C125 is a specific SERCA2b inhibitor that activates components found in the ERS pathway(s) which ultimately triggers pro-apoptotic activity in tumors. Studies have affirmed its target of antitumor activity, where 25 mg/kg/day was established as the minimum effective dosage. C125 has poor water solubility (10 μg/mL), thus present a challenge to the development of a parenteral formulation. We have developed a parenteral C125 using poly(2-ethyl-2-oxazoline) (PEOX) that is stable for >30 days. In this proposal, we will evaluate the impact of C125-PEOX given as a continuous infusion to determine whether metronomic dosing is an effective approach (SA1). Additionally, we will optimize the oral C125-PEOX formulation and evaluate it in a dosage escalation study (SA2). Finally, the strategy leading to the best antitumor activity will be combined with cytotoxic chemotherapy used for triple negative breast cancers (TNBCs) (SA3).