GTP as a biomarker of inosine monophosphate dehydrogenase (IMPDH) inhibition, in patients with advanced hematological malignancies treated with AVN944 in a phase I trial

Abstract

14515 Background: AVN944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate- limiting step in guanine nucleotide synthesis. Guanosine triphosphate (GTP) is the downstream product of IMPDH and levels of GTP are directly correlated with enzyme activity. Methods: This phase I study employed open-label dose escalations in patients (pts) with relapsed, refractory hematologic cancers with safety, pharmacokinetic (PK), pharmacodynamic, and efficacy endpoints. Between 12/05 and 12/07, a total of 117 cycles of AVN944 at 25 to 300 mg b.i.d. orally X 21d every 28d were administered to 60 pts. Peripheral blood mononuclear cell (PBMC) or leukemic blast samples were obtained from all pts pre and post-receiving AVN944 to determine effects on GTP pools, IMPDH activity and gene expression biomarkers. Nucleotide purification was accomplished by lysing PBMC followed by protein precipitation and C-18 ZIP TIP filtration. A novel LC-MS/MS method was developed and used to quantify the concentration of nucleotides. Results: The concentration of GTP was reduced in 79% of the patients after 4–8 hr of the first dose. The duration of GTP suppression higher than 50% was dose proportional at doses higher than 75 mg: 2.8 hr (100 mg), 6.3 hr (150 mg), 11.2 hr (200 mg), 13.8 hr (250 mg). This correlated with PK, which was also dose proportional. Longer GTP suppression correlated with IMPDH inhibition and gene expression biomarker movement. Conclusions: The new LC-MS/MS is a reliable method to quantify GTP suppression in clinical samples. The levels of GTP after AVN944 administration correlated with PK, enzyme activity, changes in gene expression, and disease stability. GTP is a promising biomarker for IMPDH inhibition and has potential clinical implications. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Avalon Pharmaceuticals Avalon Pharmaceuticals