Background: Notch receptors are overexpressed in TNBC. Notch activation involves the cleavage of Notch ligand/receptor complex by GS. RO4929097 (RO) is an oral inhibitor of GS. We are conducting a phase I NCT trial of intermittent RO in combination with P and C in TNBC to determine the dose limiting toxicity (DLT) and the maximum-tolerated dose (MTD) of RO. Because RO induces CYP3A4/5, plasma P and RO are quantified in real time to ensure P AUC exposure is not decreased. Methods: Women ≥ 18 years with clinical stage II/III TNBC received C AUC=6 on day 1 and weekly P 80 mg/m2 in combination with RO on days 1-3, 8-10 and 15-17 for six 21-day cycles. The starting dose of RO was 10 mg and escalated according to the 3+3 rule. DLT was defined as grade ≥3 (G3) non-hematologic toxicity (n-HT), grade 4 (G4) thrombocytopenia (TCP) or G4 neutropenia (NP) during cycle#1 (c1). Plasma specimens were analyzed for PK by a validated LC-MS/MS assay. Results: 13 pts were enrolled. Two pts enrolled at 10 mg RO with C AUC 6 developed G3,4 TCP during c1. The study was amended; the dose of C was decreased to AUC 5. No DLTs were observed with 10 mg RO and C AUC 5. Only 1 DLT ( G3 HTN) occured with 20 mg RO, but all 4 pts enrolled on this cohort required dose reductions of RO during subsequent cycles. The RO dose was de-escalated to 10 mg, additional 3 pts were treated with 10 mg RO. G≥3 HT included: G4 NP in 2 pts, G4 TCP in 1 pt, G3 NP in 6 pts, G3 anemia in 4 pts and G3 TCP in 5 pts. G≥3 n-HT included: G3 sensory neuropathy in 3 pts. G3 HTN, G3 fatigue and G3 depression occured in 1 pt each. There were no hospitalizations for treatment-related toxicities. PK studies indicate that P AUC ranged from 80% to 134% on week 3 compared to week 1. Ten pts completed 6 cycles of NCT, 3 are still receiving NCT. Five of 10 (50%) pts had complete pathologic response (pCR) in breast and axilla and 3 (30%) pts had minimal residual cancer in breast. Conclusions: The MTD of intermittent RO administered in combination with P and C is 10 mg. This MTD does not result in decreased P exposures. The pCR (50%) and minimal residual disease (30%) suggests this regimen is active in TNBC. Supported by the NCI/NIH Award Number U01CA076576. Clinical trial information: NCT01238133.