A Phase I Trial of AVN944, an IMPDH Inhibitor, in Adults With Advanced Stage Solid Tumors

Refractory Solid Tumors Clinical Trial

Official title: A Phase 1 Trial of AVN944, an IMPDH Inhibitor, in Adults With Advanced Stage Solid Tumors

Status Withdrawn

Clinical Trial Summary

Background:

• AVN944 is an experimental cancer treatment drug, not yet approved by the U.S. Food and Drug Administration. To date, AVN944 as a single drug has been tested in several studies involving humans, including healthy volunteers, patients with leukemia, and patients with advanced pancreatic cancer.

• More research is needed to determine the safety and effectiveness of AVN944.

Objectives:

• To determine the safety of AVN944.

• To determine the maximum tolerated dose (the highest dose that does not cause unacceptable side effects) of AVN944.

• To see if AVN944 has any effect on patients' tumors.

• To learn how the body breaks down AVN944.

Eligibility:

• Patients 18 years of age and older who have advanced stage solid tumors for which standard therapies do not exist or are no longer effective.

Design:

• Participants will have a screening visit and five clinic visits during the first treatment cycle. Additional treatment cycles will involve two clinic visits during each 28-day cycle. After participation in the study ends, patients will be asked to return within 28 days after the last dose of study drug for final study procedures.

• Evaluations before the treatment period:

• Physical examination, including vital signs and body weight checks, and pregnancy test for women who can become pregnant.

• Questions about medications and side effects.

• Blood and urine tests.

• Disease evaluation with CT, chest x-ray, and additional laboratory tests depending on the type of cancer.

• All patients will have blood samples taken at each visit.

• Patients will take specific doses of AVN994 as directed by researchers, and will be asked to keep a diary to record their doses and any side effects. They will be monitored with frequent blood draws at each study visit to provide information on the safety and effectiveness of the drug.

• During different cycles, patients will have their disease evaluated by researchers and will be asked if they wish to continue taking AVN994 as part of the study.

Clinical Trial Description

Background:

• 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.

Objectives:

Primary

• The dose limiting toxicities with AVN944 in patients with advanced stage solid tumors.

• The MTD with AVN944 in patients with advanced stage solid tumors.

Secondary:

• Pharmacokinetics and the pharmacodynamics of AVN944 by study cohort.

• The extent of IMPDH inhibition on tumor tissue and peripheral blood mononuclear cells (PBMC).

• The effect of AVN944 on tumors by measuring guanine nucleotide pools levels using PBMC's.

• The effect of AVN944 on tumors by analyzing expression of genes related to IMPDH.

Eligibility:

• Inclusion:

• 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.

• Exclusion:

• Patients with known active brain metastases or other CNS involvement.

• History of allergic reactions attributed to compounds of similar chemical or biologic.

• Prior treatment with an IMPDH-inhibitor.

• History of solid organ transplant and are on IMPDFI inhibitors therapy.

Design:

• 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. ;

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Refractory Solid Tumors

• NCT number: NCT00923728
• Study type: Interventional
• Source: Vertex Pharmaceuticals Incorporated
• Status: Withdrawn
• Phase: N/A
• Start date: April 2009
• Completion date: March 2010