A phase Ib/II study of eribulin in combination with cyclophosphamide in patients with advanced breast cancer.

PURPOSE: We hypothesized that eribulin combined with cyclophosphamide (EC) would be an effective combination with tolerable toxicity for the treatment of advanced breast cancer (ABC). METHODS: Patients with histologically confirmed metastatic or unresectable ABC with any number of prior lines of therapy were eligible to enroll. In the dose escalation cohort, dose level 0 was defined as eribulin 1.1 mg/m2 and cyclophosphamide 600 mg/m2, and dose level 1 was defined as eribulin 1.4 mg/m2 and cyclophosphamide 600 mg/m2. Eribulin was given on days 1 and 8 and cyclophosphamide on day 1 of a 21-day cycle. In the dose expansion cohort, enrollment was expanded at dose level 1. The primary objective was clinical benefit rate (CBR), and secondary objectives were response rate (RR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: No dose-limiting toxicities were identified in the dose escalation cohort (n = 6). In the dose expansion cohort, an additional 38 patients were enrolled for a total of 44 patients, including 31 patients (70.4%) with hormone receptor-positive (HR +)/HER2- disease, 12 patients (27.3%) with triple-negative breast cancer (TNBC), and 1 patient (2.3%) with HR + /HER2 + disease. Patients had a median age of 56 years (range 33-82 years), 1 prior line of hormone therapy (range 0-6), and 2 prior lines of chemotherapy (range 0-7). CBR was 79.5% (35/44; 7 partial response, 28 stable disease) and the median DOR was 16.4 weeks (range 13.8-21.1 weeks). Median PFS was 16.4 weeks (95% CI: 13.8-21.1 weeks). The most common grade 3/4 adverse event was neutropenia (47.7%, n = 21). Fourteen of 26 patients (53.8%) with circulating tumor cell (CTC) data were CTC-positive ([Formula: see text] 5 CTC/7.5 mL) at baseline. Median PFS was shorter in patients who were CTC-positive vs. negative (13.1 vs 30.6 weeks, p = 0.011). CONCLUSION: In heavily pretreated patients with ABC, treatment with EC resulted in an encouraging CBR of 79.5% and PFS of 16.4 weeks, which compares favorably to single-agent eribulin. Dose reduction and delays were primarily due to neutropenia. The contribution of cyclophosphamide to eribulin remains unclear but warrants further evaluation. NCT01554371.

Phase II study of irinotecan and temozolomide in breast cancer patients with progressing central nervous system disease.

PURPOSE: Breast cancer patients with progressing central nervous system (CNS) disease have limited treatment options. Few chemotherapy drugs with activity in breast cancer have well-documented CNS penetration. This phase 2 trial evaluated efficacy and safety of irinotecan 125 mg/m2 on days 1 and 15 with temozolomide 100 mg/m2 days 1-7 and days 15-21 of a 28 day cycle. METHODS: Breast cancer patients of any biological subtype and progressing brain metastases and/or leptomeningeal disease (LMD) were eligible. The primary endpoint was CNS response rate. Secondary endpoints were clinical benefit rate (CBR), time to progression (TTP), and overall survival (OS). Imaging studies evaluating intracranial and extracranial response were performed every 8 weeks. RESULTS: Thirty patients were evaluable for safety and efficacy. The most common hematologic and non-hematologic adverse events were neutropenia, and nausea and fatigue, respectively. There were two confirmed CNS partial responses (PR) and five patients with stable disease in the CNS ≥ 16 weeks, resulting in a 7% PR and 23% CBR. Median TTP was 2.3 months (range 13-444 days), and median OS from treatment initiation until death was 4.9 months (range 20-1023 days). Excluding patients with LMD, median TTP and OS were 3.1 and 5.6 months, respectively. Only one patient progressed systemically before CNS progression. CONCLUSIONS: The combination of irinotecan and temozolomide was well tolerated, demonstrated some clinical activity across multiple breast cancer subtypes with progressing CNS disease, and offers a reasonable option for patients who are not candidates for further radiation or clinical trials.