Our preclinical work showed a dramatic synergy between interleukin-12 (IL-12) and trastuzumab for stimulation of natural killer cell cytokine secretion. We aimed to determine the safety profile of IL-12 when given in combination with trastuzumab and paclitaxel to patients with metastatic HER2-overexpressing cancers. Paclitaxel was given i.v. at 175 mg/m 2 every 3 weeks. Trastuzumab was given on day 1 each week (4 mg/kg initially and 2 mg/kg thereafter) in combination with injections of IL-12 on days 2 and 5 starting in cycle 2. This trial accrued 21 patients with metastatic

Purpose In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin polymerizing agents and to anti-vascular endothelial growth factor (VEGF) directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. Patients and Methods Fifty-four patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1–3, 8–10, and 15–17, plus paclitaxel (90mg/m2) on days 2, 9, 16 and bevacizumab (10mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40% to 60% (alpha =0.10, beta=0.10). Results No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals [C.I.] 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in 7 patients showed increased acetylation of Hsp 90 and -tubulin following vorinostat. Conclusions Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.

Background: Although AIs are an effective treatment for HR-positive MBC, whether used alone or in combination with CDK4/6 inhibitors, resistance to therapy and disease progression invariably develops. Therapeutic options for AI-resistant disease include the m-TOR inhibitor everolimus in combination with the steroidal AI exemestane, or the selective estrogen receptor downregulator (SERD) fulvestrant alone. We hypothesized that the combination of fulvestrant and everolimus would be more effective than fulvestrant alone in AI-resistant MBC. Methods: Major eligibility criteria included post-menopausal women with HR-positive, HER2-negative MBC, recurrence or progression while receiving prior non-steroidal or steroidal AI therapy, ECOG PS 0-1, and ≤1 prior chemotherapy regimen for metastases. All patients received fulvestrant (500mg IM q2 weeks for 3 doses, then q4 weeks) plus oral everolimus (10mg) or placebo (1:1 randomization). Prophylactic corticosteroid mouthwash was not used. Tumor assessment was performed at baseline and every 12 weeks. Treatment continued until progressive disease (PD) by RECIST 1.1 criteria. Patients who discontinued everolimus/placebo due to toxicity continued fulvestrant until PD. The primary endpoint was progression-free survival (PFS), defined as time from start of treatment until progression or death. With accrual of 130 patients (120 eligible), the trial had 90% power to detect an improvement in median PFS from 5.4 months to 9.2 months (1-sided stratified log-rank test, type I error rate10%), with analysis planned after 98 PFS events. Results: Of 130 patients treated (64 everolimus, 66 placebo), median age was 61 years (range 35-92), and treatment arms were balanced for stratification factors used in randomization, including ECOG PS 0 vs. 1 (59%/41%), measurable disease (66%), and prior chemotherapy for metastasis (17%). Grade 3/4 AEs were more common in the everolimus arm (53%/3% vs. 23%3%), including hyperglycemia (16%/0% vs. 0%), stomatitis (11%/0% vs. 0%), hypertriglyceridemia (9%/2% vs. 0%), lymphopenia (9%/0% vs. 0%), and pneumonitis (6%/2% vs. 0%). There were 3 grade 5 events (2 everolimus, 1 placebo arm), none of which were attributed to therapy. Selected grade 2 events of interest included fatigue (17% vs. 6%), hyperglycemia (6% vs. 0%), and stomatitis (6% vs. 0%). Everolimus/placebo was discontinued for adverse events, patient withdrawal, or physician discretion in 39% in the everolimus arm and 21% in the placebo arm. After 98 PFS events, median PFS was 10.4 months in the everolimus arm versus 5.1 months in the placebo arm (hazard ratio: 0.61, 95% C.I. 0.40 – 0.92; stratified logrank p= 0.02). Conclusions: The addition of everolimus to fulvestrant significantly improved PFS in post-menopausal women with AI-resistant MBC. Everolimus used without prophylactic corticosteroid mouthwash exhibited a similar rate of oral mucositis and overall AE profile when combined with fulvestrant as when combined with exemestane. Keywords: advanced breast cancer, PrECOG 0102, endocrine resistance, everolimus, exemestane, hormone receptor-positive, mTOR inhibitor, postmenopausal. Citation Format: Kornblum NS, Manola J, Klein P, Ramaswamy B, Brufsky A, Stella PJ, Burnette B, Telli M, Makower DF, Leach J, Truica CI, Wolff AC, Soori GS, Haley B, Nagarajan A, Wassenaar TR, Goldstein L, Miller KD, Sparano JA. PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-02.