Male Breast Cancer, Recurrent Breast Cancer, Skin Metastases, Stage IV Breast Cancer
Conditions
Keywords
Breast Cancer, Stage IV, cream, topical
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.
Interventions
DRUGimiquimod
Given topically
DRUGAbraxane
Given IV
OTHERlaboratory biomarker analysis
Correlative studies
GENETICRNA analysis
Correlative studies
OTHERimmunoenzyme technique
Correlative studies
Sponsors
National Cancer Institute (NCI)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Anti-tumor Effects of Imiquimod as Assessed by Modified World Health Organization (WHO) Criteria | Baseline and then every 4 weeks until week 24 | 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. |
| Safety and Systemic Toxicity as Assessed by a Review of Medical History, Physical Exam, Systems, Performance Status, and Clinical Labs (CBC and CMP) | Baseline and weeks 5, 9 13, 16, 20, and 24 | 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. |
| Pathologic Response by Immunohistochemical (IHC)as Assessed by Skin Punch Biopsy of the Target Lesion | Pre-and post-treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline and at weeks 13 and 24 | 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. |
| Incidence of Reduction of Serum TGF-beta Levels as Assessed by ELISA and Correlation With Th1 Adaptive Immunity and Clinical Response | Baseline and at weeks 13 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Biological Therapy, Chemo) 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.
imiquimod: Given topically
Abraxane: Given IV
laboratory biomarker analysis: Correlative studies
RNA analysis: Correlative studies
immunoenzyme technique: Correlative studies | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Treatment (Biological Therapy, Chemo) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 15 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 1 / 15 |
Outcome results
Primary
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.
Time frame: Baseline and then every 4 weeks until week 24
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Biological Therapy, Chemo) | Anti-tumor Effects of Imiquimod as Assessed by Modified World Health Organization (WHO) Criteria | Total Evaluated in this Outcome Measure | 14 Participants |
| Treatment (Biological Therapy, Chemo) | Anti-tumor Effects of Imiquimod as Assessed by Modified World Health Organization (WHO) Criteria | Complete Response (CR) | 5 Participants |
| Treatment (Biological Therapy, Chemo) | Anti-tumor Effects of Imiquimod as Assessed by Modified World Health Organization (WHO) Criteria | Partial Response (PR) | 5 Participants |
| Treatment (Biological Therapy, Chemo) | Anti-tumor Effects of Imiquimod as Assessed by Modified World Health Organization (WHO) Criteria | Progressive Disease (PD) | 1 Participants |
| Treatment (Biological Therapy, Chemo) | Anti-tumor Effects of Imiquimod as Assessed by Modified World Health Organization (WHO) Criteria | Stable Disease (SD) | 3 Participants |
Primary
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.
Time frame: Pre-and post-treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Biological Therapy, Chemo) | Pathologic Response by Immunohistochemical (IHC)as Assessed by Skin Punch Biopsy of the Target Lesion | Total Number of Evaluable for Pathologic Response | 7 Participants |
| Treatment (Biological Therapy, Chemo) | Pathologic Response by Immunohistochemical (IHC)as Assessed by Skin Punch Biopsy of the Target Lesion | Evaluable Pts. with Pathologic Response Post Tx | 5 Participants |
| Treatment (Biological Therapy, Chemo) | Pathologic Response by Immunohistochemical (IHC)as Assessed by Skin Punch Biopsy of the Target Lesion | Evaluable Pts. without Pathologic Response Post Tx | 2 Participants |
Primary
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.
Time frame: Baseline and weeks 5, 9 13, 16, 20, and 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Biological Therapy, Chemo) | Safety and Systemic Toxicity as Assessed by a Review of Medical History, Physical Exam, Systems, Performance Status, and Clinical Labs (CBC and CMP) | 15 Participants |
Secondary
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.
Time frame: Baseline and at weeks 13 and 24
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Treatment (Biological Therapy, Chemo) | 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 | HER2 Antigen | Positive antigen-specific T cell immune response | 0 Participants |
| Treatment (Biological Therapy, Chemo) | 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 | HER2 Antigen | Negative antigen specific T cell immune response | 8 Participants |
| Treatment (Biological Therapy, Chemo) | 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 | IGFBP-2 Antigen | Positive antigen-specific T cell immune response | 2 Participants |
| Treatment (Biological Therapy, Chemo) | 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 | IGFBP-2 Antigen | Negative antigen specific T cell immune response | 6 Participants |
| Treatment (Biological Therapy, Chemo) | 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 | MAGE3 Antigen | Positive antigen-specific T cell immune response | 5 Participants |
| Treatment (Biological Therapy, Chemo) | 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 | MAGE3 Antigen | Negative antigen specific T cell immune response | 3 Participants |
| Treatment (Biological Therapy, Chemo) | 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 | TopoII-alpha Antigen | Positive antigen-specific T cell immune response | 2 Participants |
| Treatment (Biological Therapy, Chemo) | 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 | TopoII-alpha Antigen | Negative antigen specific T cell immune response | 6 Participants |
| HER2, IGFBP-2, MAGE3, Topo IIa Antigen - Baseline to Week 24 | 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 | TopoII-alpha Antigen | Negative antigen specific T cell immune response | 3 Participants |
| HER2, IGFBP-2, MAGE3, Topo IIa Antigen - Baseline to Week 24 | 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 | HER2 Antigen | Positive antigen-specific T cell immune response | 0 Participants |
| HER2, IGFBP-2, MAGE3, Topo IIa Antigen - Baseline to Week 24 | 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 | MAGE3 Antigen | Positive antigen-specific T cell immune response | 1 Participants |
| HER2, IGFBP-2, MAGE3, Topo IIa Antigen - Baseline to Week 24 | 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 | HER2 Antigen | Negative antigen specific T cell immune response | 3 Participants |
| HER2, IGFBP-2, MAGE3, Topo IIa Antigen - Baseline to Week 24 | 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 | TopoII-alpha Antigen | Positive antigen-specific T cell immune response | 0 Participants |
| HER2, IGFBP-2, MAGE3, Topo IIa Antigen - Baseline to Week 24 | 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 | IGFBP-2 Antigen | Positive antigen-specific T cell immune response | 1 Participants |
| HER2, IGFBP-2, MAGE3, Topo IIa Antigen - Baseline to Week 24 | 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 | MAGE3 Antigen | Negative antigen specific T cell immune response | 2 Participants |
| HER2, IGFBP-2, MAGE3, Topo IIa Antigen - Baseline to Week 24 | 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 | IGFBP-2 Antigen | Negative antigen specific T cell immune response | 2 Participants |
Secondary
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.
Time frame: Baseline and at weeks 13
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Biological Therapy, Chemo) | Incidence of Reduction of Serum TGF-beta Levels as Assessed by ELISA and Correlation With Th1 Adaptive Immunity and Clinical Response | No incidence of 25% reduction of TGF-beta at week1 | 8 Participants |
| Treatment (Biological Therapy, Chemo) | Incidence of Reduction of Serum TGF-beta Levels as Assessed by ELISA and Correlation With Th1 Adaptive Immunity and Clinical Response | Incidence of 25% reduction of TGF-beta at week 13 | 0 Participants |