Neoadjuvant/Adjuvant Chemotherapy, Vaccine & Adjuvant Radiation Therapy in p53-Overexpressing Stage III Breast Cancer

Phase 1

Completed

Conditions: Breast Cancer

Interventions: Biological: autologous dendritic cell-adenovirus p53 vaccine

Registration Number: NCT00082641

Lead Sponsor: University of Nebraska

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 24

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I	autologous dendritic cell-adenovirus p53 vaccine	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	autologous dendritic cell-adenovirus p53 vaccine	Patients receive vaccination comprising p53-infected autologous dendritic cells SC at 6, 8, 10, and 12 weeks after completion of radiotherapy.

Primary Outcome Measures

Name	Time	Method
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.
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
Percent of Patients With an Immune Response to p53-infected Autologous Dendritic Cells	Through study completion, an average of 18 months

Secondary Outcome Measures