Head and Neck CancerPhase 1NCT01310179
Safety Study of Adenovirus/PNP Coupled With Fludarabine Phosphate to Treat Solid Tumors
A Phase 1 study testing Ad/PNP and fludarabine monophosphate in people with Head and Neck Cancer, run by PNP Therapeutics, Inc. at 2 sites in United States.
Trial summary
This study will test whether it is possible to introduce new genetic material into a small portion of a tumor and have the product of the new gene not only kill those tumor cells that were infected initially, but also the surrounding tumor cells as well with limited or no harm to the patient. Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Head and Neck Cancer
- What is being tested?
- Ad/PNP and fludarabine monophosphate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 2 sitesUnited States
- Study dates
- Feb 2011to Jul 2014
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Biopsy confirmed diagnosis of a solid tumor
- Failed or exhausted all standard or approved treatment options that would provide substantive palliation
- Have at least one measurable primary or metastatic tumor on imaging studies or physical exam whose potential reduction could provide relief of symptoms or benefit
- Tumor is accessible for direct intratumoral injection
Who cannot join
- Diagnosis of leukemia
- Have previously received any gene therapy products or oncolytic viral therapy
- Receiving treatment with allopurinol
- Received radiation treatment < 4 wks prior to first injection of Ad/PNP
- Received chemotherapy < 4 wks prior to first injection of Ad/PNP
- Have signs or symptoms of active infection
- Receiving chronic systemic corticosteroids or any chronic immunosuppressive medications within 14 days prior to first injection of Ad/PNP. Subjects receiving short courses of corticosteroids are considered eligible.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Alabama at Birmingham
Birmingham, Alabama, 35233
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37212
About this study
Official title: Phase I, Open-label Study Evaluating the Safety of Escalating Doses of Ad/PNP-F-araAMP (Ad/PNP Administered Intratumorally With Co-administration of Fludarabine Phosphate Intravenously) in Subjects With Advanced Solid Tumors
This study will test whether it is possible to introduce new genetic material into a small portion of a tumor and have the product of the new gene not only kill those tumor cells that were infected initially, but also the surrounding tumor cells as well with limited or no harm to the patient. The desired effects of this approach are achieved by focusing potent chemotherapies directly within the tumor itself and, as a result, avoiding injury to the remainder of the body. In this study, we will use two components, the first of which is a virus, known as an adenovirus, that has been crippled (i.e., it cannot make more of itself) and loaded with a bacterial gene called E. coli purine nucleoside phosphorylase (PNP). Adenoviruses are considered to be relatively safe vehicles for gene delivery and are presently being used in numerous human trials and therapies worldwide, including a head and neck cancer therapy approved for use outside the United States. The loaded adenovirus will be used to deliver the PNP gene directly into a tumor in patients. This gene is not expected to have an effect itself. However, the gene produces PNP inside the tumor and this protein will activate the second component of the therapy, a drug called fludarabine phosphate, which is approved by the FDA for certain types of blood-cell cancers, but has not been shown to be effective against most solid tumors. The proposed therapy gives the patient several infusions of fludarabine following the injection of the virus carrying the PNP gene and, as the fludarabine enters the tumor, it will be converted by PNP into a second compound, fluoroadenine. Numerous studies in mice and rats have shown that fluoroadenine is a very potent anti-cancer agent and that it will kill the tumor cells where it is made as well as those in the immediately surrounding area.
Read the detailed description
For this first study, we will inject the PNP-loaded adenovirus into the tumors of patients with cancers primarily in the throat and neck and then give them the drug. This study is designed with two goals in mind: 1) assessing the overall safety of this approach for the patient; and 2) observing the effects of this anti-cancer strategy on the tumor itself. This will be accomplished in two parts. First, we will introduce a modest, fixed amount of the gene-carrying adenovirus into the tumors of three separate groups of patients and then administer small, increasingly strong amounts of the fludarabine phosphate to each successive group over a three-day period. Even in the group that will receive the highest amount of fludarabine, the total amount given to any individual patient over those three days will be significantly less than the dose approved by the FDA for patients with non-solid tumors. Finally, a more concentrated amount of the adenovirus (approximately 10 times more viruses) will be given to a fourth group of patients who will also receive the highest dose of the drug that was shown to be well tolerated in the prior three groups (the highest dose at which no serious problems were observed).
