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

Investigational New Drugs

Volumn 34, Issue 6, 2016, Pages 740-749

  Grilley Olson, J E ^a   Bedard, P L ^b   Fasolo, A ^c   Cornfeld, M ^d,e,f   Cartee, L ^d,e,g   Razak, A R Abdul ^b   Stayner, L A ^b   Wu, Y ^d,e   Greenwood, R ^d,e,f   Singh, R ^d,e   Lee, C B ^a   Bendell, J ^h   Burris, H A ^h   Del Conte, G ^c   Sessa, C ^c   Infante, J R ^h  

^a UNIVERSITY OF NORTH FLORIDA   (United States)

^b PRINCESS MARGARET HOSPITAL   (Canada)

^c SAN RAFFAELE HOSPITAL   (Italy)

^d GLAXOSMITHKLINE   (United States)

^e RTP Laboratories   (United States)

^f NOVARTIS PHARMA AG   (Switzerland)

^g UNIVERSITY OF NORTH CAROLINA   (United States)

^h SARAH CANNON RESEARCH INSTITUTE   (United States)

Author keywords

GSK2126458; MEK inhibitor; Phase I clinical trial; PI3K inhibitor; Trametinib

Indexed keywords

B RAF KINASE; OMIPALISIB; PHOSPHATIDYLINOSITOL 3 KINASE; RAF PROTEIN; RAS PROTEIN; TRAMETINIB; TROPONIN; 2,4-DIFLUORO-N-(2-(METHYLOXY)-5-(4-(4-PYRIDAZINYL)-6-QUINOLINYL)-3-PYRIDINYL)BENZENESULFONAMIDE; MAP2K1 PROTEIN, HUMAN; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; MTOR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; PYRIDONE DERIVATIVE; PYRIMIDINONE DERIVATIVE; QUINOLINE DERIVATIVE; SULFONAMIDE; TARGET OF RAPAMYCIN KINASE; TUMOR MARKER;

ABDOMINAL DISTENSION; ABDOMINAL PAIN; ACNE; ADULT; AGED; ANEMIA; APHTHOUS STOMATITIS; ARTICLE; ASTHENIA; BACKACHE; BREAST CANCER; CENTRAL SEROUS RETINOPATHY; CHILL; COLORECTAL CANCER; CONSTIPATION; COUGHING; DECREASED APPETITE; DEHYDRATION; DIARRHEA; DIZZINESS; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG INTERMITTENT THERAPY; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DRY SKIN; DYSPNEA; ERYTHEMA; EYE MELANOMA; FATIGUE; FEMALE; FEVER; FOLLICULITIS; GALLBLADDER CANCER; GENE MUTATION; HEADACHE; HEART LEFT VENTRICLE EJECTION FRACTION; HUMAN; HYPERTENSION; HYPERTRANSAMINASEMIA; HYPOKALEMIA; HYPOMAGNESEMIA; HYPONATREMIA; HYPOPHOSPHATEMIA; HYPOTENSION; INSOMNIA; KIDNEY CARCINOMA; MACULOPAPULAR RASH; MAJOR CLINICAL STUDY; MALE; MAXIMUM TOLERATED DOSE; MOUTH ULCER; MUCOSA INFLAMMATION; MULTICENTER STUDY; NAUSEA; NON SMALL CELL LUNG CANCER; ONCOGENE K RAS; ONCOGENE N RAS; OPEN STUDY; PANCREAS CANCER; PERIPHERAL EDEMA; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; PLEURA EFFUSION; PNEUMONIA; PRURITUS; RASH; RECOMMENDED DRUG DOSE; SIDE EFFECT; SKIN FISSURE; SOLID TUMOR; STOMATITIS; THROMBOCYTOPENIA; VOLUME OF DISTRIBUTION; VOMITING; XEROSTOMIA; ANTAGONISTS AND INHIBITORS; CANCER STAGING; CLINICAL TRIAL; COMBINATION DRUG THERAPY; FOLLOW UP; METABOLISM; MIDDLE AGED; NEOPLASM; PATHOLOGY; PROGNOSIS; SURVIVAL RATE; TISSUE DISTRIBUTION; YOUNG ADULT;

ADULT; AGED; BIOMARKERS, TUMOR; DRUG THERAPY, COMBINATION; FEMALE; FOLLOW-UP STUDIES; HUMANS; MALE; MAP KINASE KINASE 1; MAXIMUM TOLERATED DOSE; MIDDLE AGED; NEOPLASM STAGING; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROGNOSIS; PROTEIN KINASE INHIBITORS; PYRIDONES; PYRIMIDINONES; QUINOLINES; SULFONAMIDES; SURVIVAL RATE; TISSUE DISTRIBUTION; TOR SERINE-THREONINE KINASES; YOUNG ADULT;

EID: 84979599471     PISSN: 01676997     EISSN: 15730646     Source Type: Journal    
DOI: 10.1007/s10637-016-0377-0     Document Type: Article

References (24)

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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,
16. 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,
17. 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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