Abstract OT3-05-01: TBCRC 039: Phase II study of combination ruxolitinib (INCB018424) with preoperative chemotherapy for triple negative inflammatory breast cancer
Authors: Overmoyer B , Regan M , Polyak K , Brock J , Van Poznak C , King T , Haddad T , Stearns V , Hwang S , Winer E 
Published: February 2018

Abstract
Background: Stage III triple negative(TN) inflammatory breast cancer(IBC) is associated with a poor prognosis evidenced by a 15 month(mo) median disease free survival(DFS) and overall survival(OS) of 34 mo. The substantial incidence of developing distant metastasis may be due to the prevalence of cancer cells with stem cell-like features (e.g. CD44+/CD24-) in TNIBC. The transcriptional pathway JAK2/STAT3 is associated with the survival of CD44+/CD24- cells, and preclinical data demonstrates overexpression of activated STAT3(pSTAT3) in &gt; 95% of TNIBC. Preclinical studies have shown that ruxolitinib (Incyte®Corporation), an approved JAK1/JAK2 inhibitor, suppresses pSTAT3 in IBC patient derived xenograft models, and when combined with paclitaxel, results in a synergistic reduction in tumor weight. Given the lack of a known therapeutic target in TNIBC, this preoperative proof of principle study exploits the survival mechanism of CD44+/CD24- stem cells prevalent in this disease, by combining ruxolitinib(Rux) with paclitaxel(T) followed by doxorubicin/cyclophosphamide(AC).
Methods: Up to 64 pts with newly diagnosed stage III TNIBC (cT4d, any N, M0) are eligible if they have adequate organ function and are willing to undergo 2 research biopsies(rbx) of the affected breast. Following baseline rbx, pts are randomized to a 7 day(d) run-in phase of Rux vs Rux(15 mg bid) + T(80mg/m2/wkx1). A 2nd rbx is obtained after the run-in phase. Pts randomized to RuxT continue to receive a total of Tx12 wks+Rux. Pts randomized to Rux alone, are re-randomized to receive Tx12 wks+Rux vs Tx12wks alone. Following T, all pts receive AC (A-60mg/m2,C-600mg/m2) every 14d x 4. Pts proceed to modified radical mastectomy (MRM) followed by chest wall/regional lymph nodes radiation therapy.
Correlatives: To assess the effect of JAK inhibition with Rux on pSTAT3 and STAT3 related gene expression, molecular and genomic markers (e.g. RNA-seq, ChIPseq, FISH) will be determined in each rbx and residual tumor at MRM. The relative frequency and topology of CD44+/CD24- cell population and pSTAT3 expression by IHC will also be assessed in these tumor specimens. IL-6 and CRP plasma concentrations will be measured at baseline, prior to T and AC and prior to MRM.
Statistics: The primary endpoint is change in markers of JAK/STAT inhibition. If the proportion of rbx exhibit a biologic response to Rux alone (i.e. change from pSTAT3 expression to pSTAT3 negative) is &lt;10%, then Rux alone is minimally effective on JAK inhibition vs alternative hypothesis that Rux inhibits JAK if the proportion of biologic response is ≥33%. If ≥5/25 rbx treated with Rux alone have a biologic response then the hypothesis that biologic response is ≤10% is rejected with an error rate of 0.098 (target 0.10). If ≤4/25 rbx have a biologic response then the hypothesis that biologic response is ≥33% is rejected with an error rate of 0.05 (target 0.10). Biologic response of rbx with Rux alone will also be compared with the proportion of biologic response to RuxT (33% vs. 66% based upon presumed synergy with RuxT). Secondary endpoints are clinical: pathologic complete response in breast/lymph nodes, Residual Cancer Burden, DFS and OS. Clinical Trial Information: NCT02876302.
Citation Format: Overmoyer B, Regan M, Polyak K, Brock J, Van Poznak C, King T, Haddad T, Stearns V, Hwang S, Winer E. TBCRC 039: Phase II study of combination ruxolitinib (INCB018424) with preoperative chemotherapy for triple negative inflammatory breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-01.