Background: Trastuzumab deruxtecan, a new HER2-targeting antibody-drug conjugate, has been approved for unresectable or metastatic HER2-positive breast cancer by the Food and Drug Administration. In a phase I/II trial, trastuzumab deruxtecan showed a manageable safety profile and antitumor activity in HER2-positive various cancer types. In addition, a tissue-based HER2 test occasionally cannot identify accurate HER2 status due to spatial and temporal intratumoral heterogeneity, leading to potentially missing an opportunity for responders to receive benefit from anti-HER2-targeted therapy. Circulating tumor DNA (ctDNA) analysis can detect comprehensive somatic genome alterations by assessment of spatial and temporal intratumoral heterogeneity with minimal invasiveness. Methods: We designed an investigator-initiated multicenter phase II basket trial to evaluate efficacy and safety of trastuzumab deruxtecan in advanced solid tumor malignancies with HER2 amplification identified by Guardant360, a 74-gene sequencing ctDNA panel, as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). The key eligibility criteria are as follows: 1) Histopathologically confirmed advanced solid tumor malignancy; 2) Identified HER2 amplification by Guardant360; 3) Failed prior standard therapy. The participants will receive intravenously 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks. The primary endpoint is objective response rate (ORR). The planned sample size is 55-65. A Bayesian model considering the potential heterogeneity across cancer types will be applied to detect ORR of 5% versus 25% to a certain level while maintaining the false-positive error rate in each cancer type at 10%. Furthermore, tumor tissue, ctDNA and circulating tumor cells are serially collected and analyzed to investigate the predictive biomarkers and resistance mechanisms. The trial was activated in late 2019. At the time of the abstract submission, 2 patients have been enrolled. This trial is granted by AMED under Grant Number JP18lk0201084. Clinical trial information: JapicCTI-194707.