1. Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors
- Author
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Tolcher, Anthony W, Kurzrock, Razelle, Valero, Vincente, Gonzalez, Rene, Heist, Rebecca S, Tan, Antoinette R, Means-Powell, Julie, Werner, Theresa L, Becerra, Carlos, Wang, Chenxi, Leonowens, Cathrine, Kalyana-Sundaram, Shanker, Kleha, Joseph F, Gauvin, Jennifer, D’Amelio, Anthony M, Ellis, Catherine, Ibrahim, Nageatte, and Yan, Li
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.2 Cellular and gene therapies ,6.1 Pharmaceuticals ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Cohort Studies ,Diamines ,Dose-Response Relationship ,Drug ,Female ,Follow-Up Studies ,Humans ,MAP Kinase Kinase 1 ,MAP Kinase Kinase 2 ,Male ,Maximum Tolerated Dose ,Melanoma ,Middle Aged ,Prognosis ,Proto-Oncogene Proteins c-akt ,Pyrazoles ,Pyridones ,Pyrimidinones ,Tissue Distribution ,Triple Negative Breast Neoplasms ,Young Adult ,AKT inhibitor ,BRAF-wild type melanoma ,MEK inhibitor ,Trametinib ,Triple-negative breast cancer ,Uprosertib ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Pharmacology and pharmaceutical sciences - Abstract
PurposeThis study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.MethodsThis was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.ResultsAdverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was
- Published
- 2020