AVN944 – pro

Lay Summary: AVN-944 is reviewed.

AVN-944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate-limiting step in guanine nucleotide synthesis, and induces apoptosis in malignant hematopoietic cell lines in vitro.

Pre-clinical studies showed that AVN944 is a highly specific inhibitor of IMPDH, suppresses pools of GTP, and in cultured cells has a selective growth inhibition effect on cancer cells vs. normal cells.

An earlier single-dose, dose-escalation, healthy volunteer clinical trial conducted in the United Kingdom showed that AVN944 was well tolerated at all tested doses with no notable side effects; had good pharmacokinetic properties; and had a significant inhibitory effect on IMPDH enzyme activity.

A recent phase I study is a repeat-dose dose escalation trial in patients with advanced hematologic malignancies. Patients are dosed for 21 days on a 28-day cycle. A minimum of three patients are treated at each dose level. The study is divided into two arms, one for treatment of leukemia patients and the other for treatment of patients with lymphoma and myeloma. For the leukemia arm of the study, patients are currently being treated at the fourth dose level, 100 mg twice daily. For the lymphoma and myeloma arm, patients are currently being treated at the fifth dose level, 125 mg twice daily. There have been no drug-related Serious Adverse Events (SAEs), indicating that AVN944 is being well tolerated thus far at all dose levels. Pharmacokinetics measurements indicate dose proportional plasma levels of AVN944 during treatment and sustained plasma concentrations at the dose levels tested thus far.

Early Activity Indicators: This Phase I study has also been designed to evaluate several pharmacodynamic and efficacy-related endpoints. Upon entering the trial, all patients have refractory, progressive disease and have failed all prior therapies. Thus far, 12 of 24 patients have had stabilized disease after one cycle of treatment with AVN944. These include patients with both leukemia and multiple myeloma. Patients who have achieved stable disease following completion of a one-month treatment cycle with AVN944, as determined by the clinical investigator, may be advanced to a subsequent cycle.

Four multiple myeloma patients in the study have maintained stabilized disease for several months of treatment with AVN944; two of these patients completed five months of treatment and two others completed eight successive cycles. These two patients continue to have stable disease and are in their ninth month of treatment. it is clearly experimental.

Author(s): R. B. Klisovic, G. Tricot, S. Coutre, T. Kovacsovics, F. Giles, T. Genna, D. K. Bol, J. W. Strovel, J. M. Hamilton, B. Mitchell A phase I trial of AVN944 in patients with advanced hematologic malignancies. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 14026

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