Background: Advanced breast cancer (BC) and endometrial cancer (EC) have limited treatment options with no treatments improving survival. ONC201 is the founding member of a novel class of anticancer drugs called impiridones. The drug is orally bioavailable and crosses the blood brain barrier. Preclinical studies have demonstrated that ONC201 selectively kills various cancer cells, including all subtypes of BC and EC, while having little effect on normal cells. An on-going Phase 1 study of ONC201 has demonstrated clinical benefit in some solid tumors, including EC and glioblastomas. Trial Design: Phase 2 single arm study of ONC201 with 3 cohorts: Cohort 1, female and male hormone receptor positive breast cancer (HR+BC); Cohort 2, female and male triple negative breast cancer (TNBC); and Cohort 3, EC. All patients will receive ONC201 at the recommended Phase 2 dose of 625mg by mouth q7 days (1 cycle = 28 days). Patients will undergo a baseline biopsy as well as a biopsy after 5 doses of ONC201 (C2D2). Patients will be evaluated for response every two cycles (8 weeks) by RECIST 1.1. Eligibility Criteria: Measurable disease with >1 biopsiable lesion, willing to undergo biopsies. Cohort 1 (HR+BC) requires prior treatment with >2 lines of hormonal treatment. No prior treatment required for the other cohorts. Patients must have ECOG 0-1 and adequate organ function. Patients with asymptomatic or brain metastases treated > 4 weeks from study entry are eligible. Exclusion criteria include: symptomatic CNS metastases, radiotherapy ≤ 4 weeks from study entry, HIV, Hepatitis B or Hepatitis C. Specific Aims: Primary objectives for this study are progression free survival (PFS) at 8 months for Cohort 1 (HR+BC) and overall response rate (ORR) for Cohorts 2 and 3 (TNBC and EC). Secondary objectives include safety, clinical benefit rate (CBR = partial response + complete response + stable disease), and overall survival. Statistical Methods: This study has been designed to pause prior to full accrual to allow for evaluation of futility prior to proceeding to full accrual. In Cohort 1, if >1 of 5 patients is progression-free at 8 months, then we will recruit up to 24 patients. In Cohort 2, if >2 of 10 patients has clinical benefit then we will recruit up to 29 patients. For Cohort 3, if 1 of 13 patients has clinical benefit, then we will recruit up to 25 patients. Additional evaluations of tumor or blood samples performed will be done in an exploratory fashion, with results presented without any formal adjustment for multiple comparisons. Target Accrual: 24 patients with HR+BC, 29 patients with TNBC, and 25 patients with EC.This trial will open Summer 2017 at the National Institutes of Health (Bethesda, MD). Contact Information: Principal Investigator Alexandra S Zimmer, MD; alexandra.zimmer@nih.gov Citation Format: Gatti-Mays ME, Greer Y, Steinberg S, Soltani S, Collins J, Olson M, Ojemuyiwa M, Annunziata C, Lee J-M, Nunes A, Lipkowitz S, Zimmer A. A phase 2 study of ONC201 in recurrent/refractory metastatic breast cancer and advanced endometrial carcinoma [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 OT2-07-04.

Background: Long-term follow-up of neoadjuvant studies demonstrates poor clinical outcomes in patients with TNBC who do not achieve pathologic complete response, with only 35% remaining free of recurrence at 10 years. The addition of adjuvant capecitabine in the CREATE-X study prolonged disease free survival and overall survival (OS) in patients with HER2 negative breast cancer with residual invasive disease, with more striking benefit in patients with TNBC. Checkpoint inhibitors have not been approved in breast cancer yet, but recent studies suggest a benefit in combination with chemotherapy and low burden of disease. In the current study, we will evaluate the role of chemoimmunotherapy in the adjuvant setting for patients with TNBC with residual disease after neoadjuvant therapy. We will also investigate the role of the peripheral immunoscore (PIS) in predicting the benefit of immune checkpoint inhibition with or without chemotherapy. Trial design: OXEL is a pilot open-label three arm randomized study of nivolumab, capecitabine or the combination as adjuvant therapy for 45 patients with residual TNBC after adequate neoadjuvant chemotherapy. Patients enrolled will be randomly assigned to 1 of 3 treatment arms: nivolumab 360 mg iv q3weeks for x 6 cycles; capecitabine 1250mg/m2 po bid D1-D14 q3 weeks x 6 cycles; nivolumab 360mg iv q3weeks + capecitabine 1250mg/m2 po bid D1-D14 q3 weeks x 6 cycles. Main eligibility criteria: Patients ≥18 years of age with TNBC and ≥1cm of residual disease in the breast and/or node positive disease; receipt of neoadjuvant taxane +/- anthracycline, or platinum, and having completed definitive resection of primary tumor, with no prior use of capecitabine, fluorouracil or immunotherapy, and with no active autoimmune disease