Refractory Solid TumorsNCT00923728
A Phase I Trial of AVN944, an IMPDH Inhibitor, in Adults With Advanced Stage Solid Tumors
A study testing AVN944 in people with Refractory Solid Tumors, run by Vertex Pharmaceuticals Incorporated at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Refractory Solid Tumors
- What is being tested?
- AVN944
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2009to Mar 2010
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- 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.
- Patients with known active brain metastases or other CNS involvement with less than 6 months since curative-intent treatment
- Patients receiving growth factors
- Prior treatment with an IMPDH-inhibitor e.g. Mycophenolate Mofetil, \& Tiazofurin
- Uncontrolled current illness requiring hospitalization or intravenous antibiotics within the past 7 days
- 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.
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- History of solid organ transplant and are on IMPDH inhibitors (mycophenolate mofetil) therapy
- HIV-positive patients
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: 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.
Read more
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.
Read the 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.
- Conditions
- Refractory Solid Tumors
- Being tested
- AVN944
- Keywords
- AVN - 944, Phase I, Adult Solid Tumors, Cancer, Solid Tumor
- Medical subject headings
- Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AVN944Drug
What is being measured
The primary outcome is the main question the study is designed to answer.
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 outcomes (1)
1. Single, repeat dose pharmacokinetics; 2. Inosine monophosphate dehydrogenase inhibition; 3. Anti-neoplastic responses
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2009 (estimated)
- Study startApr 2009
- Primary completionMar 2010 (estimated)
- Study completionMar 2010 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Refractory Solid TumorsStudies of the same condition, open and under way.
- More trials run by Vertex Pharmaceuticals IncorporatedThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vertex Pharmaceuticals Incorporated
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00923728
- Sponsor's protocol ID
- 090119
- Other IDs
- 09-C-0119
- Status last verified
- Aug 2011
- First submitted
- 17 Jun 2009
- Last updated
- 10 Jan 2014
- Results posted
- No
Publications
Sintchak MD, Fleming MA, Futer O, Raybuck SA, Chambers SP, Caron PR, Murcko MA, Wilson KP. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell. 1996 Jun 14;85(6):921-30. doi: 10.1016/s0092-8674(00)81275-1.
PubMed 8681386Allison AC, Hovi T, Watts RW, Webster AD. The role of de novo purine synthesis in lymphocyte transformation. Ciba Found Symp. 1977;(48):207-24. doi: 10.1002/9780470720301.ch13.
PubMed 415850Jackson RC, Weber G, Morris HP. IMP dehydrogenase, an enzyme linked with proliferation and malignancy. Nature. 1975 Jul 24;256(5515):331-3. doi: 10.1038/256331a0. No abstract available.
PubMed 167289
Study at a glance
From the registry record, last updated by the sponsor on 10 Jan 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Trial of AVN944, an IMPDH Inhibitor, in Adults With Advanced Stage Solid Tumors
- ClinicalTrials.gov ID
- NCT00923728
- Acronym / sponsor ID
- 090119
- Conditions
- Refractory Solid Tumors
- Keywords
- AVN - 944, Phase I, Adult Solid Tumors, Cancer, Solid Tumor
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Vertex Pharmaceuticals IncorporatedIndustry (pharma, biotech, devices)
- Collaborators
- National Cancer Institute (NCI)
- Study start
- Apr 2009
- Primary completion
- Mar 2010 (estimated)
- Study completion
- Mar 2010 (estimated)
- First posted
- 18 Jun 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (16 listed)
- 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.
- Patients with known active brain metastases or other CNS involvement with less than 6 months since curative-intent treatment
- Patients receiving growth factors
- Prior treatment with an IMPDH-inhibitor e.g. Mycophenolate Mofetil, \& Tiazofurin
- Uncontrolled current illness requiring hospitalization or intravenous antibiotics within the past 7 days
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AVN944 | Drug | – |
Primary outcome
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
1 secondary outcome
1. Single, repeat dose pharmacokinetics; 2. Inosine monophosphate dehydrogenase inhibition; 3. Anti-neoplastic responses
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jan 2014.
- Background: PubMed 8681386Sintchak MD, Fleming MA, Futer O, Raybuck SA, Chambers SP, Caron PR, Murcko MA, Wilson KP. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell. 1996 Jun 14;85(6):921-30. doi: 10.1016/s0092-8674(00)81275-1.
- Background: PubMed 415850Allison AC, Hovi T, Watts RW, Webster AD. The role of de novo purine synthesis in lymphocyte transformation. Ciba Found Symp. 1977;(48):207-24. doi: 10.1002/9780470720301.ch13.
- Background: PubMed 167289Jackson RC, Weber G, Morris HP. IMP dehydrogenase, an enzyme linked with proliferation and malignancy. Nature. 1975 Jul 24;256(5515):331-3. doi: 10.1038/256331a0. No abstract available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing AVN944 in people with Refractory Solid Tumors, run by Vertex Pharmaceuticals Incorporated at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 10 Jan 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary 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. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00923728, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jan 2014.