{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T05:57:12Z","timestamp":1793858232041,"version":"4.6.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2017,10,24]],"date-time":"2017-10-24T00:00:00Z","timestamp":1508803200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","award":["Not applicable"],"award-info":[{"award-number":["Not applicable"]}],"id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Targ Oncol"],"published-print":{"date-parts":[[2017,12]]},"DOI":"10.1007\/s11523-017-0530-5","type":"journal-article","created":{"date-parts":[[2017,10,24]],"date-time":"2017-10-24T07:19:55Z","timestamp":1508829595000},"page":"775-785","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["A Multi-Arm Phase I Study of the PI3K\/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer"],"prefix":"10.1007","volume":"12","author":[{"given":"Zev A.","family":"Wainberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Alsina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heloisa P.","family":"Soares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Bra\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn D.","family":"Britten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Del Conte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Ezeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Houk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth A.","family":"Kern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Leong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuzhat","family":"Pathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen J.","family":"Pierce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian L.","family":"Siu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Vermette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"Tabernero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,24]]},"reference":[{"issue":"6","key":"530_CR1","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1200\/JCO.2009.25.3641","volume":"28","author":"KD Courtney","year":"2010","unstructured":"Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075\u201383.","journal-title":"J Clin Oncol"},{"issue":"22","key":"530_CR2","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1038\/sj.onc.1210422","volume":"26","author":"P Roberts","year":"2007","unstructured":"Roberts P, Der C. Targeting the Raf-MEK-ERK mitogen activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26(22):3291\u2013310.","journal-title":"Oncogene"},{"issue":"1","key":"530_CR3","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jmoldx.2010.11.005","volume":"13","author":"M Arcila","year":"2011","unstructured":"Arcila M, Lau C, Nafa K, Ladanyi M. Detection of KRAS and BRAF mutations in colorectal carcinoma. Roles for high-sensitivity locked nucleic acid-PCR sequencing and broad-spectrum mass spectrometry genotyping. J Mol Diagn. 2011;13(1):64\u201373.","journal-title":"J Mol Diagn"},{"issue":"4","key":"530_CR4","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1093\/annonc\/mdp347","volume":"21","author":"B Markman","year":"2010","unstructured":"Markman B, Atzori F, P\u00e9rez-Garc\u00eda J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol. 2010;21(4):683\u201391.","journal-title":"Ann Oncol"},{"issue":"6","key":"530_CR5","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.tibs.2011.03.006","volume":"36","author":"MM Mendoza","year":"2011","unstructured":"Mendoza MM, Er EE, Blenis J. The RAS-Erk and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36(6):320\u20138.","journal-title":"Trends Biochem Sci"},{"key":"530_CR6","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/1741-7015-10-161","volume":"10","author":"I Bra\u00f1a","year":"2012","unstructured":"Bra\u00f1a I, Siu LL. Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment. BMC Med. 2012;10:161\u201376.","journal-title":"BMC Med"},{"issue":"3","key":"530_CR7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrclinonc.2013.10","volume":"10","author":"J Rodon","year":"2013","unstructured":"Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10(3):143\u201353.","journal-title":"Nat Rev Clin Oncol"},{"issue":"2","key":"530_CR8","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s00280-012-1899-6","volume":"70","author":"BH Simmons","year":"2012","unstructured":"Simmons BH, Lee JH, Lalwani K, et al. Combination of a MEK inhibitor at sub-MTD with a PI3K\/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras(G12D-LSL) mice. Cancer Chemother Pharmacol. 2012;70(2):213\u201320.","journal-title":"Cancer Chemother Pharmacol"},{"issue":"6","key":"530_CR9","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s00280-013-2121-1","volume":"71","author":"CD Britten","year":"2013","unstructured":"Britten CD. PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types. Cancer Chemother Pharmacol. 