Marta Penas-Prado1, Kenneth R Hess1, Michael J Fisch1, Lore W Lagrone1, Morris D Groves1, Victor A Levin1, John F De Groot1, Vinay K Puduvalli1, Howard Colman1, Gena Volas-Redd1, Pierre Giglio1, Charles A Conrad1, Michael E Salacz1, Justin D Floyd1, Monica E Loghin1, Sigmund H Hsu1, Javier Gonzalez1, Eric L Chang1, Shiao Y Woo1, Anita Mahajan1, Kenneth D Aldape1, W K Alfred Yung1, Mark R Gilbert1. 1. Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (M.P.-P., M.D.G., V.A.L., J.F.D.G., C.A.C., M.E.L., W.K.A.Y., M.R.G.); Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas (K.R.H.); General Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (M.J.F., L.W.L.); Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.M.); Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A); Department of Neurosurgery, Kaiser Permanente Redwood City Medical Center, Redwood City, California (V.A.L.); Department of Neurological Surgery, Ohio State University Comprehensive Cancer Center, Columbus, Ohio (V.K.P.); Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); Atlanta Regional Community Clinical Oncology Program, Georgia Cancer Specialists, Canton, Georgia (G.V.-.R.); Department of Neurosciences, Medical University of South Carolina Brain & Spine Tumor Program, Charleston, South Carolina (P.G.); Department of Hematology and Oncology, The University of Kansas Cancer Center, Overland Park, Kansas (M.E.S.); Department of Hematology and Oncology, Saint Francis Medical Center, Cape Girardeau, Missouri (J.D.F.); Department of Neurosurgery, University of Texas Health Science Center, Houston, Texas (S.H.H.); Department of Neurology, West Virginia University, Morgantown, West Virginia (J.G.); Department of Radiation Oncology, Keck School of Medicine, University of Southern California, U.S.C Norris Cancer Hospital, Los Angeles, California (E.L.C.); Department of Radiation Oncology, University of Louisville, James Graham Brown Cancer Center, Louisville, Kentucky (S.Y.W.).
Abstract
BACKGROUND: Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy. METHODS: The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide. RESULTS: The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia. CONCLUSIONS: The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma. CLINICALTRIALSGOV IDENTIFIER: NCT00112502.
BACKGROUND: Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy. METHODS: The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide. RESULTS: The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia. CONCLUSIONS: The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma. CLINICALTRIALSGOV IDENTIFIER: NCT00112502.
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