Topical Imiquimod and Abraxane in Treating Patients With Advanced Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying the side effects of giving topical imiquimod together with Abraxane (paclitaxel albumin-stabilized nanoparticle formulation) to see how well it works in treating patients with advanced breast cancer. Biological therapies, such as imiquimod, may stimulate the immune system to kill tumor cells. Drugs used in chemotherapy, such as Abraxane, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving imiquimod together with Abraxane may kill more tumor cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To evaluate the safety of chemoimmunotherapy with topical imiquimod and Abraxane in breast cancer patients with recurrent chest wall disease or cutaneous metastasis. II. 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 OBJECTIVES: I. To examine whether treatment with chemoimmunotherapy consisting of topical imiquimod and Abraxane augments endogenous tumor specific immunity. II. To assess the effect of chemoimmunotherapy on circulating transforming growth factor (TGF)-beta levels. OUTLINE: Patients receive Abraxane intravenously (IV) over 30 minutes on days 1, 8, and 15 and apply topical imiquimod to cutaneous lesions once daily (QD) on days 1-4, 8-11, 15-18, and 22-25. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 1, 4, 8, and 12 weeks.

Official Title
-----------------
Phase II Study of Topical Imiquimod and Weekly Abraxane for the Treatment of Breast Cancer Cutaneous Metastases

Conditions
-----------------
Male Breast Cancer, Recurrent Breast Cancer, Skin Metastases, Stage IV Breast Cancer

Intervention / Treatment
-----------------
* Drug: imiquimod
* Drug: Abraxane
* Other: laboratory biomarker analysis
* Genetic: RNA analysis
* Other: immunoenzyme technique


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with advanced stage refractory breast cancer Progressive or relapsed disease following standard therapy with chemotherapy and/or surgery, and/or radiation Patients must have measurable (bi-dimensional) chest wall disease and/or cutaneous metastatic lesions Patients must be at least 7 days from last chemotherapy and 30 days from local radiotherapy and/or systemic steroids Patients on bisphosphonates, trastuzumab, lapatinib and/or hormonal therapy are eligible White blood cell count >= 1000/ul Absolute neutrophil count (ANC) >= 1200/ul Platelets > 75,000/ul Serum creatinine =< 2.0 mg/dL, a creatinine clearance > 60 ml/min Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 X upper limit normal (ULN) Total bilirubin < 2 X ULN Patients must have a Performance Status Score (Eastern Cooperative Oncology Group [ECOG] Scale) =< 2 Patients must have recovered from major infections and/or surgical procedures and, in the opinion of the investigator, not have a significant active concurrent medical illness precluding protocol treatment Men and women of reproductive ability must agree to contraceptive use during the study and for 1 month after imiquimod/Abraxane treatment is discontinued Exclusion Criteria: Patients with prior allergic reaction to taxanes Patients with any clinically significant active autoimmune disease requiring active treatment with systemic steroids or other immunomodulators Pregnant or breast-feeding women Patients with peripheral neuropathy >= Grade 2

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (biological therapy, chemo)<br>Patients receive Abraxane IV over 30 minutes on days 1, 8, and 15 and apply topical imiquimod to cutaneous lesions QD on days 1-4, 8-11, 15-18, and 22-25. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. | Drug: imiquimod<br>* Given topically<br>* Other names: R 837;Drug: Abraxane<br>* Given IV<br>* Other names: paclitaxel albumin-stabilized nanoparticle formulation;Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: RNA analysis<br>* Correlative studies<br>Other: immunoenzyme technique<br>* Correlative studies<br>* Other names: immunoenzyme techniques;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor Effects of Imiquimod as Assessed by Modified World Health Organization (WHO) Criteria | Tumor responses will be determined using the sum of the products of the largest perpendicular dimensions. Target lesions will be evaluated by the following response criteria: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Evaluation of target lesions per modified WHO response criteria: Complete response (CR): complete clearance (100%) of target lesion(s) Partial response (PR): ≥ 50% decrease in target lesion size Stable disease (SD): < 50% decrease in target lesion size Progressive (PD): ≥ 25% increase in target lesion size Overall Response Rate (ORR) determined at end of study treatment which was 1 week after cycle #3, unless patient was withdrawn from study. If patient was withdrawn from study, then ORR was determined after their last cycle of treatment received. | Baseline and then every 4 weeks until week 24 | 
| Safety and Systemic Toxicity as Assessed by a Review of Medical History, Physical Exam, Systems, Performance Status, and Clinical Labs (CBC and CMP) | 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 Food and Drug Administration (FDA) and National Cancer Institute (NCI) guidelines for the time frame below. Number of Participants with at Least 1 Adverse Event as Assessed by a Review of Medical History, Physical Exam, Systems, Performance Status, and Clinical Labs (CBC and CMP) under the following CTCAE categories: Constitutional (Fatigue) Neurological (Neuropathy (sensory or motor)) Cardiac (Arrhythemia) Pulmonary (Cough, Pharyngitis) GI (Constipation, Diarrhea, Mucositis, Vomiting) Dermatology (Ulceration, Hairloss/alopecia) Pain (Headache, other pain) Syndrome (Flu-like) Visual Changes Hearing/Auditory Edema Other (General) In addition they were asked the severity of the event so that a clinician could grade the event. | Baseline and weeks 5, 9 13, 16, 20, and 24 | 
| Pathologic Response by Immunohistochemical (IHC)as Assessed by Skin Punch Biopsy of the Target Lesion | This is done by IHC staining reviewed by a pathologist. This is done by comparing the baseline to the post-treatment biopsy tissue. Yes equals absence of residual disease. | Pre-and post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endogenous Immunity to Common Breast Tumor Antigens (HER2, IGFBP-2, Topoisomerase II-alpha, and p53) in Peripheral Blood as Assessed by IFN-gamma and ELISPOT Assay | Peripheral blood will be obtained at baseline, after cycle 3 (end of study treatment) and at week 24 (end of study) to assess the immune response. A positive antigen-specific T cell immune response will be defined as a T cell precursor frequency more robust than 1:20,000 PBMC if the patients did not have a detectable response prior to treatment. In patients with a pre-existent immune response, the development of an immune response twice baseline will constitute augmentation. | Baseline and at weeks 13 and 24 | 
| Incidence of Reduction of Serum TGF-beta Levels as Assessed by ELISA and Correlation With Th1 Adaptive Immunity and Clinical Response | Incidence of reduction of serum TGF-beta levels as assessed by ELISA and correlation with Th1 adaptive immunity and clinical response is defined as a reduction of at least 25% from baseline value to the value measured at week 13. | Baseline and at weeks 13 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Cancer, Stage IV, cream, topical