Phase II trial of RAD001 plus carboplatin in patients with triple-negative metastatic breast cancer.

Abstract

293 Background: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer. Methods: The primary objective of the study is to determine clinical benefit (complete remission; CR, partial remission; PR and stable disease; SD) and the toxicity of this combination in women with triple negative metastatic breast cancer who had received 0-3 prior chemotherapy regimens for metastatic disease. Prior carboplatin was allowed. Women with treated brain metastasis were eligible. Secondary objectives were to determine progression free survival. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. 5 mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a surprising amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg). Results: Eleven patients of a planned 25 have been recruited thus far. Median age is 62. Median number of prior regimens is 1. Of the 6 patients assessable for response at this time, four have SD and two have had a PR. 1 SD was achieved in a patient progressing on prior carboplatin at study entry. Five of 7 patients assessable for toxicity had grade 3 or 4 thrombocytopenia and 2 patients had grade 3 neutropenia. All patients have had treatment held and/or dose reductions secondary to hematological toxicity. There have been no non-hematological grade 3 or 4 toxicities. Conclusions: Clinical benefit was observed in all 6 evaluable patients. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing.

Everolimus

“…Triple Negative Breast Cancer Data on everolimus in triple negative breast cancer might be of interest but await confirmation in larger patient cohorts (Singh et al 2012 San Francisco Breast Cancer Symposium, abstract #108).…”

An overview of triple negative breast cancer for surgical oncologists

“…Rapamycin enhances chemotherapy-induced apoptosis and acts synergistically with platinum agents to and inhibit tumour cell growth in breast cancer cell lines [85]. The combination of RAD001 (oral mTOR inhibitor) and carboplatin appears active, with a clinical benefit rate of 50% reported in the first stage of a phase II study investigating this combination [86]. In addition, mTOR inhibitors may sensitize TNBC to EGFR inhibition [87].…”

Clinical evidence of the efficacy of everolimus and its potential in the treatment of breast cancer

“…Another Phase II study evaluated the combination of everolimus at a dose of 5 mg daily plus carboplatin (area under the curve [AUC] = 6) given every 3 weeks in patients with metastastic TNBC. 50 The primary objective was CBR. At the time of reporting, 18 out of a planned total of 25 patients had been enrolled.…”