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


N/A
18 Years
N/A
Not Enrolling
Both
Refractory Solid Tumors

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Trial Information

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


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.

Inclusion Criteria


-INCLUSION CRITERIA:

1. Patients must have histologically confirmed malignancy (histopathological
documentation of cancer confirmed in the NCI Laboratory of Pathology at the National
Institutes of Health, the Pathology Department at Walter Reed Medical Center, or the
Pathology Department at National Naval Medical Center, prior to starting this study)
that is metastatic or unresectable and for which standard therapies do not exist or
are no longer effective.

2. Patients must be at least 4 weeks since prior chemotherapy or radiation therapy and 2
weeks since prior hormonal therapy except for gonadotropin releasing hormone (GnRH)
analogues and any acute or serious side effects of those therapies should be Grade
less than 1 or returned to baseline

3. Patients must be able and willing to take oral capsules.

4. ECOG performance status less than or equal to 2

5. Life expectancy of greater than 3 months

6. Patients must have acceptable organ and marrow function as defined below:

- Leukocytes greater than or equal to 3,000/mcL

- Absolute Neutrophil Count greater than or equal to 1,500/mcL

- Platelets greater than or equal to 100,000/mcL

- Total Bilirubin less than or equal to 1.5 times institutional ULN (patients with
known Gilberts syndrome may have values as high as less than or equal to 3.0 X
ULN)

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- Creatinine less than or equal to 1.5 times institutional upper limit of normal

7. The effects of AVN944 on the developing human fetus are unknown. For this reason,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately.

8. Ability to understand and the willingness to sign a written informed consent
document.

9. Age greater than or equal to 18 Years. Because no dosing or adverse event data are
currently available on the use of AVN944 in patients less than 18 years of age,
children are excluded from this study.

EXCLUSION CRITERIA:

1. Patients who are receiving concurrent investigational therapy or who have received
investigational therapy within 14 days of the first scheduled day of dosing
(investigational therapy is defined as treatment for which there is currently no
regulatory authority approved indication). Clinically significant toxicities from
this therapy must have resolved to less than Grade 2.

2. Patients with known active brain metastases or other CNS involvement with less than 6
months since curative-intent treatment

3. Patients receiving growth factors

4. Prior treatment with an IMPDH-inhibitor e.g. Mycophenolate Mofetil, & Tiazofurin

5. Uncontrolled current illness requiring hospitalization or intravenous antibiotics
within the past 7 days

6. Pregnant women are excluded from this study because AVN944 agent has the potential
for teratogenic or abortifacient effects. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
AVN944, breastfeeding should be discontinued if the mother is treated with AVN944.

7. History of solid organ transplant and are on IMPDH inhibitors (mycophenolate mofetil)
therapy

8. HIV-positive patients

9. The following medications and/or treatments are not permitted during the trial (i.e.,
through completion of the post treatment follow-up) and would constitute exclusion
from the protocol:

- Any other investigational treatment

- Any cytotoxic chemotherapy

- Any other systemic anti-neoplastic therapy including, but not limited to,
immunotherapy or monoclonal antibody therapy.

- Any radiotherapy, including systemically administered radioisotopes.

- Systemic corticosteroids.

- Any hormonal therapy except GnRH agonists / antagonists for patients with
prostate cancer or medroxyprogesterone

- Growth factors

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

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

Authority:

United States: Federal Government

Study ID:

090119

NCT ID:

NCT00923728

Start Date:

April 2009

Completion Date:

March 2010

Related Keywords:

  • Refractory Solid Tumors
  • AVN - 944
  • Phase I
  • Adult Solid Tumors
  • Cancer
  • Solid Tumor
  • Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892