P1-13-04: Phase II Study of Topical Imiquimod and Abraxane for Treatment of Breast Cancer Cutaneous Metastases.
Authors: Salazar LG , Lu H , Gray H , Higgins D , Childs J , Yushe D , Slota M , Parker S , Disis ML 
Published: June 2012

Abstract
Background: Breast cancer (BC) cutaneous lesions can present as local chest wall recurrence or isolated sites of metastatic disease. Current treatments with full thickness chest wall resection, radiation therapy and chemotherapy are not curative; and have significant morbidity and poor overall response rates. Combining local immunomodulation and systemic chemotherapy may be more effective in treating cutaneous disease. Topical imiquimod (IMQ), a TLR-7 agonist, has shown clinical activity against cutaneous metastasis. Pre-clinical studies have shown IMQ to stimulate Th1 cytokine secretion and up-regulate immune co-stimulatory molecules at the tumor site; resulting in augmented tumor specific T cell immunity and tumor growth inhibition. Use of paclitaxel in BC, has demonstrated immunostimulatory effects of increased serum IFN-γ and enhanced NK/LAK cell activity. Abraxane (albumin-bound paclitaxel) may be used in conjunction with IMQ as steroid pre-treatment is not required. We hypothesize the immune effects of Abraxane may synergize and augment the IMQ anti-tumor effects, resulting in greater clinical response. A phase II single-arm study of chemoimmunotherapy with topical IMQ and Abraxane was initiated to determine its safety and therapeutic efficacy; and examine its effect on augmenting endogenous tumor specific immunity and inducing tumor molecular alterations associated with inhibition of tumor growth and/or common pathways of BC immune escape.
Materials and Methods: Up to 15 BC patients with cutaneous lesions no longer amenable to standard therapy are enrolled and receive 3 treatment cycles. A treatment cycle consist of topical 5% IMQ to target lesions 4 days/week (wk.) and Abraxane 100 mg/m2 on Days 1, 8, 15 every 28 Days. Toxicity is evaluated per CTCAE v3.0 on Days 1, 8, 15 of each cycle and wks. 13, 16, 20, 24. Target lesion antitumor activity is assessed per modified WHO criteria (Complete response (CR); Partial response (PR); Stable disease (SD); Progressive disease (PD)) at baseline, wks. 4, 8, 12, 16, 20, 24. 2-mm target lesion skin biopsies are obtained pre-and post-treatment for histologic analysis and RT-PCR analysis of a 7 IFN-related gene signature associated with tumor inhibition. Immunity to HER2, IGFBP-2, TOPO-IIα, p53 and serum TGF-β levels are evaluated at baseline and wks. 12, 24 with IFN-γ ELISPOT and ELISA, respectively.
Results: 10 patients have been enrolled. Median (range) values include: age, 54 years (48-92), time from metastatic diagnosis, 134 months (58-728), prior chemotherapy regimens, 5 (2-10). 5/10 patients had received prior local therapy, e.g., radiation. 5/10, 4/10, and 2/10 patients had triple negative, HER2+ and ER+/PR+ tumors, respectively. In 5 patients completing 3 treatment cycles, overall response rate (ORR) = 100% (3 CR, 2 PR). In the 5 patients who completed 1–2 treatment cycles, ORR = 80% (2 PR, 2 SD, 1 PD). Treatment related toxicity is primarily grade I/II neutropenia, anemia; grade I skin toxicity. Immunologic analyses are ongoing and will be presented with completed clinical data on all patients.
Conclusions: Chemoimmunotherapy with topical IMQ and Abraxane is well-tolerated and shows excellent clinical efficacy in treating metastatic cutaneous lesions in heavily pretreated BC patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-13-04.