Primary Objectives:~Dose escalation part:~To evaluate the safety and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of valemetostat in combination with trastuzumab deruxtecan (T-DXd).~Dose expansion part:~To evaluate the objective response rate (ORR) of valemetostat at the RDE in combination with T-DXd.~Secondary Objectives:~Dose escalation:~To determine ORR; defined as a percentage of subjects who achieve complete response (CR) or partial response (PR) by RECIST 1.1 criteria.~To determine survival outcomes, including duration of response (DoR), progression free survival (PFS), and overall survival (OS).~To determine the Clinical Benefit Rate (CBR) defined as stable disease (SD) ≥ 16 weeks + PR + CR.~Dose expansion:~To determine survival outcomes, including DoR, PFS, and OS.~DOR of the proposed treatment: the time from observing response to the valemetostat treatment until objective tumor progression (PD)~PFS: the time from starting valemetostat treatment until objective tumor progression (PD) or death due to any cause.~Overall survival (OS): the time from starting valemetostat treatment until death due to any cause.~To determine the CBR defined as SD ≥16 weeks + PR + CR.~To evaluate safety of valemetostat in combination with T-DXd.~To evaluate the pharmacokinetics (PK) of both the drugs in combination.~To evaluate the immunogenicity of T-DXd~Exploratory Objectives:~To investigate pharmacodynamic biomarkers.~To investigate biomarkers that may aid in identifying subjects who may derive clinical benefit.
To find a recommended dose of valemetostat that can be given in combination with trastuzumab deruxtecan to patients with low/ultra-low HER2-expressing metastatic breast cancer.