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01.01.2015 | Original Article

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

verfasst von: Anthony W. Tolcher, Amita Patnaik, Kyriakos P. Papadopoulos, Drew W. Rasco, Carlos R. Becerra, Alicia J. Allred, Keith Orford, Gursel Aktan, Geraldine Ferron-Brady, Nageatte Ibrahim, Jennifer Gauvin, Monica Motwani, Mark Cornfeld

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2015

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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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Titel: Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma
verfasst von: Anthony W. Tolcher
Amita Patnaik
Kyriakos P. Papadopoulos
Drew W. Rasco
Carlos R. Becerra
Alicia J. Allred
Keith Orford
Gursel Aktan
Geraldine Ferron-Brady
Nageatte Ibrahim
Jennifer Gauvin
Monica Motwani
Mark Cornfeld
Publikationsdatum: 01.01.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2015
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2615-5

Springer Medizin

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