Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors

The use of Escherichia coli purine nucleoside phosphorylase (PNP) to activate fludarabine has demonstrated safety and antitumor activity during preclinical analysis and has been approved for clinical investigation. A first-in-human phase I clinical trial (NCT 01310179; IND 14271) was initiated to ev...

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Bibliographic Details
Published in:	Annals of oncology Vol. 26; no. 7; pp. 1481 - 1487
Main Authors:	Rosenthal, E.L., Chung, T.K., Parker, W.B., Allan, P.W., Clemons, L., Lowman, D., Hong, J., Hunt, F.R., Richman, J., Conry, R.M., Mannion, K., Carroll, W.R., Nabell, L., Sorscher, E.J.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-07-2015 Oxford University Press
Subjects:	Adenoviridae - genetics Adenovirus Aged Aged, 80 and over Combined Modality Therapy Dose-Response Relationship, Drug Escherichia coli Escherichia coli - enzymology Female fludarabine Follow-Up Studies gene therapy Genetic Therapy Genetic Vectors - therapeutic use human clinical trial Humans Injections, Intralesional Male Middle Aged Neoplasm Staging Neoplasms - genetics Neoplasms - pathology Neoplasms - therapy Original Prognosis purine nucleoside phosphorylase Purine-Nucleoside Phosphorylase - administration & dosage Purine-Nucleoside Phosphorylase - genetics Tumor Cells, Cultured Vidarabine - analogs & derivatives Vidarabine - therapeutic use human clinical trial fludarabine purine nucleoside phosphorylase gene therapy
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Summary:	The use of Escherichia coli purine nucleoside phosphorylase (PNP) to activate fludarabine has demonstrated safety and antitumor activity during preclinical analysis and has been approved for clinical investigation. A first-in-human phase I clinical trial (NCT 01310179; IND 14271) was initiated to evaluate safety and efficacy of an intratumoral injection of adenoviral vector expressing E. coli PNP in combination with intravenous fludarabine for the treatment of solid tumors. The study was designed with escalating doses of fludarabine in the first three cohorts (15, 45, and 75 mg/m2) and escalating virus in the fourth (1011–1012 viral particles, VP). All 12 study subjects completed therapy without dose-limiting toxicity. Tumor size change from baseline to final measurement demonstrated a dose-dependent response, with 5 of 6 patients in cohorts 3 and 4 achieving significant tumor regression compared with 0 responsive subjects in cohorts 1 and 2. The overall adverse event rate was not dose-dependent. Most common adverse events included pain at the viral injection site (92%), drainage/itching/burning (50%), fatigue (50%), and fever/chills/influenza-like symptoms (42%). Analysis of serum confirmed the lack of systemic exposure to fluoroadenine. Antibody response to adenovirus was detected in two patients, suggesting that neutralizing immune response is not a barrier to efficacy. This first-in-human clinical trial found that localized generation of fluoroadenine within tumor tissues using E. coli PNP and fludarabine is safe and effective. The pronounced effect on tumor volume after a single treatment cycle suggests that phase II studies are warranted. NCT01310179.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The results of this study have not been presented prior to manuscript submission.
ISSN:	0923-7534 1569-8041
DOI:	10.1093/annonc/mdv196