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

NCT01310179 | Completed Phase 1 Results DMC

• 1 other identifier: PNP-001
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief 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. 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.

Conditions

Head and Neck Cancer

Keywords

gene therapy; advanced solid tumors; Head and Neck cancer; intratumoral therapy

Outcome Measures

Primary Outcomes (1)

• 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

  Entry through Study Day 56

Secondary Outcomes (1)

• Treatment Outcome and Percent Change in Tumor Volume

  Entry through Study Day 56

Study Arms (1)

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.

Genetic: Ad/PNP and fludarabine monophosphate

Interventions

Ad/PNP and fludarabine monophosphate GENETIC

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.

Ad/PNP and fludarabine monophosphate

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• PNP Therapeutics, Inc.: lead

Study Sites (2)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37212, United States

Location

Related Publications (1)

• 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.

  PMID: 25899782 DERIVED

MeSH Terms

Conditions

Head and Neck Neoplasms

Interventions

fludarabine phosphate

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms

Results Point of Contact

• Title: Eben Rosenthal, MD
• Organization: University of Alabama at Birmingham

erosenthal@uabmc.edu

205-934-9713

Study Officials

• Eben Rosenthal, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2011
• First Posted: March 8, 2011
• Study Start: February 1, 2011
• Primary Completion: June 1, 2014
• Study Completion: July 1, 2014
• Last Updated: June 10, 2015
• Results First Posted: June 10, 2015

Record last verified: 2015-05

Locations

US (2)