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Title
A Phase II Study of Topical Imiquimod and Weekly Abraxane for the Treatment of Breast Cancer Cutaneous Metastases
 
Study Design
Phase II single-arm, non-randomized, clinical trial designed to evaluate the safety and efficacy of chemoimmunotherapy with topical imiquimod and Abraxane in advanced breast cancer patients with chest wall disease and cutaneous metastases. Subjects will be sequentially enrolled to study and will receive 3 cycles of imiquimod and Abraxane. A treatment cycle will consist of topical application of imiquimod cream applied daily to target lesions on Days 1-4, 8-12, 15-18, and 22-25 in addition to Abraxane at 100 mg/m2 on Days 1, 8, and 15 every 28 Days. Thus, 28 days will define a treatment cycle and subjects will receive a maximum of 3 cycles. The treatment period will last 12 weeks followed by 3 follow-up visits at 4-week intervals.
 
Study Contact
Nicole Bates | 206.543.6620 | E-Mail
 
Rationale
Breast cancer cutaneous lesions can present either as a local chest wall recurrence or as an isolated site of metastatic disease and occur in up to 30% of breast cancer patients. The treatment of recurrent chest wall disease is difficult and full thickness chest wall resection, a common therapeutic approach, is disfiguring, not curative and associated with significant morbidity. Salvage chemotherapy used in the second-and third-line setting results in overall response rates of 20-30%, at best. Thus, the treatment of cutaneous lesions whether locoregional or a distant metastasis remains a challenge, and further investigation of novel treatment strategies is warranted.

Imiquimod, a small molecule immune response modifier that can be applied topically, generates an immune signal similar to that of pathogenic bacteria, triggering immune activation via toll-like receptor ligand (TLR). Pre-clinical studies have shown imiquimod to stimulate the secretion of cytokines, up-regulate immune costimulatory molecules, and augment immunity to tumor antigens. Imiquimod has clinical activity against a variety of cutaneous malignancies including case-reports of responses in breast cancer cutaneous metastasis. Conventional chemotherapy, such as paclitaxel, a commonly used agent in metastatic breast cancer (MBC), may also modulate immune function. Immunostimulatory effects of paclitaxel include stimulation of IL-12 production, increased serum levels of interferon-gamma (IFN-6), and enhanced NK/LAK cell activity. Abraxane, a new taxane formulation, can be administered without the immunosuppressive steroid pre-treatment required with paclitaxel. Abraxane can be used in conjunction with imiquimod without compromising anti-tumor immunity. Moreover, the chemotherapy-associated immunologic effects of Abraxane could potentially synergize and augment the antitumor effect of imiquimod. We hypothesize that imiquimod can function to enhance endogenous tumor-specific immunity, allowing the tumor itself to “auto-immunize” the patient, and that the use of topical TLR agonists, like imiquimod, can lead to higher response rates in breast cancer patients with chest wall and cutaneous metastasis when combined with chemotherapy. The purpose of this study is to evaluate the safety and clinical efficacy of imiquimod and Abraxane combination therapy. In addition, we will evaluate if treatment with imiquimod and Abraxane results in development of systemic T cell immunity directed against common breast cancer antigens as well as the development of a tumor microenvironment that would support an adaptive tumor specific immune response.
 
Study Population / Indication
Patients with advanced stage breast cancer who have measurable metastatic cutaneous lesions, including chest wall disease, that are no longer amenable to standard therapy.
 
Number of Patients: This study will accrue a maximum of 15 patients.
 
Start Date: February 2009
 
Study Location: University of Washington Medical Center | 1959 NE Pacific Street | Seattle, WA 98195
 
Current Enrollment: 0%
 
Objectives
Primary:
  1. To evaluate the safety of chemoimmunotherapy with topical imiquimod and Abraxane in breast cancer patients with recurrent chest wall disease or cutaneous metastasis.


  2. To evaluate the anti-tumor effects of chemoimmunotherapy with topical imiquimod and Abraxane in breast cancer patients with recurrent chest wall disease or cutaneous metastasis.

Secondary:

  1. To examine whether treatment with chemoimmunotherapy consisting of topical imiquimod and Abraxane augments endogenous tumor specific immunity.


  2. To assess the effect of chemoimmunotherapy on circulating TGF-B levels
Outcome Measures
Primary endpoints:
  1. Safety and systemic toxicity will be determined by chemical and clinical parameters evaluated at various time points. Toxicity grading will be evaluated according to the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and monitoring of adverse events will be done per FDA and NCI guidelines.


  2. The antitumor activity of the approach will be assessed using modified WHO criteria and tumor evaluation will be done at baseline and at 4 week intervals until week 24.
    1. All measurable cutaneous lesions will be recorded and measured at baseline and target lesions will be identified and marked using a template.


    2. Target lesions will be evaluated by the following response criteria: Complete response (CR), Partial response (PR), Stable disease (SD), or Progressive disease (PD).


    3. Additionally, a 3-mm skin punch biopsy will be taken from target lesions pre-and post-treatment for assessment of pathologic response.
Secondary Endpoints:
  1. Endogenous immunity to common breast cancer antigens will be evaluated using IFN-6 ELISPOT assay.
    1. In patients without pre-existent immune response, the acquisition of a positive immune response (PBMC precursor frequency more robust than 1:20,000) after treatment begins will constitute augmentation.


    2. In patients with pre-existent immune response to the tumor antigens, augmentation will have occurred if the final response to a tumor antigen is greater than 2 times the baseline level.


  2. Serum TGF-B levels will be evaluated at baseline, at week 12 (after cycle 3 of imiquimod/Abraxane), and at week 24 (end of study). Analysis of serum will be performed by ELISA. A decrease in serum TGF-B levels will be defined as a reduction of at least 25% from baseline value to the value measured at week 24.
Clinical Description
 
ClinicalTrials.gov Identifier: NCT00821964
 
Page last updated 4/9/09