Abstract OT1-03-08: DESIREE - A multicenter, randomized, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer

Background: The BOLERO-2 study demonstrated a relevant benefit for patients who received everolimus in addition to exemestane in patients who progressed during/after a non steroidal aromatase inhibitor (NSAI), which led to approval of everolimus in this indication. However, in routine use a high rate of intolerability due to side effects is reported. The most common side effect of everolimus is mucositis with a reported high rate of intolerability especially during the first 12 weeks of treatment. Mucositis is also considered to be the leading cause for treatment discontinuation not related to tumor progression. In the neoadjuvant GeparQuinto study, a dose-escalation schema was successfully used to improve tolerability of everolimus together with cytotoxic agents. Methods: DESIREE (NCT02387099) is a randomized, double-blind, phase II study of everolimus in addition to exemestane in patients who progressed during or after NSAI. Patients will be randomized in a 1:1 ratio to receive either everolimus 10 mg/day (week 1-3: 4x2.5 mg/day, blinded; week 4-24: 10mg/day, open according to label) or an escalating dose of everolimus as follows: week 1: 1x2.5 mg verum + 3x placebo/day; week 2: 2x2.5 mg verum + 2x placebo/day; week 3: 3x2.5 mg verum + 1x placebo/day; week 4-24: 10 mg/day (open according to label). The primary aim of the study is to evaluate the incidence of the first episode of mucositis grade 2-4 (WHO9s oral toxicity scale) any time during a 12 week period after start of everolimus treatment. Secondary objectives are to compare the cumulative rate of mucositis grade 2-4 at 24 weeks after start of treatment, the cumulative rate of mucositis grade 1 and any grade at 12 and 24 weeks after start of treatment, the rate of patients on 10 mg daily at 12 weeks and 24 weeks after start of treatment, the clinical benefit rate after 24 weeks, safety, time to onset of grade ≥2 mucositis, the cumulative everolimus dose at 4 weeks, the relative dose intensity for everolimus, and quality of life using the FACT-B and the QSDQ questionnaire. Biomaterial (whole blood, serum, plasma and optional primary tumor/metastasis tissue) will be collected to evaluate potential biomarkers predicting safety and compliance. Overall, 156 evaluable patients (78 in each arm) are required to detect a clinically relevant difference of 20% in the mucositis rate between treatment arms using a continuity-corrected χ2-test on a significance two sided level alpha of 0.2 and a power of 90%. The rate was estimated to be 40% and 20% in the control arm and the treatment arm, respectively. Results: The study will be conducted in up to 60 German centers. Recruitment will start in June 2015. Enrollment is planned to be completed within 24 months. Conclusion: The combination of everolimus and exemestane has shown to improve the outcome of patients with metastatic breast cancer. In the DESIREE trial a dose-escalating schema will be employed to enhance patient compliance and tolerability necessary to achieve an adequate dose-intensity. Citation Format: Loibl S, Furlanetto J, Barinoff J, Bauerschlag D, Herr D, Lubbe K, Maass N, Muller V, Mundhenke C, Schmidt M, Schwedler K, Thill M, Gkantiragas I, Burchardi N, von Minckwitz G. DESIREE - A multicenter, randomized, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-08.