Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma
- 1k Downloads
To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib.
Patients and methods
Eligibility criteria were advanced solid tumors, 18 years or older, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Exclusion criteria included Type 1 diabetes, active GI disease, leptomeningeal disease, or current evidence/risk of retinal venous occlusion/central serous retinopathy. Clinical safety parameters and response were evaluated and analyzed.
Twenty patients were enrolled. Dose-limiting toxicities (Grade 2 esophagitis; Grade 3 aspartate aminotransferase increased, mucosal inflammation and hypokalemia) were reported at starting dose (1.5 mg trametinib/50 mg afuresertib once daily continuously), exceeding the MTD. Subsequent de-escalation cohorts (1.5 mg/25 mg or 1.0 mg/50 mg trametinib/afuresertib) were defined as MTDs for continuous dosing. Intermittent dosing schedule [1.5 mg trametinib (continuous)/50 mg afuresertib (Days 1–10 every 28 days)] was evaluated and considered tolerable. No patients were enrolled in Phase II. The most common adverse events reported (≥10 % of all patients) included: diarrhea (60 %), dermatitis acneiform (55 %), maculo-papular rash (45 %), fatigue (30 %), dry skin (25 %), nausea (25 %), dyspnea (20 %), and vomiting (20 %). One partial response (BRAF wild-type melanoma) was reported; four patients had stable disease as best response.
Continuous daily dosing of trametinib/afuresertib combination was poorly tolerated. Evaluation of intermittent dose schedule showed greater tolerability. Given the interest in combination treatment regimens of MAPK and PI3K/AKT pathway inhibitors, further study of intermittent dose schedule or combination of trametinib with more selective inhibitors may be warranted.
KeywordsTrametinib Afuresertib AKT Inhibitor MEK Inhibitor Combination therapy
We thank the patients who participated in this study and all of the personnel who contributed to the patient care and data collection for this study. This study was sponsored by GlaxoSmithKline (GSK) and is registered on the US National Institutes of Health website ClinicalTrials.gov (NCT01476137). All listed authors meet the criteria for authorship set forth by the International Committee for Journal Medical Editors (ICJME). The authors wish to acknowledge the following individuals for their contribution and critical review during development of this manuscript: Mary Richardson, Shannon Morris, Laurie Rosenstein and Jen Beyer (GSK). Editorial support with this manuscript was provided by Kristofer Klein at Modoc Research Services, Inc. (Wilmington, NC, USA) and was funded by GSK.
Conflict of interest
Anthony W. Tolcher, Amita Patnaik, Kyriakos Papadopoulos, Carlos R. Becerra, and Drew Rasco received research funding from GSK. Geraldine Ferron-Brady, Jennifer Gauvin, Keith Orford, Mark Cornfeld, and Monica Motwani are employed by GSK. Alicia Allred, Nageatte Ibrahim, and Gursel Aktan were employed by GSK at the time the research was conducted.
The study was conducted in accordance with International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) good clinical practice (GCP) and all applicable patient privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008. The protocol and informed consent were reviewed and approved by a national, regional, or investigational center institutional review board (IRB) for each participating institution in accordance with ICH GCP and applicable country-specific requirements, including US FDA Title 21 Code of Federal Regulations (CFR) 312.3(b) for constitution of IRBs.
- 2.Carpten JD, Faber AL, Horn C, Donoho GP, 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):439–444PubMedCrossRefGoogle Scholar
- 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 417:949–954PubMedCrossRefGoogle Scholar
- 8.Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, 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 preclinical mouse model. J Clin Invest 118:3051–3064PubMedCentralPubMedGoogle Scholar
- 10.Kumar R. Discovery of an oral AKT kinase inhibitor. Presented at the American Association of Cancer Research, Washington DC, April 2013Google Scholar
- 11.Spencer A, Yoon SS, Harrison SJ, Morris SR, Smith DA, Brigandi RA, Gauvin J, Kumar R, Opalinska JB, Chen C. (2014) Novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma: phase 1 study results. Blood Jul 29. pii: blood-2014-03-559963. [Epub ahead of print]Google Scholar
- 13.GlaxoSmithKline (2014) MEKINIST [package insert]. Research Triangle Park, NCGoogle Scholar
- 14.National Cancer Institute (NCI)—common terminology criteria for adverse events, Version 4, DCTD, NCI, NIH, DHHS, 28 May 2009Google Scholar
- 15.Infante JR, Patnaik A, Jones SF, Papadopoulos KP, Bendell JC, Rasco DW, Bellew KM, 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):suppl1 (abstr B128)Google Scholar
- 16.Shimizu T, Tolcher AW, Papadopoulos KP, 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):2316–2325PubMedCrossRefGoogle Scholar
- 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 2014Google Scholar
- 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=9 NLM Identifier: NCT01449058