Breast Cancer
Conditions
Keywords
stage IV breast cancer, recurrent breast cancer
Brief summary
RATIONALE: Vaccines made from a person's white blood cells may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as vinorelbine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving vaccine therapy together with trastuzumab and vinorelbine may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving vaccine therapy together with trastuzumab and vinorelbine works in treating patients with locally recurrent or metastatic breast cancer.
Detailed description
OBJECTIVES: Primary * Determine the efficacy of multiepitope autologous dendritic cell vaccine in combination with trastuzumab (Herceptin®) and vinorelbine ditartrate in patients with locally recurrent or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2/neu). Secondary * Determine if this regimen is effective in generating functional antigen-specific T cells. OUTLINE: * Therapeutic autologous dendritic cell (DC) preparation: Patients undergo mobilization of DC and apheresis for production of therapeutic DC. DCs are expanded in vitro for 10-20 days and pulsed with E75 and E90 peptides. * Treatment: Patients receive vinorelbine ditartrate IV over 6-10 minutes, therapeutic autologous DC intradermally over 2-5 minutes, and trastuzumab (Herceptin®) IV over 30-90 minutes on day 1. Patients receive sargramostim (GM-CSF) subcutaneously on days 2, 4, and 6, or until neutrophil counts recover. Treatment repeats every 14 days for up to 6 courses (or more at the discretion of the investigator) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months.
Interventions
BIOLOGICALsargramostim
All patients will receive Leukine (GM-CSF) at 250 mcg/m2 starting one day after the administration of chemotherapy x 7 days. Patients with neutrophil counts below 1,000/mm3 on day 8 will continue GM-CSF therapy until the neutrophil count is greater than 1,000/mm3.
BIOLOGICALtherapeutic autologous dendritic cells
patients will receive (10 x 106) peptide-pulsed DCs given by i.d injection into either axilla or the inguinal region with each peptide given into a separate site. The total dose will be 20 x 106 DCs given per treatment.
BIOLOGICALtrastuzumab
Trastuzumab will be infused in the side-port of a freely flowing IV over 90 minutes and at 6mg/kg if the subject has not previously received Trastuzumab, or if it has been more than 30 days since any prior trastuzumab administration. If the subject has previously received Trastuzumab within 30 days and has no adverse history with the drug, the infusion will be given over 30 minutes. If the subject is currently receiving Trastuzumab, the first study infusion will be given at 4mg/kg over 30 minutes. Subsequently, Trastuzumab will be infused at 4 mg/kg in the side-port of a freely flowing IV over 30 minutes.
Vinorelbine 25 mg/m2 will be administered IV over six to ten minutes into the side port of a freely flowing IV line.
Sponsors
National Cancer Institute (NCI)
Susan G. Komen Breast Cancer Foundation
UNC Lineberger Comprehensive Cancer Center
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
PATIENT ELIGIBILITY 4.1 Inclusion Criteria 4.1.1 Histologically proven metastatic breast cancer with measurable or evaluable disease per investigator discretion. 4.1.2 Patients must be 18 years of age or older. Women of child bearing potential must be practicing barrier or oral contraception for the duration of the study, or documented as surgically sterile or one year post-menopausal. 4.1.3 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (See Appendix A). 4.1.5 Cardiac function by multigated acquisition scan (MUGA) with an ejection fraction (EF) \> 45% or an echocardiogram that shows normal left ventricle (LV) function. 4.1.6 Serum Creatinine \< 2.0 mg/dl. 4.1.7 Hepatic transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) ≤3.0 times the upper limit of normal if no liver metastases or ≤5 times the upper limit of normal if liver metastases are present. 4.1.8 Bilirubin no more than 2 times normal. 4.1.9 Seronegative for HIV. 4.1.10 Negative for Hepatitis B surface antigen. 4.1.11 Signed and dated informed consent. 4.1.12 HLA A0201+ by DNA genotyping. 4.1.13 Absolute neutrophil count greater than 1,500/mm3. Platelet count greater 100,000/mm3 and hemoglobin greater than or equal to 10 4.1.14. 3+ expression of HER-2/neu from original pathology (diagnostic) tumor sample by Immunohistochemistry (IHC) or 2+ expression by IHC with gene amplification by fluorescence in situ hybridization (FISH). 4.1.15. Patients will be eligible even if they have failed treatment for metastatic breast cancer with trastuzumab and a chemotherapy agent other than vinorelbine or if they have progressed within 12 months of receiving adjuvant chemotherapy using trastuzumab and a taxane. 4.2
