Phase II Trial of Metronomic Capecitabine and Cyclophosphamide with Lapatinib and Trastuzumab in Patients with HER2 Positive Metastatic Breast Cancer Who Have Progressed on a Previous Trastuzumab-Based Regimen

Background:Breast cancer is the most common cancer and second most common cause of cancer mortality in women. Around 25% of all breast cancers have overexpression of Human Epidermal growth factor 2 (HER2), which is associated with earlier recurrence and shorter overall survival. ‘Metronomic chemotherapy’ is an emerging paradigm in cancer therapy, in which frequent low doses of chemotherapeutic agents are administered at frequent intervals. We proposed a regimen with metronomic chemotherapy with dual HER2 inhibition in HER2 positive patients with MBC. We hypothesize that this regimen will be highly active in MBC and have a favorable toxicity profile.Methods:This was a single-center, phase II, single arm, open-label study. Female patients 18 years of age and older who had histologically confirmed HER2-positive metastatic breast cancer with prior trastuzumab use in the adjuvant or metastatic setting were eligible. Patients were treated on a 21-day cycle with capecitabine 1500mg PO daily, cyclophosphamide 50mg PO daily, lapatinib 1000mg PO daily and trastuzumab 6mg/kg IV once per 21-day cycle. The primary objective of this study was to estimate the progression free survival (PFS). Secondary objectives were to evaluate the overall response rate (ORR), to evaluate the clinical benefit rate (CBR; complete response, partial response, and stable disease for ≥24 weeks), to estimate the overall survival (OS) and to assess the safety and tolerability of this regimen in the study population. Results:Ten patients were accrued for the study. PFS was 13.7 (95% CI: 2.6, 16.6) months. ORR was 40% (95% CI: 15%, 70%), and CBR was 70%. Median OS was 29.6 (95% CI: 11.8, 81.9+) months. Several grade 3 toxicities were identified in 5 patients (50%): diarrhea, weight loss, fatigue, infusion related reaction, abdominal pain, oral mucositis, paronychia, AST and ALT increase, neutropenia, leukopenia and palmar-plantar erythrodysesthesia.Conclusions:The proposed regimen of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab appears to be active in patients with HER2 positive MBC but with toxicity in line with other standard therapies. Trial Registration: ClinicalTrials.gov # NCT01873833 Date: June 10, 2013