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
Tóm tắt
Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.
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McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D’Assoro AB (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzym Regul 46(1):249–279
Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14(12):1351–1356
Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, Heynck S, Stückrath I, Weiss J, Fischer F (2009) Identifying genotype-dependent efficacy of single and combined PI3K-and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci 106 (43):18351–18356
Hoeflich KP, O'Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, Januario T, Savage H, Punnoose E, Truong T (2009) In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 15(14):4649–4664
Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, Gendelman R, Bayani N, Wang NJ, Neve RM, Guan Y (2009) Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 69(2):565–572
Munster P, van der Noll R, Voest E, Specht J, Werner T, Dees E, Tan A, Daud A, Schellens J, Lolkema M (2012) PI3K kinase inhibitor GSK2126458 (GSK458): Clinical activity in select patient (PT) populations defined by predictive markers (study P3K112826). In: Ann Oncol, . Oxford univ press great clarendon ST, Oxford OX2 6DP, England, pp 153–154
Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR (2012) Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 13(8):773–781
Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247
Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz Jr LA (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14 (9):985–990. http://www.nature.com/nm/journal/v14/n9/suppinfo/nm.1789_S1.html
Gasparini M, Bailey S, Neuenschwander B (2010) Bayesian dose finding in oncology for drug combinations by copula regression. J R Stat Soc: Series C (Applied Statistics) 59(3):543–544
Riviere MK, Yuan Y, Dubois F, Zohar S (2014) A Bayesian dose-finding design for drug combination clinical trials based on the logistic model. Pharm Stat 13(4):247–257. doi:10.1002/pst.1621
Tighiouart M, Rogatko A, Babb JS (2005) Flexible Bayesian methods for cancer phase I clinical trials. Dose escalation with overdose control. Stat Med 24(14):2183–2196. doi:10.1002/sim.2106
Munster P, van der Noll R, Voest E, Dees E, Tan A, Specht J, Falchook G, Daud A, Lolkema M, Grilley-Olson J (2011) Phase I first-in-human study of the PI3 kinase inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors (study P3K112826). In: ASCO annual meeting proceedings, 15_suppl. p 3018
Tolcher A, Baird R, Patnaik A, Moreno Garcia V, Papadopoulos K, Garrett C, Olmos D, Shannon K, Zazulina V, Eubin E (2011) A phase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors. J Clin Oncol 29:3004
Infante JR, Gandhi L, Shapiro G, Burris HA, Bendell JC, Baselga J, Hsu K, Faivre T, Asatiani E, Heist RS (2012) Phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with locally advanced or metastatic solid tumors. In: J Clin Oncol, vol 15. Amer soc clinical oncology 2318 mill road, STE 800, alexandria, VA 22314 USA,
Bedard P, Tabernero J, Kurzrock R, Britten CD, Stathis A, Manuel Perez-Garcia J, Zubel A, Le NT, Carter K, (2012) Bellew KM A phase lb, open-label, multicenter, dose-escalation study of the oral pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor GSK1120212 in patients (pts) with selected advanced solid tumors. In: J Clin Oncol, vol 15. Amer soc clinical oncology 2318 mill road, STE 800, Alexandria, VA 22314 USA,
Shapiro G, LoRusso P, Kwak E, Cleary J, Musib L, Jones C, de Crespigny A, Belvin M, McKenzie M, Gates M (2011) Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors. J Clin Oncol 29(15 suppl):3005
Bendell JC, LoRusso P, Cho DC, Musib L, Yan Y, Chang I, Patel P, Chang IT, Meng RD, Shapiro GI (2014) Clinical results of a phase Ib dose-escalation study of the Mek inhibitor cobimetinib (GDC-0973) and the Akt inhibitor ipatasertib (GDC-0068) in patients (pts) with solid tumors. In: American association for cancer research annual meeting, p CT328
Kurzrock R, Patnaik A, Rosenstein L, Fu S, Papadopoulos K, Smith D, Falchook G, Chambers G, Gauvin J, Naing A (2011) Phase I dose-escalation of the oral MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor GSK2141795 (GSK795). J Clin Oncol 29:215 s
Tolcher AW, Patnaik A, Papadopoulos KP, Rasco DW, Becerra CR, Allred AJ, Orford K, Aktan G, Ferron-Brady G, Ibrahim N (2015) Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol 75(1):183–189
Hoeflich KP, Merchant M, Orr C, Chan J, Den Otter D, Berry L, Kasman I, Koeppen H, Rice K, Yang N-Y (2012) Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res 72(1):210–219
Paller CJ, Bradbury PA, Ivy SP, Seymour L, LoRusso PM, Baker L, Rubinstein L, Huang E, Collyar D, Groshen S (2014) Design of Phase I Combination Trials: Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee. Clin Cancer Res 20(16):4210–4217
Bedard PL, Tabernero J, Janku F, Wainberg ZA, Paz-Ares L, Vansteenkiste J, Van Cutsem E, Pérez-García J, Stathis A, Britten CD, Le N, Carter K, Demanse D, Csonka D, Peters M, Zubel A, Nauwelaerts H, Sessa C (2014) 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. doi:10.1158/1078-0432.ccr-14-1814
Janku F, Stathis A, Perez-Garcia J, Wainberg Z, Paz-Ares L, Vansteenkiste J, Van Cutsem E, Le N, Zubel A, Bedard P Phase Ib study of oral pan-PI3K BKM120 in combination with the oral MEK1/2 inhibitor GSK120212 in patients with selected advanced solid tumors and RAS/BRAF mutations. In: Eur J Cancer, 2013. Elsevier sci ltd the boulevard, langford lane, Kidlington, Oxford Ox5 1gb, Oxon, England, pp S162-S162