Phase I/II study of stereotactic body radiation therapy (SBRT) to metastatic lesions in the liver or lung in combination with monoclonal antibody to OX40 in patients with progressive metastatic breast cancer (mBC) after systemic therapy.

TPS3103 Background: Focal radiation mediates tumor regression not only through direct cell killing, but also by influencing adaptive immune responses. We and others have investigated pre-clinical murine tumor models using the combination of high dose per fraction radiation (SBRT) given in conjunction with T-cell checkpoint and co-stimulatory molecules. For instance, in established 3LL tumor in C57BL/6 mice, the combination of radiation (3 doses of 20 Gy over 10 days) followed by an agonistic OX40 antibody administered within 24 hours of the last dose of radiation cured 60% of mice. There were no cures using radiation or OX40 alone. The combination increased the percent of activated CD8+CD25+ T cell infiltrating the tumor and tumor-draining lymph nodes. We designed a translational study for patients with progressive metastatic breast cancer after systemic therapy. Methods: Patients with mBC, at least one liver or lung metastatic site amenable to SBRT and at least one other metastatic site that is evaluable are eligible. Patients with hormone receptor positive mBC must have received one prior anti-hormonal therapy and have progressed. Patients with hormone receptor negative mBC must have received at least one prior chemotherapy regimen. SBRT will be administered in consecutive cohorts of 3-6 patients at doses of 15 Gy x 1, 20 Gy x 1 and 20 Gy x 2 with the first dose on day 1 of anti-OX40. Anti-OX40 is administered at a dose of 0.4 mg/kg IV on days 1, 3 and 5 of a single treatment cycle. Patients are accruing to the 20Gy x 2 radiation dose presently. The primary objective is to determine the maximum tolerated dose of SBRT administered in combination with anti-OX40. Secondary objectives include response of radiated and non-irradiated tumor sites, the influence of anti –OX40 on circulating CD4+ and CD8+ T cells and the proliferation of and activity of effector and memory T cells. Exploratory studies of serum markers of cell lysis, immunogenicity and T-cell responses to breast cancer antigens are also planned. Clinical trial information: NCT01642290.