OT3-01-18: Combination Immunotherapy with Trastuzumab and the HER2 Vaccine E75 in Low and Intermediate HER2−Expressing Breast Cancer Patients To Prevent Recurrence.
Authors: Sears AK , Clifton GT , Vreeland TJ , Hale DF , Ponniah S , Mittendorf EA , Peoples GE 
Published: June 2012

Abstract
Background
In a phase II trial, the HER2−derived E75 vaccine administered with the immunoadjuvant GM-CSF has been shown to reduce breast cancer recurrence in the adjuvant setting, with a greater benefit seen in patients with low levels of HER2 expression (IHC 1+ or 2+). There has also been recent suggestion that patients with low HER2 expression may also benefit from trastuzumab. Preclinical testing of the combination of trastuzumab and the E75 vaccine has shown a synergism with combinational therapy. Finally, from our phase II trials of cytotoxic T cell-eliciting peptide vaccines, sequential treatment with trastuzumab and HER2 vaccination has resulted in no recurrences in 30 patients with a median follow-up of 48 months. Based on these results, we have designed a trial to evaluate the ability of the combination of trastuzumab and the E75 vaccine to prevent breast cancer recurrence.
Trial Design: This study will be a multi-center, prospective, randomized, single-blinded, phase II trial evaluating trastuzumab + E75+GM-CSF (immunoadjuvant) vs. trastuzumab + GM-CSF alone (no E75) in the adjuvant setting in breast cancer patients. Eligible patients include node positive (or node negative if negative for both ER and PR) disease-free breast cancer patients with low or intermediate levels of HER2 expression (IHC 1+ or 2+) and adequate cardiac function (LVEF &gt;50%). Patients must be HLA-A2/A3+ (E75 is HLA-A2/A3-restricted). Patients will be enrolled after completing standard of care multi-modal therapy and randomized between the two treatment arms with stratification by HER2 expression (1+ or 2+) and nodal status (N0, N1, N2, or N3). Vaccinations (E75+GM-CSF or GM-CSF alone) will be administered as six monthly intradermal inoculations concurrently with trastuzumab therapy. The primary efficacy endpoint is to compare disease-free survival (DFS) between treatment arms at 24 months. Secondary objectives will include evaluation of cardiac toxicity from combination therapy (periodic cardiac assessment with MUGA or ECHO), DFS at 36 months, and immunologic responses to vaccination. From previously published experience with trastuzumab, we expect a recurrence rate of 15% in trastuzumab (plus GM-CSF) treated patients and anticipate that the combination of trastuzumab with E75+GM-CSF will reduce this recurrence rate to 5%. In order to show a statistical difference between these recurrence rates, we plan to enroll 150 patients per treatment arm (300 total) with a type I error rate of 5% and 80% power to detect the primary endpoint. Trial accrual is anticipated to begin in January 2012, with a two year period of enrollment followed by a three year follow-up period.
Conclusion: We hypothesize that combination adjuvant immunotherapy with trastuzumab and E75 vaccination will result in a greater reduction in breast cancer recurrence than trastuzumab therapy alone and have designed a multi-center, prospective, randomized, single-blinded, phase II trial evaluating the efficacy of this immunotherapy combination.
Contact Information: This trial is sponsored by Genentech and RXi Pharmaceuticals through the Henry M. Jackson Foundation.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-18.