Phase I trial with carboplatin and RAD001 in metastatic breast cancer.

Abstract

e11554 Background: The mTOR inhibitor RAD001 is a promising drug in the treatment of solid tumors. Carboplatin experienced a kind of renaissance in the treatment of breast cancer. Preclinical studies suggested that combining RAD001 with carboplatin may produce higher activity than each drug alone. We present the final data of a phase I trial. The aims of this trial were to determine the maximum tolerated dose (MTD) of the carboplatin/RAD001 regimen and to assess its safety in pretreated patients (pts). Methods: In this study, pts with pretreated metastatic breast cancer received carboplatin AUC2 weekly and oral RAD001 at different dose level (level I: 2.5mg; II: 5mg; III: 7.5mg; IV: 10mg) daily of a 21-day cycle. Treatment was continued until progression or the occurrence of intolerable toxicity. 3 pts were assigned to dose level I-III, 6 to dose level IV. Dose levels were escalated strictly step by step. If no DLT occurred in 3 pts, following patients were assigned to the next dose level. Results: The study has enrolled 15 pts (median age 58). The median number of previous chemotherapies was 4 (range: 1-11). 12 pts had hormone receptor positive, 5 HER2 over-expressing disease. Dose level was escalated to level IV as no DLT occurred at level I-III. 6 pts were treated at level IV. Pts received a median of 4 cycles (range 1-13); 9 completed at least 4 cycles, 3 completed at least 8 cycles, and one patient 13 cycles. There were no DLTs at dose level I-IV during the first cycle. Based on the pre-determined definition of MTD, the maximum planned dose level IV was selected as the MTD. Overall, toxicities have been manageable. Most frequent G3/4 toxicities included thrombocytopenia in 5 pts, leukopenia in 4 pts, infection in 2 pts, dyspnea in 2 pts, and fatigue in 1 pts. Response rates in 14 pts evaluable for response were as follows: 14% PR, 43% SD, and 43% PD. In 9 pts who completed 4 cycles defined in the protocol for efficacy assessment, response rates were: 2/9 PR, 6/9 SD. Conclusions: Carboplatin/RAD001 is a well tolerated combination in heavily pretreated metastatic breast cancer. RAD001 (10 mg/d) / carboplatin (AUC 2 weekly) is defined as MTD. The 10mg dose of RAD001 is consistent with the doses recommended in other combinations. The dose is currently used in an ongoing phase II trial.