Background: Metastatic triple negative breast cancer (mTNBC) has a poor prognosis with limited durable treatment options. RSK (P90 ribosomal S6 kinase) is a signaling protein at the convergence point of PDK-1 and MAPK signaling pathways. RSK1-3 phosphorylates transcription factors, including Y-box binding protein-1 (YB-1), thereby inducing drug resistance and cancer growth genes. Phosphorylated YB-1 is involved in tumor cell survival, proliferation, and drug resistance. In human breast tumor samples, RSK2 protein is expressed across all breast cancer subtypes (TNBC, ER+ and HER2+) and is associated with poor overall survival. Expression of RSK2 is found in approximately 87% of mTNBC tumors and of those tumors approximately 41% have very high expression of RSK2. PMD-026 is a potent, oral, small molecule RSK inhibitor with high selectivity for RSK2. Preclinical in vivo studies have demonstrated activity both as a single agent and in combination with standard of care therapies. Further, a CAP/CLIA certified IHC method has been developed with Roche to determine tumor expression of RSK2. Methods: This single-arm, open-label, first-in-human, phase I/Ib study evaluates the safety and efficacy of single agent PMD-026 in patients with metastatic breast cancer for whom standard therapies are no longer effective. During dose escalation, the study utilizes an accelerated titration design with single patient cohorts until the occurrence of DLT or Grade 2+ toxicity; then reverts to 3+3 design to define the maximally tolerated dose (MTD) and recommended phase II dose (RP2D). The dose expansion portion will enroll approximately 20 patients with mTNBC. Patients are dosed orally once daily in 21-day cycles with measures to adapt the dosing schedule based on the pharmacokinetic (PK) data, as needed. Tumor tissue is required for all enrolled patients; RSK2 expression will be retrospectively correlated with clinical outcomes. The primary objectives are to determine safety and tolerability of PMD-026, determine the MTD, define a RP2D, and assess anti-tumor activity of PMD-026 in patients with TNBC. Secondary objectives are to evaluate PK, time to response, mTNBC subtyping using NanoString, and duration of response of PMD-026. To date, cohorts 1 and 2 have been completed without DLT. Enrollment to cohort 3 began in January 2020. Clinical trial information: NCT04115306.