Abstract P5-20-05: A Phase 2 trial of RAD 001 and Carboplatin in patients with triple negative metastatic breast cancer
Authors: Singh JC , Volm M , Novik Y , Speyer J , Adams S , Omene CO , Meyers M , Smith JA , Schneider R , Formenti S , Goldberg JD , Li X , Davis S , Beardslee B , Tiersten A 
Published: August 2014

Abstract
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.
MATERIALS AND METHODS: The primary objective of the study is to determine clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD more than 6 months)) and the toxicity of this combination in triple negative metastatic breast cancer who have had 0–3 prior chemotherapy regimens for metastatic disease. Twenty-five subjects were to be entered in this Phase II study. This design has greater than 80% power to test the null hypothesis that the clinical benefit rate is less than or equal to 10% versus the alternative hypothesis that clinical benefit rate is greater than or equal to 30%. Prior carboplatin is allowed. Women with treated brain metastasis are eligible. Secondary objectives are to determine progression free survival and relationship between pretreatment sensitivity (biopsy at baseline) and clinical response (biopsy post 2 cycles) using IHC staining for abundance of key proteins in the Akt-mTOR pathway and their activity using surrogate phosphorylation site-specific antibodies. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. Five 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: 23 patients of a planned 25 have been recruited thus far. Median age is 59. Of the 20 patients assessable for response at this time, there have been 1 CR, 5 PRs, 8 SDs and 6 PDs. One SD was achieved in a patient progressing on single agent Carboplatin at study entry. Median duration of CR+ SD +PR thus far is 13 weeks (range: 6–74 weeks). 5 of 22 patients assessable for toxicity had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). 13 out of eighteen patients have had treatment held and/or dose reductions secondary to hematological toxicity, however, since amendment for starting dose of Carboplatin to AUC 4 the regimen has been very well tolerated with only 1 out of eleven patients with grade 3 neutropenia and grade 3 thrombocytopenia. 1 patient suffered from grade 3 dehydration. The estimated clinical benefit rate is 45% (95% confidence interval: 23%, 67%). Median time to progression or death is 85 days from start of treatment.
CONCLUSIONS: Our study has met the primary end point of demonstrating clinical benefit in triple negative metastatic breast cancer. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-05.