Breast Cancer
Conditions
Keywords
stage IIIA breast cancer, stage IIIB breast cancer
Brief summary
RATIONALE: Vaccines may make the body build an immune response to kill tumor cells. Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving vaccine therapy before and/or after chemotherapy and radiation therapy may cause a stronger immune response. PURPOSE: This randomized phase I/II trial is studying the side effects of two regimens of vaccine therapy and to see how well they work in treating women who are receiving neoadjuvant or adjuvant chemotherapy and adjuvant radiation therapy for stage III breast cancer that overexpresses p53.
Detailed description
OBJECTIVES: * Determine the safety and toxicity of two different schedules of vaccination comprising p53-infected autologous dendritic cells in women with p53-overexpressing stage III breast cancer undergoing neoadjuvant or adjuvant chemotherapy and adjuvant radiotherapy. * Determine the immune response, in terms of humoral and cellular response, in patients treated with these regimens. * Determine antigen-specific immune responses in patients treated with these regimens. OUTLINE: This is a randomized, open-label study. Patients are randomized to 1 of 2 treatment arms. All patients undergo apheresis for the collection of peripheral blood monocytes that are cultured with interleukin-4 and sargramostim (GM-CSF) to produce dendritic cells. The dendritic cells are infected with a recombinant adenoviral vector containing the wild-type p53 gene. Patients receive doxorubicin IV and cyclophosphamide IV every 2 weeks for 8 weeks (4 courses) followed 2 weeks later by paclitaxel IV every 2 weeks for 8 weeks (4 courses). Patients with stage III disease then undergo surgery. Three weeks after completion of paclitaxel (or after surgery for patients with stage III disease), patients undergo radiotherapy once daily for 6.5 weeks. Patients are then receive vaccine therapy as per the arm to which they were randomized. * Arm I: Patients receive vaccination comprising p53-infected autologous dendritic cells subcutaneously (SC) 1 week after completion of doxorubicin and cyclophosphamide, 1 week after completion of paclitaxel (or after surgery for patients with stage III disease), and at 6 and 12 weeks after completion of radiotherapy (for a total of 4 vaccinations). * Arm II: Patients receive vaccination comprising p53-infected autologous dendritic cells SC at 6, 8, 10, and 12 weeks after completion of radiotherapy. Treatment in both arms continues in the absence of unacceptable toxicity. Patients are followed at 1 month, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 20-50 patients (10-25 per treatment arm) will be accrued for this study within 2 years.
Interventions
Given subcutaneously on one of two schedules
Sponsors
National Cancer Institute (NCI)
H. Lee Moffitt Cancer Center and Research Institute
University of Nebraska
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
19 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed invasive breast cancer meeting the following criteria: * Clinically locally advanced disease (stage III) with a primary tumor at least 4 cm by mammogram, ultrasound, or palpation AND/OR palpable axillary nodes larger than 1 cm * Planned neoadjuvant chemotherapy * p53-overexpressing tumor by immunohistochemistry * Delayed-type hypersensitivity to at least 1 of 3 standard antigens * Female * ECOG 0-1 * WBC \> 4,000/mm\^3 * Platelet count \> 100,000/mm\^3 * Bilirubin \< 2 times upper limit of normal (ULN) * Hepatitis B surface antigen negative * Hepatitis C antibody negative * Creatinine \< 2 times ULNHIV negative * Fertile patients must use effective contraception during and for at least 6 months after study participation
Exclusion criteria
* No prior or concurrent autoimmune disorder * Not pregnant or nursing/negative pregnancy test * No other concurrent illness that would preclude study participation * No prior chemotherapy * No concurrent participation in another therapeutic clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Toxicity to the Vaccine | 1 week after each vaccine dose. | This outcome measure looks at the safety of the vaccine by documenting the number of grade 2, 3, or toxicities experienced by participants related to the vaccine. |
| Percent of Patients With an Immune Response to p53-infected Autologous Dendritic Cells | Through study completion, an average of 18 months | — |
| Peak Immune Response as Measured by Number of Spots Per Cells | 6 months after last immunization | This outcome measure examined the importance of vaccine timing on antigen-specific relative to the primary cytotoxic therapy on the augmentation of antigen specific immune responses by measuring the duration of immune responses of participants |
Countries
United States
Participant flow
Pre-assignment details
One subject consented to the study voluntarily withdrew consent prior to assignment to an arm, thus only 23 subjects placed in the study arms and are included in the data analysis.
Participants by arm
| Arm | Count |
|---|---|
| Arm I Patients receive vaccination comprising p53-infected autologous dendritic cells subcutaneously (SC) 1 week after completion of doxorubicin and cyclophosphamide, 1 week after completion of paclitaxel (or after surgery for patients with stage III disease), and at 6 and 12 weeks after completion of radiotherapy (for a total of 4 vaccinations).
autologous dendritic cell-adenovirus p53 vaccine: Given subcutaneously on one of two schedules | 11 |
| Arm II Patients receive vaccination comprising p53-infected autologous dendritic cells SC at 6, 8, 10, and 12 weeks after completion of radiotherapy.
autologous dendritic cell-adenovirus p53 vaccine: Given subcutaneously on one of two schedules | 12 |
| Total | 23 |
Baseline characteristics
| Characteristic | Arm I | Arm II | Total |
|---|---|---|---|
| Age, Customized Participant >= 19 years of age | 11 Participants | 12 Participants | 23 Participants |
| Race/Ethnicity, Customized Caucasian | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 12 |
| other Total, other adverse events | 6 / 11 | 6 / 12 |
| serious Total, serious adverse events | 5 / 11 | 1 / 12 |
Outcome results
Primary
Number of Participants Who Experienced Toxicity to the Vaccine
This outcome measure looks at the safety of the vaccine by documenting the number of grade 2, 3, or toxicities experienced by participants related to the vaccine.
Time frame: 1 week after each vaccine dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Number of Participants Who Experienced Toxicity to the Vaccine | 0 Participants |
| Arm II | Number of Participants Who Experienced Toxicity to the Vaccine | 0 Participants |
Primary
Peak Immune Response as Measured by Number of Spots Per Cells
This outcome measure examined the importance of vaccine timing on antigen-specific relative to the primary cytotoxic therapy on the augmentation of antigen specific immune responses by measuring the duration of immune responses of participants
Time frame: 6 months after last immunization
Population: Due to the low numbers of participants analyze in each arm, 7 participants analyze in the Early vaccine administration 4 participants analyzed in the late vaccine administration the subjects were analyzed together for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I | Peak Immune Response as Measured by Number of Spots Per Cells | 8.54 spots per 300,000 cells |
Primary
Percent of Patients With an Immune Response to p53-infected Autologous Dendritic Cells
Time frame: Through study completion, an average of 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Percent of Patients With an Immune Response to p53-infected Autologous Dendritic Cells | 100 percentage of patients |
| Arm II | Percent of Patients With an Immune Response to p53-infected Autologous Dendritic Cells | 53 percentage of patients |