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

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.

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