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

Abstract

Background: 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.

Patients and methods: 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/m(2)) and escalating virus in the fourth (10(11)-10(12) viral particles, VP).

Results: 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.

Conclusions: 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.

Clinicaltrialsgov identifier: NCT01310179.

Keywords: fludarabine; gene therapy; human clinical trial; purine nucleoside phosphorylase.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Mechanism of E. coli purine nucleoside phosphorylase prodrug activation using fludarabine.

Figure 2.

Adverse events (AEs) by grade, relatedness, and cohort. Adverse events were tabulated on a per-patient basis (top table). All adverse events, including repeat events within patients, were graphed (bottom histogram). ALT, alanine transaminase; AST, aspartate transaminase.

Figure 3.

Treatment outcome and percent change in tumor volume by cohort. Treatment outcome was defined with tumor volume percentage cutoffs (marked with dashed lines) where progression is a percentage change in tumor volume of ≥20% increase, partial response is defined as a change of ≥30% decrease, and stable a change between −30% and +20%. Measurements were obtained at baseline before study drug injection and each patient's last measurement for the study. The response rate in cohorts 3 and 4 was significantly higher than the rate in cohorts 1 and 2.

Figure 4.

Serial tumor volume measurements for patients with complete tumor regression. Complete tumor volume measurements are plotted for two patients with complete tumor regression. A green box identifies the timeframe for the viral injection of purine nucleoside phosphorylase (PNP) and a blue box identifies the timeframe for fludarabine injection. Patient 11 was lost to follow-up for day 56.

Figure 5.

Tumor response in a cohort 4 patient. Sample images from a cohort 4 patient demonstrates serial changes from baseline (top) to day 14 (bottom).