Safety Study of Adenovirus/PNP Coupled With Fludarabine Phosphate to Treat Solid Tumors

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
PNP Therapeutics, Inc.
ClinicalTrials.gov Identifier:
NCT01310179
First received: March 3, 2011
Last updated: July 7, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Head and Neck Cancer
Advanced Solid Tumors
Genetic: Ad/PNP and fludarabine monophosphate
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by PNP Therapeutics, Inc.:

Primary Outcome Measures:
  • Evaluation of the safety of Ad/PNP-F-araAMP [ Time Frame: Entry through Study Day 56 ] [ Designated as safety issue: Yes ]
    The number of subjects with adverse events as a measure of safety across the 4 dose cohorts.


Secondary Outcome Measures:
  • Response in the injected tumor (target lesion) [ Time Frame: Entry through Study Day 56 ] [ Designated as safety issue: No ]
    Tumor response will be measured by DW-MRI and when feasible, by physical measurement with calipers or ruler


Enrollment: 12
Study Start Date: February 2011
Study Completion Date: July 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ad/PNP and fludarabine monophosphate
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 three cohorts will receive 3x10e11 VP for 3 injections and 5, 15 or 25 mg/m2 of F-araAMP daily for 3 days. Subject in the fourth cohort will receive 3x10e12 VP for 3 injections and the highest tolerated dose of F-araAMP daily for 3 days.
Genetic: Ad/PNP and 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.

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).

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01310179

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37212
Sponsors and Collaborators
PNP Therapeutics, Inc.
  More Information

No publications provided

Responsible Party: PNP Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT01310179     History of Changes
Other Study ID Numbers: PNP-001
Study First Received: March 3, 2011
Last Updated: July 7, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by PNP Therapeutics, Inc.:
gene therapy
advanced solid tumors
Head and Neck cancer
intratumoral therapy

Additional relevant MeSH terms:
Head and Neck Neoplasms
Neoplasms
Neoplasms by Site
Fludarabine
Fludarabine monophosphate
Vidarabine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on July 22, 2014