A Phase 1 Trial of AVN944, an IMPDH Inhibitor, in Adults With Advanced Stage Solid Tumors
- The rate limiting step in the synthesis of guanine nucleotides is catalyzed by the
enzyme inosine monophosphate dehydrogenase (IMPDH) and so inhibition of this enzyme
will result in depletion of guanine nucleotide pools, cessation of DNA synthesis, cell
cycle block at the Gr(1)/S interface and interference with cell division.
- The reduction in guanine nucleotide pools interferes with the ability of G-coupled
proteins to act as intracellular signal transducers. IMPDH inhibition.
- AVN944 is a small-molecule, uncompetitive inhibitor of cell proliferation.
- A Phase I study in patients with hematologic malignancies is active and accruing
subjects. The maximum-tolerated dose (MTD) has not been reached and no pattern of
organ-specific or dose-progressive toxicity has been observed.
- The dose limiting toxicities with AVN944 in patients with advanced stage solid tumors.
- The MTD with AVN944 in patients with advanced stage solid tumors.
- Pharmacokinetics and the pharmacodynamics of AVN944 by study cohort.
- The extent of IMPDH inhibition on tumor tissue and peripheral blood mononuclear cells
- The effect of AVN944 on tumors by measuring guanine nucleotide pools levels using
- The effect of AVN944 on tumors by analyzing expression of genes related to IMPDH.
- Patients must have histologically confirmed malignancy.
- Patients must be at least 4 weeks since prior chemotherapy or radiation therapy
and 2 weeks since prior hormonal therapy.
- ECOG performance status less than or equal to 2.
- Life expectancy of greater than 3 months.
- Age greater than or equal to 18.
- Patients with known active brain metastases or other CNS involvement.
- History of allergic reactions attributed to compounds of similar chemical or
- Prior treatment with an IMPDH-inhibitor.
- History of solid organ transplant and are on IMPDFI inhibitors therapy.
- Phase I Trial using 3+3 trail design using starting cohort of 150 mg twice per day
escalating to 750 mg twice per day.
- 60 patients to be enrolled over 30-36 months.
- AVN944 will be administered in 28 day treatment cycles.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
1. The dose limiting toxicities with AVN944 in patients with advanced stage solid tumors; 2. Maximum tolerated dose with AVN944 in patients with advanced stage solid tumors
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|