Abstract OT3-1-09: Combination immunotherapy with trastuzumab and the HER2 vaccine E75 (nelipepimut-S) in high-risk HER2+ breast cancer patients to prevent recurrence
Authors: Mittendorf Beth A , Schneble Erika J , Ibrahim Nuhad K , Greene Julia M , Berry John S , Trappey Alfred F , Clifton Guy T , Holmes Jarrod P , Ponniah Sathibalan , Peoples George E 
Published: May 2015

Abstract
Background: In an adjuvant phase II trial, the HER2-derived nelipepimut-S (E75) + GM-CSF vaccine (Neuvax) has been shown to reduce breast cancer recurrence. Preclinical testing of the combination of trastuzumab (Tz) and nelipepimut-S has shown synergistic cytolysis against HER2 expressing cancer cells. In pilot phase II data in HER2+ patients (pts), 55 pts dosed with CD8-eliciting HER2 derived peptide vaccines sequentially after treatment with Tz resulted in no recurrences at 36 months median follow-up compared with a 16% recurrence rate in 34 randomized controls treated with Tz without vaccine (p=.012). Based on these data, we have designed a trial to evaluate the ability of the combination of Tz and the E75 vaccine concurrently to prevent recurrence in pts with high-risk, HER2+ breast cancer.
Trial Design: This study will be a multicenter, prospective, randomized, single-blinded, phase II trial evaluating adjuvant Tz + NeuVax (E75+GM-CSF) vs. Tz + GM-CSF alone in high-risk HER2+ (IHC 3+ and/or FISH &gt;2.2) breast cancer pts. High-risk pts include: 1) those that did not achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy and HER2- targeted therapy or 2) those treated with upfront surgery that are node positive (&gt; 4+ LN or 1-3+ LN if hormone receptor negative). Pts must be HLA-A2 /A3+ to be eligible (E75 is HLA-A2/A3-restricted) with ECOG performance status 0-1. Pts will be enrolled after completing standard of care multi-modal therapy but prior to the 3rd dose of Tz maintenance therapy (monotherapy). Pts will be randomized 1:1 to receive either NeuVax or GM-CSF alone which will be administered as six monthly intradermal inoculations concurrently with Tz therapy. Pts will then receive four booster inoculations of either NeuVax or GM-CSF every 6 months. The primary efficacy endpoint is to compare disease-free survival (DFS) between treatment arms. Secondary objectives will include evaluation of local and systemic toxicity, distant recurrence free survival, and in vivo/in vitro immunologic responses. From previously published experience with Tz, we expect a recurrence rate of 20% in Tz (plus GM-CSF) treated pts and anticipate that the combination of Tz with E75+GM-CSF will reduce this recurrence rate to 5%. In order to show statistical difference between these recurrence rates, we plan to enroll 50 pts per treatment arm (100 total) with a type I error rate of 5% and 80% power to detect the primary endpoint. Trial accrual is anticipated to begin in September of 2014, with a two year period for trial enrollment followed by a three year follow-up period.
Conclusion: We hypothesize that combination adjuvant immunotherapy with Tz and NeuVax will result in a greater reduction in breast cancer recurrence than Tz therapy alone. We have designed a prospective, randomized, single-blinded, phase II trial evaluating the efficacy of this immunotherapy combination in high-risk HER2+ breast cancer pts to test this hypothesis.
Contact Information: This trial is funded by a DoD grant to EAM with matching funds from Galena Biopharma and is being conducted with the assistance of the academic CRO, Cancer InCITe, LLC.
Citation Format: Beth A Mittendorf, Erika J Schneble, Nuhad K Ibrahim, Julia M Greene, John S Berry, Alfred F Trappey, Guy T Clifton, Jarrod P Holmes, Sathibalan Ponniah, George E Peoples. Combination immunotherapy with trastuzumab and the HER2 vaccine E75 (nelipepimut-S) in high-risk HER2+ breast cancer patients to prevent recurrence [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-09.