A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer

Sant P Chawla, Howard Bruckner, Michael A Morse, Nupur Assudani, Frederick L Hall, Erlinda M Gordon, Sant P Chawla, Howard Bruckner, Michael A Morse, Nupur Assudani, Frederick L Hall, Erlinda M Gordon

Abstract

Rexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG-binding peptide for targeting abnormal Signature (SIG) proteins in tumors and encoding a dominant-negative human cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0-I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0-I were 4.3 months and 0%, and at dose II-III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation.

Keywords: 10-year cancer-free survivor; CCNG1; cell cycle control; cyclin G1 inhibitor; gene therapy; pancreas adenocarcinoma; retrovector; targeted gene delivery; tumor targeting.

Figures

Figure 1
Figure 1
Graphic Illustration of Rexin-G Vector The Rexin-G vector displaying a SIG-targeting peptide (A), for binding to Signature (SIG) proteins in the tumor microenvironment (TME) (B), and encoding a dominant-negative human cyclin G1 inhibitor gene (C). Injected intravenously, Rexin-G nanoparticles seek out and bind to abnormal SIG proteins in the TME, which augments effective vector concentration in tumors.
Figure 2
Figure 2
Kaplan-Meier Plot of Progression-free Survival in Rexin-G-Treated Gemcitabine-Resistant PDAC Progression-free survival data for the modified intent-to-treat population are displayed. The proportion of patients surviving progression-free are plotted on the vertical axis as a function of time from the beginning of treatment, plotted on the horizontal axis.
Figure 3
Figure 3
Tumor Regression during Treatment with Rexin-G Patients 12 (A) and 16 (B). Percentage change in tumor size (sum of longest diameter [SLD]) is plotted on the vertical axis, as a function of time from the beginning of Rexin-G treatment, plotted on the horizontal axis.
Figure 4
Figure 4
Tumor Regression and CA-19.9 Levels during Treatment with Rexin-G in Patient 18 (A) Percentage changes in tumor size (longest diameter [LD]) of metastatic hepatic and lymph node sub-peritoneal lesions are individually plotted on the vertical axis, as a function of time from the beginning of Rexin-G treatment, plotted on the horizontal axis. (B) Serum levels of tumor marker CA-19.9 (U/mL) are plotted on the veritical axis, as a function of time from the beginning of Rexin-G treatment, plotted on the horizontal axis.
Figure 5
Figure 5
Kaplan-Meier Plot of Overall Survival of PDAC Patients following Rexin-G Treatment at Escalating Dose Levels Analysis of overall survival in the ITT population suggests a dose-response relationship between overall survival and Rexin-G dosage (p = 0.03). The proportion of patients surviving are plotted on the vertical axis as a function of time from beginning of treatment, plotted on the horizontal axis.

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