Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer

Abstract

BackgroundAlteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC.MethodsThe primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5\u2009mg daily; eribulin 1.4\u2009mg/m2\u2009days 1 and 8 every 3\xa0weeks), A2 (everolimus 7.5\u2009mg daily; eribulin 1.4\u2009mg/m2, days 1 and 8 every 3\xa0weeks), and B1 (everolimus 5\u2009mg daily; eribulin 1.1\u2009mg/m2\u2009days 1 and 8 every 3\xa0weeks).ResultsTwenty-seven patients with median age 55\u2009years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥\u2009grade 3 toxicity, 44% had ≥\u2009grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6\u2009months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3\u2009months (95% CI [5.5, undefined]).ConclusionEribulin 1.1\u2009mg/m2\u2009days 1 and 8 every 3\xa0weeks with everolimus 5\u2009mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle.Trial registrationClinicalTrials.gov, NCT02120469. Registered 18 April 2014