Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial

PRIMARY OBJECTIVES: I. Evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of trastuzumab deruxtecan (DS-8201a) in combination with ceralasertib (AZD6738) in advanced solid tumors with HER2 expression. (Escalation Phase) II. Assess differential pharmacodynamic (PD) profile of tumor tissue (deoxyribonucleic acid \[DNA\] damage \& repair) between Top1 inhibition and dual inhibition of Top1 and ATR in patients with colorectal cancer and gastroesophageal cancer with HER2 expression. (Expansion Phase) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To evaluate pharmacokinetics (PK) of DS-8201a and AZD6738 and immunogenicity of DS8201a. EXPLORATORY OBJECTIVES: I. Evaluate association between HER2 heterogeneity and response to DS-8201a plus (+) AZD6738 therapy using central protein expression assessment. II. Determine predictive biomarkers (including but not restricted to: HER2 protein levels, HER2 gene copy number, alterations of TP53, ATM and RAS) of DS-8201a + AZD6738 efficacy in advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2 expression. III. To characterize PD biomarkers for efficacy of DS-8201a + AZD6738 efficacy in advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2 expression (such as phosphorylated \[p\]RAD50 and SLFN11). IV. To establish a biorepository of tissue, blood and pre-clinical models (PDXs) for HER2 expressing advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer). OUTLINE: This is a dose-escalation study of ceralasertib with fixed dose trastuzumab deruxtecan followed by a dose-expansion study. Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 of each cycle and ceralasertib orally (PO) twice daily (BID) on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion phase, the first 6 patients in each disease cohort (gastroesophageal cancer \[cohort A\] and colorectal cancer \[cohort B\]) receive only trastuzumab deruxtecan for the first cycle, followed by trastuzumab deruxtecan and ceralasertib together in subsequent cycles. Additionally, patients undergo tissue biopsy on study and blood sample collection, computed tomography (CT) or positron emission tomography (PET)/CT and echocardiography (ECHO) or multigated acquisition scan (MUGA) throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.