Exclusion criteria
4.2.1 Patients with any serious medical, cardiac, or psychiatric condition which, in the opinion of the investigator, would make the patient unsuitable for study participation or would impede probable compliance with the protocol. 4.2.2 Patients with central nervous system metastases must have stable disease for at least 3 months prior to study entry. 4.2.3 Patient is currently taking steroid medications. Systemic steroid treatment is not allowed. 4.2.4 Patients that have failed prior therapy with vinorelbine + trastuzumab will not be eligible for therapy. 4.2.5 Patient has received hormonal or cytotoxic chemotherapy within 14 days of apheresis and within 28-30 days prior to study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response | 5-6 years | Response: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Generation of E75/E90 Tetramer-positive CD8+ T Cells | 13 weeks | Evaluate the ability of peptide-pulsed dendritic cells plus trastuzumab to induce functional antigen specific T cells. Measured by percentage of intracellular cytokine staining for E75/E90 tetramer-positive CD8+ T cells |
| Generation of Interferon Gamma Positive CD8+T Cells | 13 weeks | Evaluate the ability of peptide-pulsed dendritic cells plus trastuzumab to induce functional antigen specific T cells. Measured by percentage of intracellular cytokine staining for interferon gamma positive CD8+ T cells |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from University of North Carolina (UNC) at Chapel Hill.
Pre-assignment details
105 patients were consented for this study, 103 were on-study, and 17 began treatment.
Participants by arm
| Arm | Count |
|---|---|
| Dendritic Cell Vaccine Therapeutic autologous dendritic cells (Dendritic Cell Vaccine) i.d. injection, 20 x 106 DCs given per treatment Trastuzumab infusion Vinorelbine ditartrate infusion
sargramostim: All patients will receive Leukine (GM-CSF) at 250 mcg/m2 starting one day after the administration of chemotherapy x 7 days. Patients with neutrophil counts below 1,000/mm3 on day 8 will continue GM-CSF therapy until the neutrophil count is greater than 1,000/mm3.
therapeutic autologous dendritic cells: patients will receive (10 x 106) peptide-pulsed DCs given by i.d injection into either axilla or the inguinal region with each peptide given into a separate site. The total dose will be 20 x 106 DCs given per treatment.
trastuzumab: Trastuzumab will be infused in the side-port of a freely flowing IV over 90 minutes and at 6mg/kg if the subject has not previously received Trastuzumab, or if it has been more than 30 days since any prior trastuzumab administration. | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Dendritic Cell Vaccine |
|---|---|
| Age, Continuous | 65.18 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment United States | 17 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 15 / 17 |
| other Total, other adverse events | 12 / 17 |
| serious Total, serious adverse events | 2 / 17 |
Outcome results
Primary
Number of Participants With Response
Response: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 5-6 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dendritic Cell Vaccine | Number of Participants With Response | 0 Participants |
Secondary
Generation of E75/E90 Tetramer-positive CD8+ T Cells
Evaluate the ability of peptide-pulsed dendritic cells plus trastuzumab to induce functional antigen specific T cells. Measured by percentage of intracellular cytokine staining for E75/E90 tetramer-positive CD8+ T cells
Time frame: 13 weeks
Population: One patient failed to have blood drawn for correlative studies following second vaccine.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dendritic Cell Vaccine | Generation of E75/E90 Tetramer-positive CD8+ T Cells | 3.63 Percentage |
Secondary
Generation of Interferon Gamma Positive CD8+T Cells
Evaluate the ability of peptide-pulsed dendritic cells plus trastuzumab to induce functional antigen specific T cells. Measured by percentage of intracellular cytokine staining for interferon gamma positive CD8+ T cells
Time frame: 13 weeks
Population: Three subjects had insufficient samples due to early withdraw from study, and one subject was removed from study before the vaccine was administered.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dendritic Cell Vaccine | Generation of Interferon Gamma Positive CD8+T Cells | 15.99 percentage of cells |