TY - JOUR
T1 - 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
AU - Tarhini, Ahmad A.
AU - Belani, Chandra P.
AU - Luketich, James D.
AU - Argiris, Athanassios
AU - Ramalingam, Suresh S.
AU - Gooding, William
AU - Pennathur, Arjun
AU - Petro, Daniel
AU - Kane, Kevin
AU - Liggitt, Denny
AU - Championsmith, Tony
AU - Zhang, Xichen
AU - Epperly, Michael W.
AU - Greenberger, Joel S.
PY - 2011/3/1
Y1 - 2011/3/1
N2 - 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 30mg. 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 30mg (four patients). The median dose of radiation was 77.7Gy (range 63-79.10Gy). 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 30mg.
AB - 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 30mg. 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 30mg (four patients). The median dose of radiation was 77.7Gy (range 63-79.10Gy). 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 30mg.
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U2 - 10.1089/hum.2010.078
DO - 10.1089/hum.2010.078
M3 - Article
C2 - 20873987
AN - SCOPUS:79952686010
SN - 1043-0342
VL - 22
SP - 336
EP - 342
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 3
ER -