or chronic use of systemic steroids. Specific aims: The primary endpoint is assessing the immunologic effects of capecitabine, nivolumab or the combination in the adjuvant setting by PIS. Additional endpoints include toxicity assessment, distant recurrence free survival (DRFS) and OS at 3-years, association between changes in PIS and circulating tumor DNA at different timepoints with clinical outcome variables and characterization of the immune contexture in residual tumors. Statistical methods: The study is designed to assess the change in PIS at 6 weeks from baseline in each arm. The sample size of 15 per arm (45 total for 3 arms) will provide preliminary results. A sample size of 15 per arm will have 85% power to detect an effect size of 1 (the difference of the change in PIS from baseline to week 6 between two arms divided by the standard deviation) at 5% significance level. Present accrual and target accrual: The Institutional Review Board at Georgetown University Medical Center has approved the study. Clinicaltrials.gov NCT03487666. Enrollment of the first patient is expected in July 2018 with a total of 45 patients planned to be recruited. Recruitment sites are MedStar Georgetown University Hospital, MedStar Washington Hospital Center, Hackensack University Medical Center. This trial is supported by Bristol-Meyers Squibb, P30CA051008-25 from NCI, Inivata and the Nina Hyde Center for Breast Cancer Research. Citation Format: Khoury K, Isaacs C, Gatti-Mays ME, Donahue RN, Schlom J, Wang H, Gallagher C, Graham D, Warren R, Dilawari A, Swain SM, Pohlmann PR, Lynce F. Nivolumab or capecitabine or combination therapy as adjuvant therapy for triple negative breast cancer (TNBC) with residual disease following neoadjuvant chemotherapy: The OXEL study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-01.

Background: Women under the age of 40 account for approximately 7% percent of breast cancer patients. Breast tumors from young women are often ER-negative, occur in African-American patients, and have other indicators of high risk: yet, multivariate analyses demonstrated that young age is an independent predictor of poor outcome. Due to the unique nature of the patient population served by DOD, a disproportionate number of breast cancer cases in young women are seen. We compare the characteristics, treatment, and outcomes of young patients diagnosed with breast cancer with those of older patients. Methods: The databases of the Military Health System Repository and the DOD Central Registration were used to identify female breast cancer patients treated at DOD facilities between 1998 and 2007. Information on demographics, breast cancer stage at diagnosis, definitive surgical treatments, systemic treatment, recurrence rate and overall survival was analyzed by age groups at the time of diagnosis (less than 40 years old, 40 to 49 years, and 50 years or older) using X2 testing with significance defined as p< 0.05. Results: We identified 10,066 women who were diagnosed with invasive breast cancer at DOD facilities between 1998 and 2007, of which 11.3% (1139) were less than 40 years old at diagnosis. 53% of this young cohort were white, 25% were African-American and 8% were Hispanic (14% undisclosed). The percentage of breast cancer among African-American women in the young cohort was higher than in the older cohorts (19.3% in 40-49yo and 10.6% in ≥50yo). High-grade tumors were significantly more frequent in the younger cohort when compared to the older group (49.5% vs 34.7% and 25.2%, p<0.001). <40yo most commonly presented with Stage II disease (45.3%) at diagnosis, while older groups were mostly diagnosed with Stage I disease (41.6% and 52.4%). The most common subtype of breast cancer across ages was ER+ disease, however, <40yo group had proportionally less ER+ (49% vs 61% and 67.3%, P<0.001). There was a higher rate of bilateral mastectomies among the young women (18.4% vs 9.1% and 5.0%, p<0.0001). Independently of the stage of disease, chemotherapy was given significantly more frequently to <40y (90.43%) and 40-49yo (81.44%) than ≥50yo (53.71%). The 10-year overall survival of younger women was similar to the ≥50yo cohort, despite intensive treatment. Discussion: This study is one of the largest retrospective studies of women under 40 years old with breast cancer. Younger women with invasive breast cancer had more aggressive tumors presenting at higher stages. In this group with good access to healthcare, younger women still had a similar overall survival rate to older women despite receiving more aggressive treatment and potentially having fewer comorbidities than the older group. Citation Format: Zimmer AS, Gatti-Mays M, Soltani S, Lipkowitz S, Steeg PS, Zhu K, Perkins JG, Hu H, Shao S, Brown D, Shriver CD. Analysis of breast cancer in young women in the department of defense (DOD) database [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 PD6-01.