- Conditions
- Head and Neck Cancer
- Being tested
- Ad/PNP and fludarabine monophosphate
- Keywords
- gene therapy, advanced solid tumors, Head and Neck cancer, intratumoral therapy
- Medical subject headings
- Head and Neck Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ad/PNP and fludarabine monophosphateGenetic
Subjects in the first 3 cohorts will receive 3x10e11 VP for 3 injections and escalating dose levels of F-araAMP (15, 45, and 75 mg/m2 in each sequential cohort) daily for 3 days. The fourth cohort will receive 3x10e12 for 3 injections and 75 mg/m2 fludarabine daily for 3 days.
| Study group | Role | What they receive |
|---|---|---|
| Ad/PNP and fludarabine monophosphate | Experimental | Ad/PNP will be injected three times into the tumor over 2 days followed by three daily intravenous infusions of F-araAMP (fludarabine monophosphate). Subjects in the first 3 cohorts will receive 3x10e11 VP for 3 injections and escalating dose levels of F-araAMP (15, 45, and 75 mg/m2 in each sequential cohort) daily for 3 days. The fourth cohort will receive 3x10e12 for 3 injections and 75 mg/m2 fludarabine daily for 3 days. Receives: Genetic: Ad/PNP and fludarabine monophosphate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Side Effects After Ad/PNP-F-araAMP Treatment
Number of participants who had the most frequently observed undesirable effects after exposure to study drug
Measured: Entry through Study Day 56
Secondary outcomes (1)
Treatment Outcome and Percent Change in Tumor Volume
Measurement of tumor response to study drug, as measured by the percentage of change in tumor volume as measured by a physicial measurement using a ruler
Measured: Entry through Study Day 56
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2011 (estimated)
- Study startFeb 2011
- Primary completionJun 2014
- Study completionJul 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Head and Neck CancerStudies of the same condition, open and under way.
- 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 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- PNP Therapeutics, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Eben Rosenthal, MD, Principal investigator, University of Alabama at Birmingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01310179
- Sponsor's protocol ID
- PNP-001
- Status last verified
- May 2015
- First submitted
- 3 Mar 2011
- Last updated
- 10 Jun 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Rosenthal EL, Chung TK, Parker WB, Allan PW, Clemons L, Lowman D, Hong J, Hunt FR, Richman J, Conry RM, Mannion K, Carroll WR, Nabell L, Sorscher EJ. Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors. Ann Oncol. 2015 Jul;26(7):1481-7. doi: 10.1093/annonc/mdv196. Epub 2015 Apr 21.
PubMed 25899782
Study at a glance
From the registry record, last updated by the sponsor on 10 Jun 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I, Open-label Study Evaluating the Safety of Escalating Doses of Ad/PNP-F-araAMP (Ad/PNP Administered Intratumorally With Co-administration of Fludarabine Phosphate Intravenously) in Subjects With Advanced Solid Tumors
- ClinicalTrials.gov ID
- NCT01310179
- Acronym / sponsor ID
- PNP-001
- Conditions
- Head and Neck Cancer
- Keywords
- gene therapy, advanced solid tumors, Head and Neck cancer, intratumoral therapy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- PNP Therapeutics, Inc.Industry (pharma, biotech, devices)
- Study start
- Feb 2011
- Primary completion
- Jun 2014 (actual)
- Study completion
- Jul 2014 (actual)
- First posted
- 8 Mar 2011 (estimated)
- Results
- Posted 10 Jun 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will test whether it is possible to introduce new genetic material into a small portion of a tumor and have the product of the new gene not only kill those tumor cells that were infected initially, but also the surrounding tumor cells as well with limited or no harm to the patient. The desired effects of this approach are achieved by focusing potent chemotherapies directly within the tumor itself and, as a result, avoiding injury to the remainder of the body. In this study, we will use two components, the first of which is a virus, known as an adenovirus, that has been crippled (i.e., it cannot make more of itself) and loaded with a bacterial gene called E. coli purine nucleoside phosphorylase (PNP). Adenoviruses are considered to be relatively safe vehicles for gene delivery and are presently being used in numerous human trials and therapies worldwide, including a head and neck cancer therapy approved for use outside the United States. The loaded adenovirus will be used to deliver the PNP gene directly into a tumor in patients. This gene is not expected to have an effect itself. However, the gene produces PNP inside the tumor and this protein will activate the second component of the therapy, a drug called fludarabine phosphate, which is approved by the FDA for certain types of blood-cell cancers, but has not been shown to be effective against most solid tumors. The proposed therapy gives the patient several infusions of fludarabine following the injection of the virus carrying the PNP gene and, as the fludarabine enters the tumor, it will be converted by PNP into a second compound, fluoroadenine. Numerous studies in mice and rats have shown that fluoroadenine is a very potent anti-cancer agent and that it will kill the tumor cells where it is made as well as those in the immediately surrounding area.
