the most appropriate patient population in upcoming phase II trials.