This is a Phase 2, randomized, international, multi-center, double-blinded study of ONT-380 or placebo in combination with capecitabine and trastuzumab in patients with progressive, unresectable locally recurrent or metastatic HER2+ breast cancer who have had prior treatment with a taxane, trastuzumab, pertuzumab, and T-DM1. After signing informed consent and meeting all eligibility criteria (including assessments based on screening MRI), patients will be randomized in a 2:1 ratio using a dynamic hierarchical randomization scheme to receive ONT-380 or placebo in combination with capecitabine and trastuzumab. Stratification factors will include known history of treated or untreated CNS metastases (yes/no), ECOG PS (0 vs. 1), and region of world (US vs. Canada vs. Western Europe). Stratification for presence of CNS metastases will be based upon investigator assessment of screening MRI. Treatment will be administered in cycles of 21 days each. ONT-380 300 mg or placebo will be given orally twice daily (PO BID). Capecitabine will be given at 1000 mg/m2 PO BID on Days 1 14 of each 21-day cycle. Trastuzumab will be given as a loading dose of 8 mg/kg intravenously (IV) followed by 6 mg/kg once every 21 days, except in specific circumstances where it may be given weekly to compensate for modifications in treatment schedule. Dose modifications of ONT-380 or placebo and capecitabine will be allowed. Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. In the absence of clear evidence of clinical or radiographic progression, development of CNS symptoms, or radiographic changes thought to pose potential immediate risk to the patient, all efforts should be made to continue treatment until unequivocal evidence of radiologic or clinical progression occurs. No crossover from placebo to ONT-380 will be allowed. However, patients assessed as having CNS progression per the RANO-BM criteria, but without having non-CNS progression per the RECIST 1.1 criteria, may be eligible to continue on study treatment after undergoing local therapy to CNS disease, with approval from the medical monitor, until non-CNS progression or second CNS progression.
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Leftover breast biopsy and surgical tissues from DCIS patients at 60 years of age will be used for studying the effect of aging on the properties of human MaSCs. A randomized case-control study will be carried out for testing if seven-day rapamycin treatment can reduce malignant markers and MaSC number.