Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma
Abstract
Purpose 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.Results 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.Conclusion 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.
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High toxicities of targeting PI3K, AKT or mTOR in combination with MEK inhibitors have prevented their approval for use in human patients.
“However, high toxicities of targeting PI3K, AKT or mTOR, in combination with MEK inhibitors, have prevented their approval for use in human patients (81–83).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [81]
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- Authors
- Tolcher, A. W., Patnaik, A., Papadopoulos, K. P., Rasco, D. W., Becerra, C. R., Allred, A. J., Orford, K., Aktan, G., Ferron-Brady, G., Ibrahim, N., Gauvin, J., Motwani, M., & Cornfeld, M.
- Affiliations
- South Texas Accelerated Research Therapeutics (US)
- Texas Oncology (US)
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Allred, Alicia J.
- ORCID
- Venue
- Cancer Chemotherapy and Pharmacology
- Published
- 2014-11-25
- Volume
- 75
- Issue
- 1
- Pages
- 183-189
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- OpenAlex
- W1992880310
- Cited by
- 158
- References
- 16
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 15 · 2022: 9 · 2021: 18 · 2020: 22 · 2019: 17 · 2018: 16 · 2017: 17 · 2016: 15 · 2015: 7
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cancer Chemotherapy and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Food and Drug Administration
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- trametinib, MEK inhibitors, AKT inhibitors, combination therapy, maximum tolerated dose, dose-limiting toxicity, solid tumors, multiple myeloma, intermittent dosing, MAPK signaling, PI3K/Akt signaling, BRAF wild-type melanoma, adverse events
- MeSH terms
- Adult, Aged, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Multiple Myeloma, Neoplasms, Pyrazoles, Pyridones, Pyrimidinones, Thiophenes, Cohort Studies, Tumor Burden, Protein Kinase Inhibitors, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Proto-Oncogene Proteins c-akt, Early Termination of Clinical Trials
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