Phase I/II and phase II studies of targeted gene delivery in vivo: intravenous Rexin-G for chemotherapy-resistant sarcoma and osteosarcoma

Sant P Chawla, Victoria S Chua, Lita Fernandez, Doris Quon, Andreh Saralou, William C Blackwelder, Frederick L Hall, Erlinda M Gordon, Sant P Chawla, Victoria S Chua, Lita Fernandez, Doris Quon, Andreh Saralou, William C Blackwelder, Frederick L Hall, Erlinda M Gordon

Abstract

Rexin-G, a pathotropic nanoparticle bearing a cytocidal cyclin G1 construct was tested in a phase I/II study for chemotherapy-resistant sarcomas and a phase II study for chemotherapy-resistant osteosarcoma. Twenty sarcoma patients and 22 osteosarcoma patients received escalating doses of Rexin-G intravenously from 8 x 10(11) to 24 x 10(11) colony forming units (cfu)/cycle. Treatment was continued if there was <or= grade 1 toxicity. No dose-limiting toxicity (DLT) was observed, and no vector DNA integration, replication-competent retrovirus (RCR) or vector-neutralizing antibodies were noted. In the phase I/II study, 3/6 patients had stable disease (SD) at the lowest dose; median progression-free survival (PFS) was 1.2 months, and overall survival (OS), 3.3 months. At higher doses, 10/14 patients had SD; median PFS was 3.7 months and median OS, 7.8 months. In this phase I/II study, a dose-response relationship with Rexin-G dosage was observed for progression-free and OS times (P = 0.02 and 0.005, respectively). In the phase II study, 10/17 evaluable patients had SD, median PFS was >or=3 months and median OS, 6.9 months. These studies suggest that Rexin-G is safe, may help control tumor growth, and may possibly improve survival in chemotherapy-resistant sarcoma and osteosarcoma.

Figures

Figure 1
Figure 1
Analyses of progression-free survival (PFS) of patients in the phase I/II sarcoma study using various radiologic imaging criteria. Kaplan-Meier analyses show a dose–response relationship between progression-free survival and Rexin-G dosage, as determined (a) by RECIST, (b) by International PET criteria, and (c) by CHOI criteria.
Figure 2
Figure 2
Analyses of overall survival of patients in the phase I/II sarcoma study and the phase II osteosarcoma study. Kaplan-Meier analyses show the survival curves of patients in (a) the phase I/II sarcoma study and (b) the phase II osteosarcoma study.
Figure 3
Figure 3
Histopathological findings in the lung metastases of a patient with chemotherapy-resistant osteosarcoma after Rexin-G treatment. Representative H&E stained tissue sections from resected residual lung nodules in a Rexin-G treated patient. (a) 2.5 cm cystic mass with organized clot and rare osteosarcoma cells; (b) 0.9 cm calcified tumor mass with reparative fibrosis, immune infiltrate and osteosarcoma cells with rare mitosis.

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