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

January 8, 2014 updated by: Vertex Pharmaceuticals Incorporated

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed 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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

-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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
1. Single, repeat dose pharmacokinetics; 2. Inosine monophosphate dehydrogenase inhibition; 3. Anti-neoplastic responses

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Vertex Pharmaceuticals Incorporated

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2009

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2010

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2010

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 17, 2009

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 17, 2009

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 18, 2009

Study Record Updates

Last Update Posted (ESTIMATE)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 10, 2014

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 8, 2014

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 090119
  • 09-C-0119

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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