544 Background: CCI-779, a novel mTOR kinase inhibitor, is well tolerated and has shown antitumor activity in heavily pretreated patients (pts) with metastatic breast cancer (MBC). The combination of CCI-779 (CCI) and antiestrogens has an additive effect in preclinical models of breast cancer. Thus, the objective of this clinical trial is to evaluate preliminary activity of CCI in combination with letrozole.
Randomization is in a 1:1:1 ratio (∼30 evaluable pts/arm), letrozole alone: letrozole with CCI daily (CCI daily arm): letrozole with CCI daily for 5 days every 2 weeks (CCI intermittent arm). All pts receive 2.5 mg letrozole daily.
Fifty-five pts have been enrolled. Initially, 6 pts were enrolled on each of the high-dose (HD) schedules, 25 mg CCI daily and 75 mg CCI intermittent; 3 pts in each arm had toxicity that resulted in dose delay/reduction or discontinuation. Thus, the protocol was amended and doses were reduced to low-dose (LD) schedules, 10 mg CCI daily and 30 mg CCI intermittent. As of 01 Dec 2003, 12 and 23 pts were enrolled on the HD and LD schedules, respectively. The median age was 60 yrs (range, 42-81). Safety data are available for 12 pts treated with the HD schedules (25 mg, 6 pts; 75 mg, 6 pts), 11 pts treated with the LD schedules (10 mg, 4 pts; 30 mg, 7 pts), and 12 pts treated with letrozole alone. The most frequently occurring grade 3-4 CCI-related toxicity was stomatitis for the HD schedules (2/6 pts, 2/6 pts) and diarrhea for the LD schedules (0 pts, 1/7 pts). No grade 3-4 toxicities were reported for pts treated with letrozole alone. Of 55 pts, 7 have been on study for 40+ wks. Preliminary tumor responses (RECIST) are available for 19 evaluable pts. CCI pts (n=13) had 1 complete response (HD schedule), 3 partial responses (HD schedules), 9 stable disease (6 pts on HD schedules, 3 on LD schedules; SD ≥ 24 wks for 4 pts on HD schedules). Letrozole-alone pts (n=6) had 2 PR and 4 SD (SD ≥ 24 wks for 1 pt).
The combination of letrozole with 10 mg CCI daily or 30 mg CCI intermittent showed favorable results for tolerability. Accrual is continuing. A phase 3 study will be performed to confirm efficacy. [Table: see text].
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