NeuVax

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 >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 (> 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.

Abstract: TPS3126 Background: We completed phase I/II clinical trials with NeuVax (nelipepimut-S), a HLA-A2/A3-restricted, HER2-derived peptide vaccine. The vaccine was administered in the adjuvant setting t...

Abstract: one high-risk feature. A recent joint analysis of the NSABP B-31 and NCCTG N9831 randomized phase III trials that led to these approvals showed that adjuvant trastuzumab added to chemotherapy increased 10-year overall survival from 75.2% to 84% and 10-year DFS from 62.2% to 73.7%, Salazar said. “So the question becomes, if you add the vaccine to trastuzumab to prevent recurrence, does it improve survival even more? And with this vaccine, it’s limited to those who are HLA-A2+, so that’s a small pool of breast cancer patients.” (About 40%–55% of the population has the HLA-A2 allele.) Mittendorf acknowledged that obstacles to bringing a HER2 vaccine forward exist. “The HER2 space is crowded,” she said. “Trastuzumab is no longer the only player. There is TDM-1 (Kadcyla). There is pertuzumab (Perjeta). These agents are being tested in the neoadjuvant and adjuvant setting. We will need to further investigate and see who really needs what. [HER2-targeted] therapies are expensive regimens” to combine, and they have side effects. The vaccine is nontoxic, is very inexpensive and might stimulate a memory response that would work against HER2 for life.” And that excites researchers. “The logic to test these vaccines is there and the potential is definitely there,” Slamon said. “It’s been known for a long time you that you could get an immune response to what you are immunizing against. But just because you can measure an immune response doesn’t mean it will translate into a clinical response or clinical benefit. You only know that by looking at clinical outcomes and that takes time.” Norwell owns the GP2 vaccine. Mittendorf is the principal investigator on vaccine trials that Galena Biopharma (NeuVax), Antigen Express (AE37), and Norwell sponsored. The M. D. Anderson Cancer Center receives financial support for each study patient enrolled. George E. Peoples Jr., M.D., F.A.C.S., a coauthor of the GP2 study, holds inventor rights to GP2.