title: A phase I study of concurrent chemotherapy (paclitaxel and carboplatin) and thoracic radiotherapy with swallowed manganese superoxide dismutase plasmid liposome protection in patients with locally advanced stage III non-small-cell lung cancer.
abstract: Manganese superoxide dismutase (MnSOD) is a genetically engineered therapeutic DNA/liposome containing the human MnSOD transgene. Preclinical studies in mouse models have demonstrated that the expression of the human MnSOD transgene confers protection of normal tissues from ionizing irradiation damage. This is a phase I study of MnSOD plasmid liposome (PL) in combination with standard chemoradiation in surgically unresectable stage III non-small-cell lung cancer. Chemotherapy (carboplatin and paclitaxel) was given weekly (for 7 weeks), concurrently with radiation. MnSOD PL was swallowed twice a week (total 14 doses), at three dose levels: 0.3, 3, and 30 mg. Dose escalation followed a standard phase I design. Esophagoscopy was done at baseline, day 4, and 6 weeks after radiation with biopsies of the squamous lining cells. DNA was extracted and analyzed by PCR for the detection of the MnSOD transgene DNA. Ten patients with AJCC stage IIIA (three) and IIIB (seven) completed the course of therapy. Five had squamous histology, two adenocarcinoma, one large cell, and two not specified. Patients were treated in three cohorts at three dose levels of MnSOD PL: 0.3 (three patients), 3 (three patients), and 30 mg (four patients). The median dose of radiation was 77.7 Gy (range 63-79.10 Gy). Overall response rate for the standard chemoradiation regimen was 70% (n = 10). There were no dose-limiting toxicities reported in all three dosing tiers. It is concluded that the oral administration of MnSOD PL is feasible and safe. The phase II recommended dose is 30 mg.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Tarhini
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
authors.forename: James D
authors.initials: JD
authors.lastname: Luketich
authors.forename: Athanassios
authors.initials: A
authors.lastname: Argiris
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: William
authors.initials: W
authors.lastname: Gooding
authors.forename: Arjun
authors.initials: A
authors.lastname: Pennathur
authors.forename: Daniel
authors.initials: D
authors.lastname: Petro
authors.forename: Kevin
authors.initials: K
authors.lastname: Kane
authors.forename: Denny
authors.initials: D
authors.lastname: Liggitt
authors.forename: Tony
authors.initials: T
authors.lastname: Championsmith
authors.forename: Xichen
authors.initials: X
authors.lastname: Zhang
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004947:Esophagus / Q000187:drug effects / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D016133:Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D016190:Carboplatin; D013482:Superoxide Dismutase; D017239:Paclitaxel