Manta: A Randomized Phase Ii Study Of Fulvestrant In Combination With The Dual Mtor Inhibitor Azd2014 Or Everolimus Or Fulvestrant Alone In Estrogen Receptor-Positive Advanced Or Metastatic Breast Cancer

Background: Resistance to endocrine therapy remains a major clinical challenge in ER+ breast cancer. Aberrant PI3K/AKT/mTOR pathway activation frequently occurs in ER+ breast cancer and is associated with resistance to endocrine therapy. Randomised clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine treatment. However, there is increasing evidence that inhibition of only mTORC1 with rapalogues such as everolimus sets off a negative feedback mechanism that leads to increased AKT signalling and is linked with treatment resistance. AZD2014 is a dual inhibitor of both mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycin insensitive); compared to rapalogues, AZD2014 has a broader range of growth inhibitory activity in preclinical models based on a more profound mTORC1 inhibition and the additional inhibition of mTORC2. AZD2014 is especially effective in ER+ breast cancer models, showing superior activity to everolimus both in hormone-sensitive and resistant models. Trial objectives: The main aims of this trial are (i) to determine whether dual inhibition of mTORC1 and mTORC2 with AZD2014 will increase the activity of endocrine therapy with fulvestrant in ER+ breast cancer, (ii) whether inhibition of mTORC1 and mTORC2 using AZD2014 will have superior anti-tumour activity compared to inhibition of mTORC1 alone with everolimus, and (iii) to compare the safety and efficacy of two schedules of AZD2014. Methods: MANTA is an international investigator led, sponsored, open-label, randomised phase II trial. Patients are randomised in a 2:3:3:2 ratio to receive either fulvestrant (500mg) alone, fulvestrant and AZD2014 at a continuous daily schedule (50mg BD), fulvestrant and AZD2014 at an intermittent schedule (2 days on, 5 days off; 125mg BD) or fulvestrant and everolimus (10mg OD). Patients are stratified by disease measurability and response to prior endocrine therapy. Treatment is given until disease progression (RECIST 1.1), intolerable toxicity or elective withdrawal. Eligibility criteria: This study enrols post-menopausal women with ER+, HER2-negative, advanced or metastatic, hormone refractory breast cancer. Patients must have at least one measurable lesion and no life-threatening visceral disease. Patients with significant pulmonary dysfunction, cardiovascular disease or uncontrolled diabetes are excluded. Patients must not have had previous treatment with fulvestrant, PI3K/Akt or mTOR inhibitors or no more than one line of chemotherapy for metastatic breast cancer. Endpoints: The primary endpoint is progression-free survival . Secondary endpoints include objective response rate, change in tumour size, clinical benefit rate, overall survival, duration of response, patient reported outcomes and pharmacokinetic parameters of AZD2014 and fulvestrant. Archival tumour tissue must be available to evaluate biomarkers associated with therapeutic response and resistance. Target accrual: Approximately 316 patients will be enrolled at ∼90 sites in the UK, Germany, Spain, Portugal, France, Hungary, Romania, Georgia, and South Korea. Recruitment opened in 2014 and 121 patients have been recruited to date. NCT02216786. Citation Format: Schmid P, Ferreira M, Dubey S, Zaiss M, Harper-Wynne C, Makris A, Brown V, Kristeleit H, Patel G, Perello A, Jones A, Mithal N, Ruiz I, Kummel S, Brunt AM, Guerra JA, Gonzalez Cao M, Saura C, Mousa K, Sarker S-J, Coetzee C, Swann R, Cortes J. MANTA: A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or 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 OT1-03-12.