pyrimidinones and afuresertib

To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib.. 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.

Topics: 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

Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance.

Topics: Adolescent; Adrenal Cortex Hormones; Butadienes; Combined Modality Therapy; Cytarabine; Disease Progression; Drug Resistance; Drug Therapy, Combination; Enzyme Activation; Exons; HEK293 Cells; Hematopoietic Stem Cell Transplantation; Histiocytosis, Langerhans-Cell; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Molecular Targeted Therapy; Mutation; Nitriles; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrazoles; Pyridones; Pyrimidinones; Recombinant Fusion Proteins; Sequence Deletion; Thiophenes; Vincristine