2013;71(6):1395\u2013409.","journal-title":"Cancer Chemother Pharmacol"},{"issue":"11","key":"530_CR10","doi-asserted-by":"crossref","first-page":"e113037","DOI":"10.1371\/journal.pone.0113037","volume":"9","author":"TM Pitts","year":"2014","unstructured":"Pitts TM, Newton TP, Bradshaw-Pierce EL, et al. Dual pharmacological targeting of the MAP kinase and PI3K\/mTOR pathway in preclinical models of colorectal cancer. PLoS One. 2014;9(11):e113037.","journal-title":"PLoS One"},{"issue":"17","key":"530_CR11","doi-asserted-by":"crossref","first-page":"3946","DOI":"10.1158\/1078-0432.CCR-14-3377","volume":"21","author":"S Mohan","year":"2015","unstructured":"Mohan S, Vander Broek R, Shah S, et al. MEK inhibitor PD-0325901 overcomes resistance to PI3K\/mTOR inhibitor PF-5212384 and potentiates antitumor effects in human head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(17):3946\u201356.","journal-title":"Clin Cancer Res"},{"issue":"3","key":"530_CR12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1177\/1758834015571111","volume":"7","author":"E Jokinen","year":"2015","unstructured":"Jokinen E, Koivunen JP. MEK and PI3K inhibition in solid tumors: rationale and evidence to date. Ther Adv Med Oncol. 2015;7(3):170\u201380.","journal-title":"Ther Adv Med Oncol"},{"issue":"11","key":"530_CR13","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1158\/1535-7163.MCT-11-0185","volume":"10","author":"J Yuan","year":"2011","unstructured":"Yuan J, Mehta PP, Yin MJ, et al. PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity. Mol Cancer Ther. 2011;10(11):2189\u201399.","journal-title":"Mol Cancer Ther"},{"issue":"3","key":"530_CR14","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s10637-013-0062-5","volume":"32","author":"CD Britten","year":"2014","unstructured":"Britten CD, Adjei AA, Millham R, et al. Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Investig New Drugs. 2014;32(3):510\u20137.","journal-title":"Investig New Drugs"},{"issue":"1","key":"530_CR15","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ygyno.2016.04.019","volume":"142","author":"JM Campo Del","year":"2016","unstructured":"Del Campo JM, Birrer M, Davis C, et al. A randomized, phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol Oncol. 2016;142(1):62\u20139.","journal-title":"Gynecol Oncol"},{"issue":"10","key":"530_CR16","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1158\/1078-0432.CCR-10-1694","volume":"17","author":"R Mallon","year":"2011","unstructured":"Mallon R, Feldberg LR, Lucas J, et al. Antitumor efficacy of PKI-587, a highly potent dual PI3K\/mTOR kinase inhibitor. Clin Cancer Res. 2011;17(10):3193\u2013203.","journal-title":"Clin Cancer Res"},{"key":"530_CR17","doi-asserted-by":"crossref","unstructured":"Wainberg ZA, Brega N, Davis C, et al. Randomized phase Ib\/II study of PF-05212384 plus 5-fluorouracil-leucovorin-irinotecan (FOLFIRI) vs bevacizumab plus FOLFIRI in metastatic colorectal cancer (B2151007; NCT01937715). J Clin Oncol. 2014;32(15 suppl):TPS3657.","DOI":"10.1200\/jco.2014.32.15_suppl.tps3657"},{"issue":"15 suppl","key":"530_CR18","doi-asserted-by":"crossref","first-page":"TPS3649","DOI":"10.1200\/jco.2014.32.15_suppl.tps3649","volume":"32","author":"J Tabernero","year":"2014","unstructured":"Tabernero J, Brega N, Davis C, et al. A randomized phase 2 study (B2151005) of PF-05212384 plus irinotecan versus cetuximab plus irinotecan in patients with wild-type KRAS metastatic colorectal cancer. J Clin Oncol. 2014;32(15 suppl):TPS3649.","journal-title":"J Clin Oncol"},{"issue":"8","key":"530_CR19","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1158\/1078-0432.CCR-14-1306","volume":"21","author":"GI Shapiro","year":"2015","unstructured":"Shapiro GI, Bell-McGuinn KM, Molina JR, et al. First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin Cancer Res. 2015;21(8):1888\u201395.","journal-title":"Clin Cancer Res"},{"issue":"6","key":"530_CR20","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1158\/1078-0432.CCR-09-1883","volume":"16","author":"PM LoRusso","year":"2010","unstructured":"LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK\/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16(6):1924\u201337.","journal-title":"Clin Cancer Res"},{"issue":"8","key":"530_CR21","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1158\/1078-0432.CCR-09-1920","volume":"16","author":"EB Haura","year":"2010","unstructured":"Haura EB, Ricart AD, Larson TG, et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16(8):2450\u20137.","journal-title":"Clin Cancer Res"},{"issue":"29","key":"530_CR22","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1200\/JCO.2007.12.0949","volume":"25","author":"LB Saltz","year":"2007","unstructured":"Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007;25(29):4557\u201361.","journal-title":"J Clin Oncol"},{"issue":"30","key":"530_CR23","doi-asserted-by":"crossref","first-page":"4914","DOI":"10.1200\/JCO.2006.06.7595","volume":"24","author":"H-J Lenz","year":"2006","unstructured":"Lenz H-J, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006;24(30):4914\u201321.","journal-title":"J Clin Oncol"},{"key":"530_CR24","doi-asserted-by":"crossref","unstructured":"Lim R, Sun Y, Im SA, et al. Cetuximab plus irinotecan in pretreated metastatic colorectal cancer patients: the ELSIE study. World J Gastroenterol. 