Abstract P4-02-05: A Phase II Trial of Fulvestrant and RAD001 (Everolimus) in Patients with Metastatic Estrogen Receptor Positive Breast Cancer after Aromatase Inhibitor Failure; a Study in Progress

Background: Fulvestrant is a potent estrogen receptor (ER) antagonist that has superior antitumor activity in preclinical models. Unfortunately, clinical data showed a more modest antitumor effect for fulvestrant and it is currently reserved for use after aromatase inhibitor (AI) failure in metastatic disease. Reasons for the disappointing clinical results of fulvestrant may be related to suboptimal dosing and possibly to growth factor signaling that may render breast cancer resistant to ER inhibition by fulvestrant. The PI3K/AKT/mTOR pathway is frequently aberrant in breast cancer and preclinical data suggest that it may mediate fulvestrant resistance. We rationalized that using RAD001, an orally active mTOR inhibitor, with fulvestrant may overcome resistance and prolong time to progression. Methods: We conducted a phase II trial of fulvestrant and RAD001 in postmenopausal women with metastatic ER positive breast cancer if they had progressed/relapsed after AI use within 6 months of enrollment. Fulvestrant is administered as a loading dose (500 mg IM d1, 250 mg day 14, 250 mg day 28 and monthly thereafter). RAD001 was initially given at 5 mg orally once daily in the first month to the first 5 patients in order to assess safety and tolerability, and then increased to 10 daily thereafter and for subsequent patients. Patients are required to have measurable or evaluable disease and have adequate performance status and organ function. Primary endpoint is time to progression (TTP) and secondary endpoints include safety, response rate, and tissue biomarker assessment. 40 evaluable patients are required to meet a median TTP of 7.0 months compared to 3.7 months for fulvestrant alone as reported in the EFECT trial. Patients are followed monthly for clinical and lab evaluation and imaging studies for tumor assessment are obtained every 2 months. Results: Median age at entry is 49 years (Range 40-71). To date, 11 patients have enrolled. 8 patients are off study; 7 because of disease progression, and 1 because of a serious adverse event-grade 3 renal failure. Most common adverse events to date are mucositis in 7 patients, rash in 5 and nausea in 3. Most common lab abnormalities are elevated cholesterol in 6 patients, hypokalemia in 5, elevated ALT/AST in 5, and hyperglycemia in 4. Most of the toxicities are grade 1. There were 4 serious adverse events reported; acute renal failure, acute cholecystitis, and two grade 3 vomiting events in the same subject. No grade 4 toxicities occurred. Overall, treatment is well tolerated. Current analysis reveals a median TTP of 389 days (13 months). Bayesian interim monitoring of TTP indicates >90% posterior probability of mean TTP greater than the null value of 3.7 months. Credible intervals and stopping bounds also indicate continuation of patient accrual. Conclusions: Combined RAD001 with fulvestrant in this trial shows promising antitumor activity in metastatic breast cancer and has manageable toxicity. The trial remains open for accrual and updated efficacy and toxicity data will be presented. Clinical trials that target endocrine therapy resistance are critical and can help patients avoid the early use of more toxic treatments. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-05.