Detailed description
For this first study, we will inject the PNP-loaded adenovirus into the tumors of patients with cancers primarily in the throat and neck and then give them the drug. This study is designed with two goals in mind: 1) assessing the overall safety of this approach for the patient; and 2) observing the effects of this anti-cancer strategy on the tumor itself. This will be accomplished in two parts. First, we will introduce a modest, fixed amount of the gene-carrying adenovirus into the tumors of three separate groups of patients and then administer small, increasingly strong amounts of the fludarabine phosphate to each successive group over a three-day period. Even in the group that will receive the highest amount of fludarabine, the total amount given to any individual patient over those three days will be significantly less than the dose approved by the FDA for patients with non-solid tumors. Finally, a more concentrated amount of the adenovirus (approximately 10 times more viruses) will be given to a fourth group of patients who will also receive the highest dose of the drug that was shown to be well tolerated in the prior three groups (the highest dose at which no serious problems were observed).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Ad/PNP and fludarabine monophosphate | Experimental | Genetic: Ad/PNP and fludarabine monophosphateAd/PNP will be injected three times into the tumor over 2 days followed by three daily intravenous infusions of F-araAMP (fludarabine monophosphate). Subjects in the first 3 cohorts will receive 3x10e11 VP for 3 injections and escalating dose levels of F-araAMP (15, 45, and 75 mg/m2 in each sequential cohort) daily for 3 days. The fourth cohort will receive 3x10e12 for 3 injections and 75 mg/m2 fludarabine daily for 3 days. |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Biopsy confirmed diagnosis of a solid tumor
- Failed or exhausted all standard or approved treatment options that would provide substantive palliation
- Have at least one measurable primary or metastatic tumor on imaging studies or physical exam whose potential reduction could provide relief of symptoms or benefit
- Tumor is accessible for direct intratumoral injection
Key exclusion criteria (7 listed)
- Diagnosis of leukemia
- Have previously received any gene therapy products or oncolytic viral therapy
- Receiving treatment with allopurinol
- Received radiation treatment < 4 wks prior to first injection of Ad/PNP
- Received chemotherapy < 4 wks prior to first injection of Ad/PNP
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 |
|---|---|---|
| Ad/PNP and fludarabine monophosphateSubjects in the first 3 cohorts will receive 3x10e11 VP for 3 injections and escalating dose levels of F-araAMP (15, 45, and 75 mg/m2 in each sequential cohort) daily for 3 days. The fourth cohort will receive 3x10e12 for 3 injections and 75 mg/m2 fludarabine daily for 3 days. | Genetic | Ad/PNP and fludarabine monophosphate |
Primary outcome
Number of Participants With Side Effects After Ad/PNP-F-araAMP Treatment
Time frame: Entry through Study Day 56
Number of participants who had the most frequently observed undesirable effects after exposure to study drug
1 secondary outcome
Treatment Outcome and Percent Change in Tumor Volume
Time frame: Entry through Study Day 56
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jun 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 25899782Rosenthal EL, Chung TK, Parker WB, Allan PW, Clemons L, Lowman D, Hong J, Hunt FR, Richman J, Conry RM, Mannion K, Carroll WR, Nabell L, Sorscher EJ. Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors. Ann Oncol. 2015 Jul;26(7):1481-7. doi: 10.1093/annonc/mdv196. Epub 2015 Apr 21.
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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.
Eben Rosenthal, MD principal investigator
University of Alabama at Birmingham
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Ad/PNP and fludarabine monophosphate in people with Head and Neck Cancer, run by PNP Therapeutics, Inc. at 2 sites 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 4 inclusion and 7 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: finished, as of the sponsor's last update on 10 Jun 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Jun 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Number of Participants With Side Effects After Ad/PNP-F-araAMP Treatment (time frame: Entry through Study Day 56). 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 NCT01310179, which also lists 1 linked publication.
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 Jun 2015.