Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma

Cancer Chemotherapy and Pharmacology

Volumn 75, Issue 1, 2015, Pages 183-189

  Tolcher, Anthony W ^a   Patnaik, Amita ^a   Papadopoulos, Kyriakos P ^a   Rasco, Drew W ^a   Becerra, Carlos R ^b   Allred, Alicia J ^c   Orford, Keith ^c   Aktan, Gursel ^c   Ferron Brady, Geraldine ^c   Ibrahim, Nageatte ^c   Gauvin, Jennifer ^c   Motwani, Monica ^c   Cornfeld, Mark ^c  

^a South Texas Accelerated Research Therapeutics (START)   (United States)

^b BAYLOR UNIVERSITY MEDICAL CENTER   (United States)

^c GLAXOSMITHKLINE   (United States)

Author keywords

Afuresertib; AKT inhibitor; Combination therapy; MEK inhibitor; Trametinib

Indexed keywords

AFURESERTIB; ASPARTATE AMINOTRANSFERASE; TRAMETINIB; ANTINEOPLASTIC AGENT; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2; PROTEIN KINASE B; PROTEIN KINASE INHIBITOR; PYRAZOLE DERIVATIVE; PYRIDONE DERIVATIVE; PYRIMIDINONE DERIVATIVE; THIOPHENE DERIVATIVE;

ADULT; ANEMIA; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BLEEDING; BREAST TUMOR; CANCER PATIENT; CLINICAL ARTICLE; COLORECTAL CANCER; CONSTIPATION; DERMATITIS; DIARRHEA; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG ERUPTION; DRUG SAFETY; DRUG TOLERABILITY; DRY SKIN; DUODENAL ULCER BLEEDING; DYSPNEA; ELECTROLYTE DISTURBANCE; ENDOMETRIUM CANCER; ESOPHAGITIS; FATIGUE; FEMALE; GASTROESOPHAGEAL REFLUX; HEAD AND NECK CANCER; HUMAN; HYPOKALEMIA; INTESTINE OBSTRUCTION; MACULOPAPULAR RASH; MALE; MAXIMUM TOLERATED DOSE; MELANOMA; MULTICENTER STUDY; MULTIPLE MYELOMA; NAUSEA; NEUTROPENIA; NON SMALL CELL LUNG CANCER; OVARY CANCER; OVARY TUMOR; PANCREAS TUMOR; PERIPHERAL EDEMA; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; SOLID TUMOR; TRIPLE NEGATIVE BREAST CANCER; URINARY TRACT INFECTION; VOMITING; WILD TYPE; AGED; ANTAGONISTS AND INHIBITORS; BLOOD; CLINICAL TRIAL; COHORT ANALYSIS; DRUG EFFECTS; EARLY TERMINATION OF CLINICAL TRIAL; ENZYMOLOGY; MIDDLE AGED; NEOPLASMS; TUMOR VOLUME;

ADULT; AGED; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; COHORT STUDIES; DOSE-RESPONSE RELATIONSHIP, DRUG; EARLY TERMINATION OF CLINICAL TRIALS; FEMALE; HUMANS; MALE; MAP KINASE KINASE 1; MAP KINASE KINASE 2; MIDDLE AGED; MULTIPLE MYELOMA; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; PYRAZOLES; PYRIDONES; PYRIMIDINONES; THIOPHENES; TUMOR BURDEN;

EID: 84925229980     PISSN: 03445704     EISSN: 14320843     Source Type: Journal    
DOI: 10.1007/s00280-014-2615-5     Document Type: Article

References (18)

1. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489-501
2. Carpten JD, Faber AL, Horn C, Donoho G.P., Briggs SL, Robbins CM, Hostetter G, Boguslawski S., Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448(7152):439-444
3. Davies MA, Stemke-Hale K, Tellez C., Calderone TL, Deng W, Prieto VG, Lazar A.J., Gershenwald JE, Mills GB (2008) A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer 99(8):1265-1268
4. Allen LF, Sebolt-Leopold J, Meyer MB (2003) CI-140 (PD184352), a targeted signal transduction inhibitor of MEK (MAPK). Semin Oncol 30(5 Suppl 16):105-166
5. Davies H, Bignell GR, Cox C, Stephens P., Edkins S, Clegg S, Teague J., Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949-954
6. Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5:875-885
7. Carracedo A, Pandolf PP (2008) The PTEN-PI3 K pathway: of feedbacks and cross-talks. Oncogene 27(41):5527-5541
8. Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster T.H., Gao H., Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C, Abate-Shen C (2008) Targeting AKT/mTOR and ERK MAPK signalling inhibits hormone-refractory prostate cancer in a pre-clinical mouse model. J Clin Invest 118:3051-3064
9. Russo AE, Torrisi E, Bevelacqua Y., Perrotta R, Libra M, McCubrey J.A., Spandidos DA, Stivala F, Malaponte G (2009) Melanoma: molecular pathogenesis and emerging target therapies (Review). Int J Oncol 34(6):1481-1489
10. Kumar R. Discovery of an oral AKT kinase inhibitor. Presented at the American Association of Cancer Research, Washington DC, April 2013
11. Spencer A, Yoon SS, Harrison S.J., Morris SR, Smith DA, Brigandi RA, Gauvin J, Kumar R., Opalinska JB, Chen C. (2014) Novel AKT inhibitor afuresertib shows favorable safety, phar-macokinetics, and clinical activity in multiple myeloma: phase 1 study results. Blood Jul 29. pii: blood-2014-03-559963. [Epub ahead of print]
12. Flaherty KT, Robert C, Hersey P et al. (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107-114
13. GlaxoSmithKline (2014) MEKINIST [package insert]. Research Triangle Park, NC
14. National Cancer Institute (NCI)-common terminology criteria for adverse events, Version 4, DCTD, NCI, NIH, DHHS, 28 May 2009
15. Infante JR, Patnaik A, Jones S.F., Papadopoulos KP, Bendell JC, Rasco DW, Bellew K.M., Cox DS, Durante MG, Park JJ, Burris HA, Ngocdiep TL and Tolcher AW (2011) A phase IB study of the MEK inhibitor GSK1120212 combined with everolimus in patients with solid tumors: interim results. Mol Cancer Ther 10(11):suppl 1 (abstr B128)
16. Shimizu T, Tolcher AW, Papadopoulos K.P., Beeram M., Rasco DW, Smith LS, Gunn S, Smetzer L., Mays TA, Kaiser B, Wick MJ, Alvarez C, Cavazos A, Mangold GL, Patnaik A (2012) The clinical effect of the dual-targeting strategy involving PI3 K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 18(8):2316-2325
17. Bedard PL, Grilley-Olson JE, Cornfeld M., Cartee L, Warwick S, Razak AAR, Stayner L, Wu Y, Greenwood R, Viana-Gilmartin V, Lee CB, Bendell J, Burris HA, Gianni L, Sessa C, Infante JR, Fasolo A. A phase I dose-escalation study of trametinib (T) in combination with continuous or intermittent GSK2126458 in patients (pts) with advanced solid tumors. Presented at the American Association for Cancer Research annual meeting, San Diego, CA, April 2014
18. Novartis Pharmaceuticals. A phase Ib study of MEK162 plus BYL719 in adult patients with selected advanced solid tumors. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 Aug 20]. http://clinicaltrials.gov/ct2/show/NCT01449058?term=byl719&rank=9NLMIdentifer:NCT01449058