2011;17(14):1879\u201388.","DOI":"10.3748\/wjg.v17.i14.1879"},{"issue":"2","key":"530_CR25","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.celrep.2013.12.035","volume":"6","author":"F Janku","year":"2014","unstructured":"Janku F, Hong DS, Fu S, et al. Assessing PIK3CA and PTEN in early-phase trials with PI3K\/AKT\/mTOR inhibitors. Cell Rep. 2014;6(2):377\u201387.","journal-title":"Cell Rep"},{"issue":"3","key":"530_CR26","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s11523-017-0482-9","volume":"12","author":"TM Wise-Draper","year":"2017","unstructured":"Wise-Draper TM, Moorthy G, Salkeni MA, et al. A phase Ib study of the dual PI3K\/mTOR inhibitor dactolisib (BEZ235) combined with everolimus in patients with advanced solid malignancies. Target Oncol. 2017;12(3):323\u201332.","journal-title":"Target Oncol"},{"issue":"1","key":"530_CR27","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1158\/0008-5472.CAN-12-1726","volume":"73","author":"F Janku","year":"2013","unstructured":"Janku F, Wheler JJ, Naing A, et al. PIK3CA mutation H1047R is associated with response to PI3K\/AKT\/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res. 2013;73(1):276\u201384.","journal-title":"Cancer Res"},{"issue":"4","key":"530_CR28","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1158\/1078-0432.CCR-14-1814","volume":"21","author":"PL Bedard","year":"2015","unstructured":"Bedard PL, Tabernero J, Janku F, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1\/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21(4):730\u20138.","journal-title":"Clin Cancer Res"},{"issue":"6","key":"530_CR29","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1007\/s10637-016-0377-0","volume":"34","author":"JE Grilley-Olson","year":"2016","unstructured":"Grilley-Olson JE, Bedard PL, Fasolo A, et al. A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K\/mTOR inhibitor GSK2126458 in patients with advanced solid tumors. Investig New Drugs. 2016;34(6):740\u20139.","journal-title":"Investig New Drugs"},{"issue":"9","key":"530_CR30","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1158\/1535-7163.MCT-12-0290","volume":"11","author":"R Dienstmann","year":"2012","unstructured":"Dienstmann R, Serpico D, Rodon J, et al. Molecular profiling of patients with colorectal cancer and matched targeted therapy in phase I clinical trials. Mol Cancer Ther. 2012;11(9):2062\u201371.","journal-title":"Mol Cancer Ther"},{"issue":"9","key":"530_CR31","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1158\/1078-0432.CCR-13-2403","volume":"20","author":"KP Papadopoulos","year":"2014","unstructured":"Papadopoulos KP, Tabernero J, Markman B, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K\/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res. 2014;20(9):2445\u201356.","journal-title":"Clin Cancer Res"},{"issue":"4","key":"530_CR32","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1007\/s10637-014-0082-9","volume":"32","author":"J Rodon","year":"2014","unstructured":"Rodon J, Bra\u00f1a I, Siu LL, et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Investig New Drugs. 2014;32(4):670\u201381.","journal-title":"Investig New Drugs"},{"key":"530_CR33","doi-asserted-by":"crossref","unstructured":"LoRusso PM. Inhibition of the PI3K\/AKT\/mTOR pathway in solid tumors. J Clin Oncol. 2016;34(31):3803\u201315.","DOI":"10.1200\/JCO.2014.59.0018"}],"container-title":["Targeted Oncology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11523-017-0530-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s11523-017-0530-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11523-017-0530-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T22:39:00Z","timestamp":1570228740000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s11523-017-0530-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,24]]},"references-count":33,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,12]]}},"alternative-id":["530"],"URL":"https:\/\/doi.org\/10.1007\/s11523-017-0530-5","relation":{},"ISSN":["1776-2596","1776-260X"],"issn-type":[{"value":"1776-2596","type":"print"},{"value":"1776-260X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,24]]}}}