PMID- 20921209 OWN - NLM STAT- MEDLINE DCOM- 20111017 LR - 20211020 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 16 IP - 22 DP - 2010 Nov 15 TI - Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. PG - 5573-80 LID - 10.1158/1078-0432.CCR-10-1453 [doi] AB - PURPOSE: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. METHODS: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. RESULTS: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. CONCLUSIONS: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed. CI - (c)2010 AACR. FAU - Sarkaria, Jann N AU - Sarkaria JN AD - Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA. sarkaria.jann@mayo.edu FAU - Galanis, Eva AU - Galanis E FAU - Wu, Wenting AU - Wu W FAU - Dietz, Allan B AU - Dietz AB FAU - Kaufmann, Timothy J AU - Kaufmann TJ FAU - Gustafson, Michael P AU - Gustafson MP FAU - Brown, Paul D AU - Brown PD FAU - Uhm, Joon H AU - Uhm JH FAU - Rao, Ravi D AU - Rao RD FAU - Doyle, Laurence AU - Doyle L FAU - Giannini, Caterina AU - Giannini C FAU - Jaeckle, Kurt A AU - Jaeckle KA FAU - Buckner, Jan C AU - Buckner JC LA - eng GR - U10 CA025224-25/CA/NCI NIH HHS/United States GR - P50 CA108961/CA/NCI NIH HHS/United States GR - U24 CA114740-04/CA/NCI NIH HHS/United States GR - U24 CA114740/CA/NCI NIH HHS/United States GR - U10 CA025224-24/CA/NCI NIH HHS/United States GR - U10 CA025224-28S1/CA/NCI NIH HHS/United States GR - P50 CA108961-050001/CA/NCI NIH HHS/United States GR - P50 CA108961-010001/CA/NCI NIH HHS/United States GR - U10 CA025224-23/CA/NCI NIH HHS/United States GR - P50 CA108961-020001/CA/NCI NIH HHS/United States GR - U10 CA025224-24S1/CA/NCI NIH HHS/United States GR - P50 CA108961-019004/CA/NCI NIH HHS/United States GR - U24 CA114740-03/CA/NCI NIH HHS/United States GR - U10 CA025224-30S2/CA/NCI NIH HHS/United States GR - U10 CA025224-24S2/CA/NCI NIH HHS/United States GR - U10 CA025224-220017/CA/NCI NIH HHS/United States GR - U10 CA025224-23S1/CA/NCI NIH HHS/United States GR - U10 CA025224-30/CA/NCI NIH HHS/United States GR - U24 CA114740-05/CA/NCI NIH HHS/United States GR - U10 CA025224-28/CA/NCI NIH HHS/United States GR - U10 CA025224-31S1/CA/NCI NIH HHS/United States GR - U10 CA025224-23S10004/CA/NCI NIH HHS/United States GR - U24 CA114740-01/CA/NCI NIH HHS/United States GR - P50 CA108961-039004/CA/NCI NIH HHS/United States GR - CA-114740/CA/NCI NIH HHS/United States GR - CA-25224/CA/NCI NIH HHS/United States GR - U10 CA025224-28S3/CA/NCI NIH HHS/United States GR - U10 CA025224-29/CA/NCI NIH HHS/United States GR - U10 CA025224-30S3/CA/NCI NIH HHS/United States GR - U10 CA025224-31/CA/NCI NIH HHS/United States GR - CA-108961/CA/NCI NIH HHS/United States GR - U10 CA025224-27/CA/NCI NIH HHS/United States GR - P50 CA108961-049004/CA/NCI NIH HHS/United States GR - U10 CA025224-230004/CA/NCI NIH HHS/United States GR - U10 CA025224-32/CA/NCI NIH HHS/United States GR - P50 CA108961-029004/CA/NCI NIH HHS/United States GR - P50 CA108961-059004/CA/NCI NIH HHS/United States GR - U10 CA025224-28S2/CA/NCI NIH HHS/United States GR - U24 CA114740-02/CA/NCI NIH HHS/United States GR - U10 CA025224-23S10017/CA/NCI NIH HHS/United States GR - U10 CA025224-220004/CA/NCI NIH HHS/United States GR - U10 CA025224/CA/NCI NIH HHS/United States GR - P50 CA108961-030001/CA/NCI NIH HHS/United States GR - P50 CA108961-040001/CA/NCI NIH HHS/United States GR - U24 CA114740-05S1/CA/NCI NIH HHS/United States GR - U10 CA025224-26/CA/NCI NIH HHS/United States GR - U10 CA025224-230017/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20101004 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 624KN6GM2T (temsirolimus) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Aged MH - Antineoplastic Agents/adverse effects/therapeutic use MH - Brain Neoplasms/*diagnosis/immunology/*therapy MH - Combined Modality Therapy MH - Dose-Response Relationship, Drug MH - Female MH - Glioblastoma/*diagnosis/immunology/*therapy MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Protein Kinase Inhibitors/adverse effects/therapeutic use MH - Risk Factors MH - Sirolimus/adverse effects/*analogs & derivatives/therapeutic use MH - Treatment Outcome PMC - PMC2982871 MID - NIHMS236833 EDAT- 2010/10/06 06:00 MHDA- 2011/10/18 06:00 PMCR- 2011/11/15 CRDT- 2010/10/06 06:00 PHST- 2010/10/06 06:00 [entrez] PHST- 2010/10/06 06:00 [pubmed] PHST- 2011/10/18 06:00 [medline] PHST- 2011/11/15 00:00 [pmc-release] AID - 1078-0432.CCR-10-1453 [pii] AID - 10.1158/1078-0432.CCR-10-1453 [doi] PST - ppublish SO - Clin Cancer Res. 2010 Nov 15;16(22):5573-80. doi: 10.1158/1078-0432.CCR-10-1453. Epub 2010 Oct 4.